0|:: L¯| № 133.

1
Mode|Ing of Cene Regu|atIve Networks
In 0eve|opmenta| 5ystems
/ o|::ertut|on :uom|tteo to
L¯| Zur|ch
íor the oegree oí
0octor oí Sc|ence:
pre:enteo oy
¯|| |o¬|
0|p|-lníorm, Un|ver:|tut 0ortmuno, Cermuny
oorn /pr|| 3, 1_/_
c|t|zen oí Cermuny
uccepteo on the recommenout|on oí
|roí 0r Lc|urt Z|tz|er, e·um|ner
|roí 0r Sven 3ergmunn, co-e·um|ner
|roí 0r |uo|ger S|mon, co-e·um|ner
.cc_
Institut f¨ ur Technische Informatik und Kommunikationsnetze
Computer Engineering and Networks Laboratory
¯lK-SC||l|¯LN|Ll|L N| 111
¯|m |ohm
Mode|Ing of Cene Regu|atIve Networks
In 0eve|opmenta| 5ystems
/ o|::ertut|on :uom|tteo to
L¯| Zur|ch
íor the oegree oí 0octor oí Sc|ence:
0|:: L¯| № 133.1
|roí 0r Lc|urt Z|tz|er, e·um|ner
|roí 0r Sven 3ergmunn, co-e·um|ner
|roí 0r |uo|ger S|mon, co-e·um|ner
L·um|nut|on oute. 0ecemoer 13, .cc_
Acknow|edgments
Fiisl of all, I woulo liko lo lhank Lckail Zilzloi foi his suppoil ano supoi-
vision, as woll as Svon Loignann ano Iuoigoi Sinon foi lhoii willingnoss
lo ioviow lhis lhosis.
Aooilional lhanks goos lo all nonLois of lho SY-S1LM piojocl foi an infoi-
nalivo ano insighlful lino ano joyous piojocl noolings lhioughoul Luiopo,
ano in pailiculai lo Iuoigoi Sinon foi inspiiing oiscussions ano his on-
ouianco in answoiing ny quoslions aLoul lho funclioning of planl Liology.
Nol lo foigol ny colloaguos al lho 1IK foi an inloiosling ano ioally gooo
lino ouiing lho pasl foui yoais, wilh a spocial lhanks lo Johannos who
always look his lino lo holp no oul wilh whalovoi quoslions I hao wilh
iospocl lo vaiious giaphics.
Finally, I woulo liko lo acknowloogo funoing of lho SY-S1LM Iiojocl Ly lho
Luiopoan Connission unooi lho Maiio Cuiio Iosoaich 1iaining Nolwoik,
Iiojocl ¸¸¸6.
Abstract
On lhoii way fion a foililizoo ogg lo a fully giown oiganisn, highoi oi-
ganisns iun lhiough a soiios of oovolopnonlal slagos. 1his oovolopnonl
can Lo soon as a piogian lhal is sloioo in lho gonono of lho oiganisn
ano lho oxoculion of lhis piogian is ooloininoo Ly lho gonos iogulaling
oach olhoi’s aclivilios. Up lo now, lho oxacl nochanisns foi luining a ono-
oinonsional gonono inlo a fully lhioo-oinonsional oiganisn ionain hiooon.
Invosligaling lho unooilying piocossos, oovolopnonlal Liologisls liy lo un-
voil lhoso nochanisns Lul oovolopnonlal syslons conslilulo a oifficull Looy
of iosoaich: lho iogulalivo piocossos lono lo Lo non-linoai ano connonly
involvo sovoial gonos sinullanoously. Al lho sano lino, aovancos lo iogisloi
lhoso piocossos oxpoiinonlally aio hanpoioo Ly lho facl lhal lhoy nol only
oopono on local infoinalion liko a singlo coll’s slalo al a givon poinl in lino
Lul on spalial aspocls as woll, i.o., olhoi colls’ slalos. In iosull, lho spalial
conpononl conplicalos oxpoiinonlal oala acquisilion in suilaLlo iosolulion
ano lho non-linoaiily of lho iogulalivo piocossos hanpois inluilivo inloi-
piolalion of lho availaLlo oala. 1o aio oala inloipiolalion, nalhonalical
noools havo Locono ono of lho koy lools. 1hoy piovioo possiLililios lo foi-
nalizo cuiionl knowloogo, lo valioalo hypolhosos, ano lo assisl in oosigning
now oxpoiinonls.
In lho piocoss of noooling oovolopnonlal syslons, ono connonly slails
fion an inilial hypolhosis aLoul lho unooilying iogulalivo piocossos lhal
is lianslaloo inlo a noool of appiopiialo oolail, oflon in foin of couploo
oiffoionlial oqualions. 1hon, lho iosulling noool has lo Lo caliLialoo using
lho availaLlo oxpoiinonlal oala Lofoio il can Lo usoo. Whilo iosoaichois aio
assisloo in solling up suilaLlo noools Ly a iango of foinalisns, lho piocoss of
noool caliLialion is loss unooislooo: ouo lo lho oifficullios in oxpoiinonlally
ooloinining syslon Lohavioi, oala lonos lo Lo of qualilalivo naluio whoioas
oxisling gonoial puiposo caliLialion nolhoos ioly on quanlilalivo oala.
In lhis conloxl of noooling gono iogulalivo nolwoiks unooilying oovolop-
nonlal syslons, lhis lhosis aooiossos lwo lopics:
vIII /o:truct
• Whal is a suilaLlo nolhoo lo caliLialo noools using qualilalivo oala
only´ Invosligaling lhis quoslion, oxisling cuslon lailoioo caliLialion
lochniquos aio ioviowoo ano now concopls aio oovolopoo in oiooi lo
cono up wilh lochniquos lhal can Lo usoo foi noool caliLialion Lasoo
on qualilalivo oala. Spocifically, nolhoos lo quanlify lho nalch Lolwoon
qualilalivo oala ano noools aio pioposoo, suilaLlo ciiloiia lo guioo a
caliLialion piocoss aio invosligaloo, ano nolhoos lo inlogialo oiffoionl
souicos of oonain knowloogo aio sluoioo.
• 1ho oovolopoo nolhoos aio usoo lo Luilo a noool foi lho gono iogulalivo
nolwoik unooilying lho oovolopnonl ano nainlonanco of lho shool apical
noiislon of Arabidopsis thaliana. 1ho shool apical noiislon is a lissuo
lhal is iosponsiLlo foi lho aoiial giowlh of planls. 1o nainlain giowlh,
il haiLois a pool of slon colls lhal piovioo nocossaiy unoiffoionlialoo
colls foi lho giowlh. 1ho syslon is of inloiosl sinco invosligaling lho ox-
acl iogulalivo nochanisns conliolling slon coll honooslasis can piovioo
fuilhoi insighls inlo slon coll iogulalion in gonoial ano ovonlually nighl
onaLlo influoncing aspocls liko ciop sizos. 1ho Luill noool is lhon usoo
lo oxploio lho paianoloi spaco lhal allows slon coll nainlonanco, ano
lo sinulalo lho consoquoncos of nulalions, gono nisoxpiossion ano coll
aLlalions.
In iosull, lho piosonloo shool apical noiislon noool in conLinalion wilh
lho oovolopoo caliLialion nolhoos iopiosonls a Lasis lhal can Lo oxlonooo lo
incluoo suLsyslons iosponsiLlo foi fuilhoi aspocls of planl oovolopnonl—fi-
nally lo Locono a viilual noiislon oi ovon planl lhal woulo Lo a conpio-
honsivo knowloogo-Laso foi planls. In aooilion, lho pioposoo fianowoik
ano caliLialion lochniquos foin a usoful loolkil foi noooling olhoi oovol-
opnonlal syslons.
Zusammenfassung
Auf oon Wog von oinoi Lofiuchlolon Lizollo hin zu oinon ausgowachso-
non LoLowoson ouichlaufon hohoio Oiganisnon oinon Lnlwicklungspiozoss,
ooi sich in voischiooono Ihason unloiloill. Diosoi Iiozoss folgl oinon Iio-
giann, oas in Gonon oos Oiganisnus gospoichoil isl. Doi Iiogiannfluss
wiio oaLoi ouich oio gogonsoiligo Iogulalion ooi Loloiliglon Gono goslouoil.
In oioson Zusannonhang sino alloioings Lis oalo oio gonauon Mochanisnon
unLokannl, oio fui oio Unsolzung oos oinoinonsionalon Gonons in oin oioi-
oinonsionalos LoLowoson voianlwoillich sino. Dolails oiosoi Mochanisnon
woioon in ooi LnlwicklungsLiologio unloisuchl, woLoi oio Loliachlolon iogu-
lalivon Iiozosso noisl nichllinoai sino uno von nohioion Gonon gloichzoilig
aLhangon. DaiuLoi hinaus sino oio Loliachlolon Syslono nui schwoi nil
akluollon oxpoiinonlollon Molhooon zuganglich, oa oio iogulalivon Iiozosso
zusalzlich zu lokalon Ligonschaflon auch von iaunlichon Aspoklon aLhang-
on uno oioso iaunlichon Loziohungon nui schwoi oxpoiinonloll oinilloll
woioon konnon. Unloi lokalon Ligonschaflon zahll hioiLoi ooi Zuslano
oinoi Zollo zu oinon Loslinnlon Zoilpunkl, wahiono iaunlicho Aspoklo
z.L. oio ALhangigkoilon ooi Lnlwicklung oinoi Zollo von oon Zuslanoon
LonachLailoi Zollon unfasson. Sonil sino fui onlwicklungsLiologischo Sys-
lono oflnals nui unzuioichonoo Dalon voifugLai, un Iuckschlusso auf oio
zugiunoo liogonoon iogulalivon Iiozosso zu oilauLon.
Un Dalon oonnoch inloipiolioion zu konnon, haLon sich in oivoison An-
wonoungon nalhonalischo Mooollo Lowahil: sio oilauLon oino konpaklo,
foinalo Daislollung ooi gosannollon Likonnlnisso, uno konnon oingosolzl
woioon, un Hypolhoson zu loslon oooi nouo Lxpoiinonlo zu onlwickoln.
In Konloxl von onlwicklungsLiologischon Syslonon Loginnl ooi Moool-
lioiungspiozoss lypischoiwoiso nil oinoi oislon Hypolhoso Lozuglich ooi oi-
wailolon iogulalivon Iiozosso uno Loloiligloi Gono. Dioso Hypolhoso wiio
oann in oin Moooll gooignoloi Dolailslufo uLoisolzl. Lin in oioson Zusan-
nonhang haufig voiwonoolos Moooll sino Syslono von Diffoionzialgloichun-
gon. Lovoi oioso Mooollo joooch Lonulzl woioon konnon, nusson zunachsl
Mooollpaianoloi kaliLiioil woioon. Wahiono os fui oio ÜLoisolzung von
x Zu:ummeníu::ung
Hypolhoson in Mooollo oivoiso Foinalisnon giLl, isl ooi Iiozoss ooi Moool-
lkaliLiioiung wonigoi gul unloisuchl: oxpoiinonloll gowonnono Dalon sino
uLlichoiwoiso qualilaliv, wahiono gangigo Molhooon zui MooollkaliLiioiung
oio VoifugLaikoil quanlilalivoi Dalon voiaussolzon.
In oioson Iahnon Lofassl sich oioso AiLoil nil oon folgonoon Loioon 1ho-
nonkonploxon:
• Wio siohl oino gooignolo Molhooo aus, oio zui KaliLiioiung von Moooll-
paianoloin nui qualilalivo Dalon voiwonool´ In Lauf ooi Unloisuchung
oiosoi Fiagoslollung woioon in ooi Liloialui ookunonlioilo, lypischoi-
woiso pioLlonspozifischo Molhooon analysioil, un nouo Ansalzo fui oin
gonoioll oinsolzLaios Voifahion zu oiaiLoilon. In Dolail woioon Molho-
oon onlwickoll, oio os oinoglichon oio ÜLoioinslinnung zwischon Moooll
uno qualilalivon Dalon zu quanlifizioion. Ls woioon Vaiianlon unloi-
suchl, wio oioso Quanlifizioiung in oon KaliLiioiungspiozoss oingoLun-
oon woioon kann. Zuoon woioon Moglichkoilon goloslol, oio os oilauLon,
pioLlonspozifischos Wisson in oon KaliLiioiungspiozoss oinzuLoziohon.
• Dio oaLoi onlwickollon Molhooon woioon voiwonool, un oin Moooll
fui oas goniogulalivo Nolzwoik zu oislollon, oas ooi Lnlwicklung uno
oon Lihall ooi Spiossapikalnoiislono in Arabidopsis thaliana zugiunoo
liogl. Moiislono sino GowoLo, oio fui oas oLoiiioischo Wachslun ooi
Iflanzo voianlwoillich sino. Un oas Wachslun zu oinoglichon, Lo-
hoiLoigon oioso Moiislono Slannzollon, oio oio Iflanzo nil unoiffoion-
zioilon Zollon voisoigon. Dio gonauo Iogulioiung oiosoi Slannzollan-
sannlungon isl oaLoi aus zwoi Giunoon inloiossanl: zun oinon hal sio
oinon gowisson Mooollchaiakloi fui Slannzolliogulalion in anooion Oi-
ganisnon, z.L. auch fui WiiLollioio, zun anooion konnlo oolaillioilos
Voislanonis oiosoi Iiozosso os oinoglichon, oiioklon Linfluss auf Aspoklo
wio Linlooiliago zu nohnon. Das iosullioionoo Moooll wiio in Iahnon
oiosoi AiLoil oazu Lonulzl, Looingungon zu unloisuchon, oio oon Lihall
oiosoi Slannzollon oilauLon. Doswoiloion woioon nil Hilfo von Sinu-
lalionon Mulalionsoxpoiinonlo, Misoxpiossionsoxpoiinonlo uno ZollaL-
liagungsoxpoiinonlo nachvollzogon.
Zu:ummeníu::ung xI
Zusannon nil oon onlwickollon Molhooon zui MooollkaliLiioiung, slolll
oas Spiossapikalnoiislonnoooll sonil oino Lasis oai, oio loichl un woiloio
iogulalivo Konpononlon oiwoiloil woioon kann. Auf lango Sichl isl oios
oin oisloi Schiill hin zu oinon viiluollon Moiislon oooi gai oinoi viiluollon
Iflanzo – oin GoLiloo, oas Wisson Lunooll uno oinfach aLiufLai nachl.
DaiuLoi hinaus Liolol oio KonLinalion aus MooollioiungsungoLung uno
KaliLiioiungsnolhooon oinon Ausgangspunkl, un woiloio onlwicklungsLio-
logischo Syslono zu nooollioion.
Contents
± IntroductIon ±
11 |e:eurch Comp|e·e: . . . . . . . . . . . . . . . . . . . . . . . . . _
111 |urumeter L:t|mut|on íor |ooe|: |n 0eve|opmentu| 3|o|ogy
unoer (uu||tut|ve 0utu . . . . . . . . . . . . . . . . . . . . (
11. |ooe||ng oeve|opment uno |u|ntenunce oí the S/||n / rho!|ono _
1. Contr|out|on: uno 0verv|ew . . . . . . . . . . . . . . . . . . . . . _
z Mode|Ing CRNs §
.1 3|o|og|cu| 3uc|grouno . . . . . . . . . . . . . . . . . . . . . . . . 1c
.. |ooe||ng /pprouche: . . . . . . . . . . . . . . . . . . . . . . . . 11
..1 Cruph |epre:entut|on: . . . . . . . . . . . . . . . . . . . . 11
... 3uye:|un Networ|: . . . . . . . . . . . . . . . . . . . . . . 1.
.._ 3oo|eun uno Ceneru||zeo Log|cu| Networ|: . . . . . . . . . . 1_
..( 0|fferent|u| Lquut|on |ooe|: . . . . . . . . . . . . . . . . . 1_
.._ Stochu:t|c |ooe|: . . . . . . . . . . . . . . . . . . . . . . 16
..6 0|:cu::|on . . . . . . . . . . . . . . . . . . . . . . . . . . 1/
._ Chu||enge: |n |ooe||ng 0ynum|c Sy:tem: . . . . . . . . . . . . . . 13
_ Mode|s for Pattern FormatIon In ßIo|ogIca| 5ystems z±
_1 |euct|on 0|ffu:|on Sy:tem: . . . . . . . . . . . . . . . . . . . . . ..
_. S|mu|ut|on 3y Numer|cu| lntegrut|on . . . . . . . . . . . . . . . . . .6
_.1 L·p||c|t Scheme: . . . . . . . . . . . . . . . . . . . . . . . ./
_.. lmp||c|t Scheme: . . . . . . . . . . . . . . . . . . . . . . . ._
_._ lmp||c|t L·p||c|t Scheme . . . . . . . . . . . . . . . . . . . ._
_.( 0|:cu::|on . . . . . . . . . . . . . . . . . . . . . . . . . . _c
µ Methods for Mode| Ca|IbratIon: Cenera| ConsIderatIons _±
(1 |ounout|on: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . __
(11 |rumewor| íor S|mu|ut|on: oí 0eve|opmentu| Sy:tem: . . . . __
(. |ethoo íor |ooe| |urumeter 0pt|m|zut|on . . . . . . . . . . . . . . _(
xIv Content:
(_ |ooe| |urumeter 0pt|m|zut|on on |0 :y:tem:. Lmergence oí Sput|u|
|uttern|ng . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . __
(_1 3u:e||ne /pprouch . . . . . . . . . . . . . . . . . . . . . . (c
(_. lntegrut|on oí 0omu|n Know|eoge . . . . . . . . . . . . . . (1
(__ |e:u|t: . . . . . . . . . . . . . . . . . . . . . . . . . . . . (.
(( |urumeter Spuce L·p|orut|on íor |0 |ooe|: . . . . . . . . . . . . . (_
((1 Segment |o|ur|ty Networ| . . . . . . . . . . . . . . . . . . ((
((. |roo|em |ormu|ut|on . . . . . . . . . . . . . . . . . . . . . (_
((_ /pprouch . . . . . . . . . . . . . . . . . . . . . . . . . . . (6
((( S|mu|ut|on: uno |e:u|t: . . . . . . . . . . . . . . . . . . . _1
(_ /utomuteo (uunt|ficut|on oí S|m||ur|ty oetween (uu||tut|ve |uttern: . _(
(_1 S|m||ur|ty |eu:ure . . . . . . . . . . . . . . . . . . . . . . __
(_. vu||out|on oí |ropo:eo /pprouch . . . . . . . . . . . . . . . _3
(6 Conc|u:|on: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.
_ Methods for Mode| Ca|IbratIon: IncorporatIng 0omaIn Know|edge 6_
_1 L·p|o|tut|on oí Ceneru| /nu|yt|cu| |e:u|t: . . . . . . . . . . . . . . . 66
_11 /pprouch . . . . . . . . . . . . . . . . . . . . . . . . . . . 6/
_1. S|mu|ut|on: uno |e:u|t: . . . . . . . . . . . . . . . . . . . /_
_. ||erurch|cu| /pprouch to |ooe| Cu||orut|on . . . . . . . . . . . . . . /3
_.1 /pprouch . . . . . . . . . . . . . . . . . . . . . . . . . . . /_
_.. |e:u|t: uno 0|:cu::|on . . . . . . . . . . . . . . . . . . . . 3_
__ Conc|u:|on: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . _c
6 Mode|Ing PatternIng In the 5AM of A. thaliana §_
61 3|o|og|cu| 3uc|grouno on S/| |egu|ut|on . . . . . . . . . . . . . . __
6. S/| |ooe| . . . . . . . . . . . . . . . . . . . . . . . . . . . . . __
6.1 |ooe||ng 0etu||: . . . . . . . . . . . . . . . . . . . . . . . __
6.. |ooe| Cu||orut|on . . . . . . . . . . . . . . . . . . . . . . 1c1
6._ S|mu|ut|on 0etu||: . . . . . . . . . . . . . . . . . . . . . . 1c.
6_ S|mu|ut|on |e:u|t: . . . . . . . . . . . . . . . . . . . . . . . . . . 1c(
6_1 S|mu|ut|on oí w||otype . . . . . . . . . . . . . . . . . . . . 1c/
6_. S|mu|ut|on: oí mutunt: uno :y:tem perturout|on: . . . . . . . 1c/
6( 0|:cu::|on . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11(
Content: xv
) Conc|usIons ±±)
/1 |uture |er:pect|ve: . . . . . . . . . . . . . . . . . . . . . . . . . 11_
A Comp|ementary 5Imu|atIons on 5AM MaIntenance In A. thaliana ±z±
ß Mode|s for 0Ifferent 5tages of 0ecomposed 5AM 0eve|opment ±z§
Acronyms ±µ_
CurrIcu|um vItae ±µ_

IntroductIon
The mystery of our own origin and mode of development has for
over  years stimulated interest in vertebrate development. Fun-
damental processes of early development appear conserved among the
vertebrates. By studying a particular vertebrate model organism we
can therefore draw conclusions about vertebrate development in gen-
eral and ultimately come up with models about our own development.
(Haffloi ano Nussloin-Volhaio [__[)
2 Chupter + lntroouct|on
1his slalononl concoining voiloLialos can Lo oxlonooo lo incoipoialo olhoi
oukaiya. Il ioflocls on lho ono hano lho cuiiosily aLoul lho oiigin of lifo in
gonoial ano on lho olhoi hano pionouncos lho inloiosl in answoiing noio in-
nooialo quoslions in snalloi scalo liko how coilain lissuos oi oigans onoigo
ano aio nainlainoo—ovonls lhal aio sluoioo in lho fiolo of oovolopnonlal
Liology. In oolail, oovolopnonlal Liology is concoinoo wilh olucioaling pio-
cossos iosponsiLlo foi lho inliicalo lonpoial ano spalial conliol lhal lakos
placo ouiing lho lianslalion fion gonos lo oiganisns.
Dovolopnonlal syslons iopiosonl a oifficull Looy of iosoaich: piocossos nooo
lo Lo liackoo wilh iospocl lo Lolh, lino ano spaco, ano aio laking placo in
a conplox onviionnonl involving a nulliluoo of gonos ano gono piooucls
iogulaling oach olhois aclivily. Foi oxanplo, following lho ovonls iosull-
ing in lho onoigonco of a flowoi in a planl nocossilalos lo follow changos
(lino) in gono oxpiossion lovols oi iospoclivo gono piooucl conconlialions
foi all involvoo gonos in all colls Lolonging lo lho consiooioo lissuo (spaco); a
lask lhal iopiosonls a najoi challongo foi cuiionlly availaLlo oxpoiinonlal
lochniquos [6(, _/[. In consoquonco, availaLlo oala lonos lo Lo of ialhoi
qualilalivo naluio in foin of a palloining concoining gono oxpiossion pio-
filos ano coll ioonlilios of iospoclivo lissuos [__[. In aooilion, inloiaclions
Lolwoon syslon conpononls aio usually non-linoai which oflon piovonls in-
luilivo unooislanoing of oLsoivoo syslon oynanics [1c_[ ano conplicalos
oala inloipiolalion.
In luin, nalhonalical noooling can assisl in uniavoling lhoso gono iogula-
livo nolwoiks unooilying syslon Lohavioi givon lho availaLlo oxpoiinonlal
oala [6(, 1c_[. Foi oovolopnonlal syslons, a connon lypo of noools aio
oiffoionlial oqualion foinalisns [3c, 1c6[ lhal piovioo lho possiLilily lo foi-
nalizo hypolhosos on syslon sliucluio ano Lohavioi as woll as lhoy allow
lo losl such hypolhosos Ly piovioing a glinpso on lho syslon Lohavioi io-
sulling fion lho inilial hypolhosos. 1hoioLy, hypolhosos can Lo oiioclly
conpaioo lo lho oflon qualilalivo oxpoiinonlal iosulls, allowing lo valioalo
ano fuilhoi iofino woiking hypolhosos as woll as il can guioo lho oosign
of now oxpoiinonls, o.g., in lho conloxl of planl oovolopnonl [3, ._, _/[,
++ |e:eurch Comp|e·e: 3
oi noool oiganisns fion lho oonain of aninals liko zoLiafish [3., 1c3[ oi
Drosophila [., 1c/[.
1ho consiooioo sconaiio of oovolopnonlal syslons lhoioLy oiffois fion olhoi
sconaiios in syslons Liology foi which conpulalional noooling is a connon
lool [..[: oovolopnonlal syslons aio nulli coll syslons. In consoquonco, (i)
oolailoo quanlilalivo noools lono lo Locono lo conplox lo ionain con-
pulalionally liaclaLlo ouo lo lho inhoionl paiallolisn, ano (ii) iigoious ox-
poiinonlal analysis of lho syslons is hanpoioo Ly nissing spalial iosolu-
lion—iosulling in availaLilily of noslly qualilalivo oala foi lhoso syslons;
lwo aspocls lhal nooo lo Lo lakon inlo accounl ouiing noooling. Slill, lho
piocoss of lianslaling hypolhosis inlo noools is woll invosligaloo ano io-
soaichois aio assisloo in lhis lask Ly a iango of foinalisns [/6, __, 1c6[.
Novoilholoss, in oiooi lo uso noools foi hypolhosis valioalion, hypolhosis
iofinononl, oi oxpoiinonlal oosign, lho noools fiisl nooo lo Lo caliLialoo
lo oxpoiinonlal oala. In lhis iogaio, lho lask of noool caliLialion foi lho
consiooioo lypo of syslons ionains a pioLlon foi which up lo now lhoio is
no gonoial solulion: whilo paianoloi filling foi noools using quanlilalivo
oala is ialhoi woll oxploioo [/_, //[, as nonlionoo aLovo foi oovolopnon-
lal syslons oflon only qualilalivo oala is availaLlo. In consoquonco, cuiionl
appioachos foi noool caliLialion unooi qualilalivo oala usually aio cuslon-
lailoioo foi coilain syslons ano oflon involvo looious nanual inloiaclions
[3, _/, 61, 33, 1c3[.
1.1 · Research Comp|exes
In lho conloxl of noooling of gono iogulalivo nolwoiks unooilying oovol-
opnonlal syslons, lhis lhosis is concoinoo wilh lho following lwo lopics
lhal havo Loon invosligaloo sinullanoously: (i) a nolhooology nocossaiy
foi noool caliLialion foi lhis lypo of syslons, ano (ii) lho applicalion of
nalhonalical noools lo invosligalo lho oovolopnonl ano nainlonanco of
lho shool apical noiislon in Arabidopsis thaliana. In oolail, lho invosli-
galoo iosoaich conploxos aio:
4 Chupter + lntroouct|on
1.1.1 · Parameter LstImatIon for Mode|s In 0eve|opmenta| ßIo|ogy under Qua|-
ItatIve 0ata
As poinloo oul aLovo, noool caliLialion foi lho syslons consiooioo in oo-
volopnonlal Liology is a pioLlon foi which up lo now no gonoial solulion
oxisls. Novoilholoss, noool paianolois nooo lo Lo caliLialoo Lofoio noo-
ols can Lo usoo. 1ho caliLialion lask is oifficull Locauso foi such syslons
noslly qualilalivo oala is availaLlo naking il haio lo infoi quanlilalivo
paianoloi valuos. In aooilion, lho non-linoaiily of inloiaclions Lolwoon io-
sponsiLlo gonos fuilhoi conplicalos oxliapolalion of suilaLlo sollings. Foi
noools in lho liloialuio, lho following usually cuslon lailoioo appioachos
havo Loon iopoiloo: (i) noools aio solvoo analylically lo ooloinino suilaLlo
paianoloi sollings [61[—an appioach lhal ouo lo ils conploxily is only vi-
aLlo foi snall noools. (ii) Lasoo on analylical iosulls foi iolaloo syslons,
noool paianolois aio lunoo Ly hano [_/, 1c3[. Again, a nolhoo only viaLlo
foi snall syslons ouo lo lho oxpononlially giowing paianoloi spacos. (iii)
Houiislics aio usoo lo ioonlify suilaLlo paianoloi sollings [3, 33[. Allhough
such houiislics aio pionising lo solvo lho paianoloi caliLialion lask, lhoy
as woll suffoi fion lho oxpononlial giowlh of a oifficullly sliucluioo paian-
oloi spaco ano fion lho pioLlon lhal quanlifying noool fil wilh iospocl lo
a qualilalivoly oofinoo laigol palloin ionains uncloai—a slop lhal is noc-
ossaiy foi aulonaloo paianoloi caliLialion. 1o cono up wilh an offoclivo
ano officionl houiislic foi noool caliLialion unooi qualilalivo oala lhoiofoio
conpiisos answoiing lwo koy quoslions:
• how sinilaiilios Lolwoon qualilalivoly oofinoo, oxpoiinonlally ooloininoo
syslon Lohavioi ano noool oulpul can Lo noasuioo ano in whal foin
lhis oiffoionco noasuio is naoo accossiLlo foi a suilaLlo nolhoo foi pa-
ianoloi oplinizalion in gonoial´
• Sinco availaLlo oxpoiinonlal oala lonos lo Lo scaico wilh iospocl lo
lino iosolulion, whal fuilhoi souicos of knowloogo coulo assisl in lho
caliLialion piocoss ano how nighl lhoy Lo incoipoialoo´ In lhis iogaio,
fuilhoi oonain knowloogo is supposoo lo facililalo accossiLilily of lho
paianoloi spaco sliucluio as woll as il coulo assisl in iooucing ils ovoiall
sizo ano lhoioLy counloi oxpononlial giowlh.
+2 Contr|out|on: uno 0verv|ew 5
1.1.2· Mode|Ing deve|opment and MaIntenance of the 5hoot ApIca| MerIstem
In Arabidopsis thaliana
1ho shool apical noiislon is a lissuo lhal is iosponsiLlo foi lho aoiial giowlh
of planls. 1o nainlain giowlh il haiLois a pool of slon colls, piovioing
nocossaiy unoiffoionlialoo colls foi lho giowlh. 1ho koy quoslion in lhis
conloxl is whal piocossos aio iosponsiLlo foi oslaLlishing lhis pool ano ils
honooslasis. A quoslion, lho answoi of which can piovioo fuilhoi insighls
inlo slon coll iogulalion in gonoial ano ovonlually nighl onaLlo influonco
on aspocls liko ciop sizos.
Wilh iospocl lo noooling lho shool apical noiislon, in lho liloialuio lhoio
aio lwo noools alioaoy aooiossing iolaloo aspocls, a noool Ly Jonsson
ol al. [_/[ lhal is concoinoo wilh invosligaling iogulalion of lho so calloo oi-
ganizing conloi, a funclional oonain lhal is iosponsiLlo foi onoigonco ano
nainlonanco of lho slon coll oonain. 1ho socono noool Ly Goioi ol al.
[._[ oosciiLos lho slon coll oonain ano oiganizing conloi as coll pools lhal
aio connocloo via oiffoionlialion ialos ano oxpano ouo lo coll piolifoialion,
which is iogaiooo as an oxloinally conliolloo paianoloi. Using lhoso noo-
ols as a Lasis, lhoy can Lo conLinoo ano oxlonooo wilh iospocl of aooing
oxplicil iopiosonlalion of lho slon coll oonain ano ils foooLack on lho oiga-
nizing conloi ano consiooiing nol only pool sizos Lul lho spalial aiiangononl
of lho funclional oonains.
1.2· ContrIbutIons and DvervIew
Lofoio lhoso lwo iosoaich conploxos aio aooiossoo, lhis lhosis piovioos an
ovoiviow on lochniquos foi noooling of Liological syslons wilh a focus on
gono iogulalivo nolwoiks (Chaploi ·). In lhis conloxl, lho oovolopnonl of
a spalial palloining wilh iospocl lo gono oxpiossion piofilos lhal aio oL-
soivoo in oovolopnonlal syslons ioquiios spocial allonlion. 1hoiofoio, in
Chaploi ¸ a gonoial nochanisn foi palloin foinalion in Liological syslons
is inliooucoo, nanoly ioaclion-oiffusion syslons. 1hoy aio lho nosl pioni-
nonl appioach lo oxplain palloin foinalion ano piovioo lho Lasis foi lho
noooling iosulls piosonloo laloi on.
6 Chupter + lntroouct|on
Following lhoso inliooucloiy chaplois, in Chaploi ¸ funoanonlals concoin-
ing noool caliLialions aio piosonloo. In lhis iogaio, lho chaploi conliiLulos
lo answoiing lho quoslions of (i) whal ciiloiia aio suilaLlo lo guioo an opli-
nizalion nolhoo lowaios lho ioonlificalion of paianoloi sollings lhal allow
foi lho foinalion of a spalial palloining [(6[, (ii) how lo piosonl such ciilo-
iia lowaios lho oplinizalion nolhoo [(/[, ano (iii) how lo quanlify sinilai-
ilios Lolwoon oxpoiinonlally ooloininoo, qualilalivo lissuo palloining ano
noool oulpuls [(_[. All lhioo slops aio invosligaloo on Lasis of a fianowoik
foi noooling of oovolopnonlal syslons ano a gonoial puiposo oplinizalion
houiislic, nanoly an ovolulion slialogy. Lolh, fianowoik ano ovolulion
slialogy aio oosciiLoo alongsioo.
Whilo lho pioposoo lochniquos piovioo a valuaLlo fiisl slop lowaios a solu-
lion of lho paianoloi caliLialion lask, il Locano appaionl lhal an inclusion
of fuilhoi infoinalion souicos is nocossaiy in oiooi lo ooviso a ioliaLlo op-
linizalion slialogy foi lhis lask. 1hoiofoio, Chaploi ¸ (i) invosligalos a
nolhoo lo gonoializo analylical iosulls wilh iospocl lo nocossaiy conoilions
foi palloin foinalion foi lho consiooioo ioaclion-oiffusion syslons such lhal
lhoy can Lo incoipoialoo in lho oplinizalion piocoss [(3[, ano (ii) a nolhoo
is piosonloo lhal allows lo oxploil lho facl lhal oovolopnonlal piocossos aio
oiganizoo in hioiaichios of liansionl slalos.
In conLinalion, lhoso aspocls foin a nolhoo foi paianoloi caliLialion foi
noools of oovolopnonlal syslons using only qualilalivo oala ano ils con-
sliluonls aio usoo lo caliLialo a noool foi oovolopnonl ano honooslasis of
lho shool apical noiislon in Arabidopsis thaliana piosonloo in Chaploi 6,
iosulling in a ioLusl noool lhal is conplianl wilh known conliol oxpoii-
nonls. 1his noool iovoaloo lhal lho usoo lwo conLinoo foooLack syslons
aio sufficionl lo oxplain onoigonco ano nainlonanco of lho funclional oo-
nains in lho shool apical noiislon liko lho alioaoy nonlionoo pool of slon
colls.
1his lhosis is concluooo wilh a sunnaiy of lho naoo conliiLulions ano a
shoil oiscussion of inplioo noxl slops foi fuluio woiks wilh iospocl lo Lolh,
noool caliLialion foi oovolopnonlal syslons in gonoial ano uniavoling lho
+2 Contr|out|on: uno 0verv|ew 7
iogulalion unooilying nainlonanco of shool apical noiislons in Arabidopsis
thaliana.

Mode|Ing Cene
Regu|atIve Networks
Malhonalical noooling has Loconing ono of lho koy lools assisling Liol-
ogisls in inloipioling oala gonoialoo foi conplox syslons, oflon sluoioo
on lho lovol of gono iogulalivo piocossos. 1his chaploi piovioos a gonoial
ovoiviow on lochniquos foi noooling gono iogulalivo nolwoiks (GINs). Il
focusos on syslons in oovolopnonlal Liology which aio al lho hoail of lhis
lhosis. Foi lhoso syslons lho oynanics loaoing lo lho onoigonco of oo-
nains oi cluslois of colls showing sinilai gono oxpiossion piofilos aio sluo-
ioo—piocossos suLsunoo unooi lho loin ’palloin foinalion’ (soo Chap-
loi ¸).
1his chaploi fiisl piovioos a Liiof inlioouclion lo lho iogulalion of gono
oxpiossion, followoo Ly a lisl of connonly usoo noooling appioachos. Il is
concluooo wilh a piosonlalion of lho paianoloi oplinizalion pioLlon, ono of
lho paianounl challongos whon Luiloing nalhonalical noools foi Liological
syslons. 1his chaploi lhoioLy sols lho slago foi lho woik on paianoloi
oplinizalion foi oiffoionlial oqualion noools in oovolopnonlal syslons (soo
10 Chupter 2 |ooe||ng C|N:
DNA
transcription
mRNA translation
gene
products
nucleus
transport
FIgure z.±. Schemut|c v|ew on the proce:: oí gene e·pre::|on íor un eu|uryot|c ce|| |ect-
ung|e: :ymoo||ze uct|on: our|ng gene e·pre::|on, e|||p:e: repre:ent o|o|og|cu| ent|t|e: |n the
e·pre::|on proce::, uno urrow: |no|cute wh|ch ent|t|e: huve un |nfluence on uct|on: ¯he
ou:heo ||ne out||ne: the nuc|eu:, o|v|o|ng the ce|| |n the two compurtment:, nuc|eu: uno cy-
to:o|
Chaplois ¸ ano ¸) as woll as lho pioposoo noool foi nainlonanco of lho
shool apical noiislon in Arabidopsis thaliana piosonloo in Chaploi 6 of
lhis lhosis.
2.1 · ßIo|ogIca| ßackground
1ho gonono of an oiganisn iopiosonls all ils hoiooilaiy infoinalion coooo in
DNA oi INA. Il is connonly iofoiioo lo as Lluopiinl of an oiganisn, con-
laining lho nocossaiy infoinalion foi oiganisn oovolopnonl ano iogulalion.
Il can Lo lhoughl of as a piogian, lho conliol-flow of which is oslaLlishoo
on lho lovol of gonos, i.o., lho Lasic unils of hoiooilaiy infoinalion. 1ho
slalo of lhis piogian is ooloininoo Ly occuiiing gono oxpiossion piofilos foi
a givon lino as woll as iosulling conconlialion lovols of coiiosponoing gono
piooucls. 1ho iogulalion of lhis piogian lakos placo Ly nooulaling gono
oxpiossion [1[, i.o., lho piocoss fion gono lo gono piooucl. 1his iogulalion
can occui ouiing all slagos of gono oxpiossion, affocling gono liansciiplion
fion DNA lo nINA, liansciipls on lhoii way lo lianslalion, oi pioloins
iosulling fion lianslalion (soo Fig. ·.¡).
22 |ooe||ng /pprouche: 11
Ioconl aovancos in oxpoiinonlal lochniquos lhoioLy Login lo allow galh-
oiing laigo-scalo oala concoining oiffoionl slagos of gono oxpiossion: lho
gonono [1_[, lho gono liansciipls oi liansciiplono [6.[, lho gono piooucls
in foin of pioloins oi pioloono [16, .1[, oi nolaLolilos piooucoo in Lio-
chonical ioaclions [._, _.[. Slill, ospocially foi oovolopnonlal syslons in-
volving spalially confinoo oonains wilh spocific oxpiossion piofilos, cuiionl
high-lhioughpul lochniquos lack lho nocossaiy spalial iosolulion. Foi oo-
volopnonlal syslons lhoiofoio oflon only qualilalivo oala concoining gono
iogulalivo piocossos is availaLlo. Using oilhoi lypo of oala, olucioaling gono
iogulalivo piocossos ionains oifficull ouo lo lho ovoiall conploxily of lho
nolwoiks syslons. In oiooi lo uniavol lho usually non-linoai ooponooncios
Lolwoon gonos, nalhonalical noooling can Lo of holp.
2.2· Mode|Ing Approaches
Malhonalical noools piovioo conpacl oosciiplions of Liological syslons
lhal allow lo sinulalo ano piooicl coilain aspocls of syslon sliucluio oi
Lohavioi. Moooling appioachos can Lo oala-oiivon, o.g., infoionco of GINs
fion high-lhioughpul oala, oi hypolhosis-oiivon, o.g., noooling a hypolh-
osis on pulalivo inloiaclions Lolwoon Liological ioonlilios ano conpaiing
noooling iosulls wilh oxpoiinonlal oLsoivalions. Kooping in nino lho
scaiconoss of quanlilalivo oala foi oovolopnonlal syslons ano lhoiofoio
focusing on lho lalloi caso, such conpaiisons holp lo aoapl unooislanoing
of lho invosligaloo oovolopnonlal syslon ano lhoii unooilying GINs. In
aooilion, such conpaiisons can guioo lho oosign of now oxpoiinonls (soo
Fig. ·.·). 1his soclion piovioos a Liiof ano Ly no noans oxhauslivo
ovoiviow on connonly usoo appioachos foi gono iogulalivo piocossos, cov-
oiing slalic, noio oosciiplivo nolhoos as woll as oynanic noools. A noio
oolailoo ioviow of oxisling nolhoos can Lo founo in oo Jong [1_[.
2.2.1 · Craph RepresentatIons
1ho sinplosl noool lo iopiosonl GINs is lo uso a oiiocloo giaph G = (V, E)
consisling of a sol of voilicos V synLolizing lho gonos ano a sol of oogos
12 Chupter 2 |ooe||ng C|N:
model
prediction
regulatory
system
simulate
build model
compare
experiment data
design
experiment
biological
knowledge
FIgure z.z. lnterp|uy oetween e·per|ment: uno mooe||ng when |nve:t|gut|ng o|o|og|cu| :y:-
tem: |ectung|e: :ymoo||ze uct|on:, e|||p:e: repre:ent |níormut|on, uno urrow: |no|cute |n-
íormut|on flow
E ⊆ V × V iopiosonling a iogulaling influonco Lolwoon gonos. Lach oogo
e = (v
s
, v
e
) ∈ E is oosciiLoo Ly a luplo naiking an oiiginaling voilox
v
i
∈ V ano a laigol voilox v
j
∈ V . 1ho luplos can Lo oxlonooo inliooucing
fuilhoi annolalions, o.g., lypos of inloiaclions liko inhiLilion oi aclivalion.
Giaph iopiosonlalions aio slalic noools lhal aio connonly usoo lo visualizo
knowloogo on iogulalions foi consiooioo syslons Lul allow coilain analysos
as woll: il can Lo losloo if coilain gonos aio connocloo, cyclos in nolwoiks can
Lo ioonlifioo, oi slalislics concoining connocloonoss oi gonoial nooo oogioos
can Lo galhoioo. 1hoioLy, iogulalivo palhways, foooLacks nocossaiy foi
honooslasis, oi infoinalion on nooulos oi nolwoik chaiacloiislics can Lo
gainoo. In aooilion, giaphs foin lho Lasis foi noio conplox noools such
as slalo nachinos, Iolii nols, oi Layosian nolwoiks.
2.2.2· ßayesIan Networks
Layosian nolwoik noools iopiosonl a slalislical appioach lo givo a conpacl
iopiosonlalion of lho joinl pioLaLilily oisliiLulion unooilying, o.g., gono ox-
piossion piofilos. 1ho consiooioo GINs aio iopiosonloo Ly oiiocloo acyclic
giaphs G = (V, E) whoio V is a sol of n Liological onlilios, o.g., gono oxpios-
sion lovols oi gono piooucl conconlialions, iopiosonloo Ly ianoon vaiiaLlos
22 |ooe||ng /pprouche: 13
X
i
wilh 1 ≤ i ≤ n. 1ho oogos e = (v
p
, v
c
) ∈ E iopiosonl iogulalivo inloiac-
lions Lolwoon nooos ano aio oxpiossoo in loins of conoilionals on iospoclivo
nooos. 1ho joinl pioLaLilily oisliiLulion unooilying lho oxpiossion piofilos
of a GIN is lhon givon Ly:
p (X) =
n

i=1
p (X
i
|parents (X
i
)) ,
whoio parents (X
i
) coiiosponos lo lho nooos v ∈ V wilh an inconing oogo
oi iogulaling influonco on nooo v
i
. Foi Layosian nolwoiks, lho local Maikov
piopoily is assunoo, i.o., ovoiy voilox v is inooponoonl of any nooo apail
fion ils innooialo paionls oi oosconoanls. 1wo giaphs oi Layosian nol-
woiks inplying lho sano inooponooncos cannol Lo oislinguishoo using oL-
soivalions of lho noooloo pioLaLilily oisliiLulion ano honco aio oqual [.6[.
Layosian nolwoik appioachos can Lo usoo lo infoi lho sliucluio of gono iog-
ulalivo nolwoiks givon oxpiossion oala ano havo lho aovanlago lhal lhoii
slalislical Lasis holps lhon lo hanolo slochaslicily ano noiso incluooo in
Liological oala [.6[. In aooilion, lhoy piovioo lho possiLilily of Loing appli-
caLlo lo suLsols oi inconplolo oala. Novoilholoss, Layosian nolwoiks aio in
piinciplo nol oosignoo lo capluio oynanics of gono iogulalivo piocoss Lul
ialhoi consiooi sono soil of avoiago Lohavioi.
2.2.3· ßoo|ean and Cenera|Ized LogIca| Networks
Invosligaling oynanics of gono iogulalivo nolwoiks, il Loconos appaionl
lhal lho oynanics in nany casos oosciiLo liansilions Lolwoon oiffoionl
sloaoy slalos. 1his loaos lo lho nolion lhal conlinuous syslon oynanics
can Lo oosciiLoo Ly liansilions Lolwoon oisciolo syslon slalos whoio lho
liansilion iulos aio oofinoo Ly logical funclions [/, _3[. Following lhis iooa,
Liological onlilios ano lhoii iospoclivo slalo can Lo oxpiossoo Ly Looloan
vaiiaLlos, o.g., a gono can oilhoi Lo oxpiossoo (on oi liuo) oi nol oxpiossoo
(off oi falso), ano lho slalo of oach onlily is ooloininoo consiooiing lho
slalos of a sol of iogulaling onlilios following a Looloan funclion. Assuning
a oisciolo nolion of lino, lho noxl slalo of a nolwoik X (t + 1) conlaining
n onlilios is ooloininoo ovalualing lho noxl slalo of oach noooloo onlily
14 Chupter 2 |ooe||ng C|N:
x₂
x₁
x₃
x₁(t+1) = (NOT x₁(t)) OR x₃(t)
x₂(t+1) = x₁(t) AND x₃(t)
x₃(t+1) = x₁(t) OR x₂(t)
A B
FIgure z._. /. 3oo|eun networ| con:|:t|ng oí three gene: repre:enteo oy u |og|c c|rcu|t .
1
,
.
.
, uno .
_
ure the 3oo|eun vur|uo|e: repre:ent|ng the gene: uno the |og|cu| gute: |mp|ement
the regu|ut|ng 3oo|eun íunct|on: thut oeterm|ne the e·pre::|on :tute oí the re:pect|ve gene:
3. 3oo|eun trun:|t|on íunct|on: |mp||eo oy the |og|cu| c|rcu|t :hown
x
i
(t + 1) (wilh 1 ≤ i ≤ n) in a synchionous fashion using lhoii iospoclivo
Looloan funclions b
i
ano lho cuiionl slalo of lho nolwoik X (t) as inpul.
An oxanplo foi a snall Looloan nolwoik is shown in Fig. ·.¸.
1ho oisciolizalion of lho noool vaiiaLlos Liings lho aovanlago lhal lho slalo
spaco of a givon noool Loconos finilo, o.g., in caso of Linaiy logic lho slalo
spaco of a noool consisling of n onlilios has a caioinalily of 2
n
, iosulling
in lho facl lhal lho oynanics of a Looloan nolwoik always convoigos lo
a sloaoy slalo oi cyclo ano il is possiLlo lo ooloinino all slailing slalos
lhal convoigo lo a spocific sloaoy slalo—giving infoinalion on ioachaLilily
of coilain syslon slalos ano paililioning lho nolwoik in nol nocossaiily
oisjuncl nooulos involvoo in piooucing coilain syslon Lohavioi.
Slill, lho assunoo oisciolizalion of slalos ano lino as woll as lho ooloi-
ninisn wilh iospocl lo liansilions linils possiLlo oynanics oLsoivaLlo in
Looloan nolwoiks. 1o aooioss lhoso linilalions vaiianls havo Loon inlio-
oucoo, o.g., allowing lo incoipoialo slochaslicily in liansilions [./[ oi allow-
ing foi slill oisciolo Lul noio lhan lwo slalos foi noool onlilios [1c.[.
22 |ooe||ng /pprouche: 15
2.2.4· 0IfferentIa| LquatIon Mode|s
Whilo Looloan nolwoiks oisciolizo polonlially conlinuous noool onlilios liko
nINA oi gono piooucl conconlialions iooucing lhon lo oisciolo sloaoy
slalos, oiffoionlial oqualion (DL) foinalisns piovioos a way lo follow GIN
oynanics Ly noooling lho lino-ooponoonl changos of conconlialions of Li-
ological onlilios. 1ho lino oovolopnonl of conconlialions foi a noool con-
sisling of n noooloo onlilios is noooloo Ly ialo oqualions:
∂x
i
∂t
= f
i
(x) ,
whoio x
i
is lho conconlialion of noool onlily i wilh 1 ≤ i ≤ n ano
f
i
: R
n
−→ R is a lypically non-linoai funclion conpuling lho chango
in conconlialion x
i
al lino t laking inlo accounl lho slalo of lho noool
x = [x
1
, . . . , x
n
]

al lino t. 1ho aovanlagos of DL noools aio lhal lhoy aio
capaLlo of iopiosonling conlinuous syslon oynanics, lhoy allow lo convo-
nionlly nap Liological ioaclions using lho law of nass aclions oi foinalisns
liko S-syslons [__, 1c6[ oi lho connoclionisl noool [/6[. In aooilion, DL
noools aio highly floxiLlo such lhal, o.g., conslanl oolays in ioaclions, can
oasily Lo incoipoialoo as woll as lhoy allow lo lako inlo accounl spalial in-
fluoncos of lho sinulaloo oonain: insloao of only lino-ooponoonl oioinaiy
oiffoionlial oqualion (ODL) noools ono lhon gols a syslon of pailial oif-
foionlial oqualions (IDLs) ooponoing on lino ano spaco. Hoio, lho spalial
conpononl is ospocially inpoilanl whon consiooiing gono iogulalivo pio-
cossos in oovolopnonlal syslons sinco lhoio lho oxpiossion piofilo of a coll
in a consiooioo lissuos nol jusl ooponos on ilsolf Lul is influoncoo Ly oxloinal
signals fion noighLoiing colls as woll.
Allhough DL syslons aio oxlionoly voisalilo, lhis conos al lho cosl lhal
analyzing lhon oflon luins oul lo Lo oxlionoly oifficull. 1ho sizo of lho
noools ano lho involvoo non-linoai loins piovonl analylical solulions foi
nosl syslons, o.g., Ly noans of linoai slaLilily oi Lifuicalion analysis [1c1[.
In oiooi lo slill oLlain knowloogo on possiLlo nunLois ano slaLilily of sloaoy
slalos oi ioLuslnoss, lwo possiLlo ioulos can Lo followoo: (i) facililaling
analysis Ly sinplifying non-linoai ioaclion oqualions, o.g., Ly appioxinaling
oflon occuiiing signoioal iosponso cuivos Ly pioco-wiso linoai oqualions, oi
16 Chupter 2 |ooe||ng C|N:
(ii) insloao of analylical chaiacloiizalion, noools can Lo solvoo nunoiically.
1hoioLy, syslon Lohavioi is invosligaloo foi spocific sinulaloo conoilions
giving an iooa on syslon Lohavioi foi coilain casos, Lul loaving opon ovoiall
syslon Lohavioi foi changing conoilions.
In aooilion, using DL foinalisns ono assunos conlinuous conconlialions
ano lhal lho noooloo ioaclions lako placo in a woll nixoo conpailnonl
whoio oach noloculos can fiooly inloiacl wilh oach olhoi, assunplions lhal
in coilain casos oo nol holo: whon lho nunLoi of ioacling noloculos Loconos
snall, conconlialions no longoi aio conlinuous Lul Locono oisciolo ano io-
aclions no longoi can Lo ioliaLly appioxinaloo Ly a ooloininislic schono
inposoo Ly using DL noools Lul ono nooos lo iosoil lo slochaslic sin-
ulalions whoio noloculos aio oxplicilly iopiosonloo ano ioaclions Lolwoon
noloculos aio lioaloo as slochaslic piocossos.
2.2.5· 5tochastIc Mode|s
In oiooi lo ciicunvonl pioLlons slonning fion lho assunplion of conli-
nuily of conconlialions as woll as lho ooloininisn assunoo foi occuiiing
ioaclions, slochaslic noools oxplicilly consiooiing ioacling noloculos can Lo
usoo. In oiffoionco lo DL noools, as slalo vaiiaLlos insloao of conconlia-
lions oisciolo nunLois of noloculos X aio usoo which aio acconpanioo Ly
a pioLaLilily oisliiLulion p (X, t) quanlifying lho pioLaLilily of occuiionco
of lhoso noloculo nunLois al a poinl in lino t. 1ho pioLaLilily of Loing in
a coilain slalo X al a coilain lino poinl t +δt is lhon givon as [__[:
p (X; t +δt) = p (X; t)


1 −
m

j=1
α
j
δt


+
m

j=1
B
i
δt,
whoio lho α
j
aio lho pioLaLililios lhal ono of lho m ioaclion lakos placo
such lhal lho syslon loavos slalo X ano lho B
i
aio lho pioLaLililios lhal
lho syslon is in anolhoi slalo Lul onlois slalo X Ly noans of ono of lho m
22 |ooe||ng /pprouche: 17
ioaclions laking placo. Lolh pioLaLililios aio quanlifioo wilh lho lino slop
δt. 1his can Lo iofoinulaloo inlo lho nasloi oqualion [__[:

∂t
p (X; t) =
m

j=1
(B
j
−α
j
p (X; t)) .
Whilo lho syslon oosciiplion in loins of nasloi oqualions piovioos an olo-
ganl way lo oosciiLo syslon oynanics, lhoy aio ovon noio oifficull lo solvo
analylically oi nunoiically lhan DL noools. 1hoioLy fuilhoi iosliiclions
aio inposoo wilh iospocl lo liaclaLlo syslon sizos. 1o oaso lhis pioLlon al
loasl lwo vaiianls oxisl: (i) Ly convoiling lho slochaslic syslon inlo a sol of
ODLs conlaining a slochaslic loin [_([, a nolhoo lhal is only foasiLlo foi
coilain syslons; (ii) Ly oxplicilly sinulaling a nunLoi of slochaslic liajoc-
loiios noooling lho syslon Lohavioi ano lhoioLy iopiooucing an onpiiical
pioLaLilily oisliiLulion unooilying lho syslon oynanics [__[.
In aooilion lo lho incioaso in nocossaiy conpulalion lino lo solvo such noo-
ols, lhis lypo of noool ioquiios oolailoo ano conplolo knowloogo of ioaclions
laking placo in lho consiooioo iogulaloiy syslons. In conliasl, foi nany of
lho conplox syslons consiooioo in oovolopnonlal Liology nol all involvoo
faclois aio known Ly now Lul nooo lo Lo appioxinaloo Ly supplononlaiy
faclois inplononling pulalivo inloiaclions, lhoiofoio ionooiing slochaslic
nolhoos as haio lo apply.
2.2.6· 0IscussIon
Whilo slalic noools aio woll suiloo lo infoi oi visualizo lho gonoial sliucluio
of GINs, lho koy aspocl of oovolopnonlal syslons aio lhoii oynanics loao-
ing lo a soquonco of liansionl slagos lhoso syslons iun lhiough. 1hoiofoio,
oynanical noooling lochniquos aio nocossaiy lo capluio lhoso piocossos. In
luin, sliucluial infoinalion nocossaiy lo Luilo oynanic noools coulo Lo
galhoioo using slalic noools.
Consiooiing oynanical noools, lho piosonloo appioachos Looloan nolwoiks,
DL noools, ano slochaslic noools piovioo a liaoo-off Lolwoon oogioo of
18 Chupter 2 |ooe||ng C|N:
FIgure z.µ ¯ruoe-off: oetween
|eve|: oí mooe||ng uno tructuo|e
:y:tem :|ze: íor oynum|cu|
mooe||ng upprouche:
tractable system size
level of detail
computational cost
Boolean
Networks
Differential
Equation
Models
Stochastic
Models
conploxily iopiosonlaLlo Ly a givon noool on lho ono hano sioo ano conpu-
lalional cosl as woll as nocossaiy oogioo of sliucluial infoinalion availaLlo
Lofoiohano on lho olhoi sioo (soo Fig. ·.¸). Foi noools of oovolopnonlal
syslons DL syslons aio lho nosl connon appioach.
Anolhoi aspocl of noooling nol oiscussoo so fai is noool paianolois lhal
nooo lo Lo sol onconpassing lwo lypos of paianolois: (i) nolhoo spocific
paianolois liko lho choico of piiois foi Layosian appioachos, oi (ii) oi Li-
ological syslon spocific paianolois liko lhiosholos usoo foi oisciolizalion
in Looloan nolwoiks oi Liological conslanls liko ialo conslanls nocossaiy
foi DL oi slochaslic noools. 1hoioLy, ospocially lho choico of suilaLlo Li-
ological conslanls is oflon oifficull—a lopic lhal is oiscussoo in lho noxl
soclion.
2.3· Cha||enges In Mode|Ing 0ynamIc 5ystems: Parameter
DptImIzatIon of Mode| Parameters
Using nalhonalical noooling lo assisl iosoaich on Liological syslons in-
volvos a lhioo slop piocoss: (i) lho noool is sol up, a piocossos lhal in nany
caso is sliaighl foiwaio oi nakos uso of oslaLlishoo foinalisns, o.g., lho uso
of lho law of nass aclion lo lianslalo Lio-chonical ioaclions inlo DLs. (ii)
Moool paianolois nooo lo Lo sol, oilhoi in lho foin of nolhoo spocific pa-
ianolois oi syslon spocific paianolois. 1ypical nolhoo spocific paianolois
aio, o.g., piiois usoo in Layosian appioachos, whilo syslon spocific paian-
olois aio, o.g., ialo conslanls nocossaiy lo sol up DL oi slochaslic noools
(soo Fig. ·.¸). (iii) 1ho noools aio solvoo oi sinulaloo lo gonoialo oala
lhal can Lo conpaioo lo oxpoiinonlal oLsoivalions. In aooilion, foi such
2: Chu||enge: |n |ooe||ng 0ynum|c Sy:tem: 19
FIgure z._ /. Comp|e· íormut|on oí two mo|ecu|e: /
uno 3 to C w|th un|nown rute con:tunt k 3. Corre-
:pono|ng o|o-chem|cu| rute equut|on C. |e:u|t|ng t|me-
oepenoent 0L mooe||ng concentrut|on chunge: oí the
comp|e· C
A
B
C
k
A B C
A B
C
k
[ ]
[ ][ ]
C
k A B
t

=

conpaiisons noliics quanlifying lho oogioo of sinilaiily Lolwoon noool ano
oxpoiinonls nooo lo Lo oofinoo.
Whilo lho fiisl slop of solling up a suilaLlo noool is alioaoy woll-sluoioo,
lhis soclion focusos on lho slop of luning noool paianolois ano in ils couiso
aooiossos lho lask of quanlifying oogioos of sinilaiily Lolwoon noool ano
oxpoiinonls nonlionoo unooi slop lhioo. In aooilion, sinco DL noools aio
lho Losl iopiosonloo noooling appioach lo invosligalo piocossos in oovolop-
nonlal syslons ano foi DL noools luning of nolhoo spocific paianolois is
woll-unooislooo, only paianolois Lolonging lo lho noooloo Liological sys-
lon aio consiooioo hoio.
As nonlionoo aLovo such paianolois involvo Liological conslanls liko ialo
conslanls, oissocialion conslanl, oi ioaclion oioois. In an iooal caso, lhoso
paianolois woulo Lo noasuioo oiioclly in oxpoiinonls Lul in nosl casos
oxpoiinonlalisls havo no oiiocl accoss lo lhoso faclois. Slill, foi sconaiios
whoio high iosolulion quanlilalivo oala is availaLlo lhoio oxisls a iango of
houiislics foi infoionco of paianoloi sollings fion quanlilalivo lino couiso
oala [/_, //[. Unfoilunaloly, foi syslons in oovolopnonlal Liology noslly
only quanlilalivo oala concoining ioachoo slaLlo syslon slalos is availaLlo,
ionooiing uso of lho foinoi nolhoos inpossiLlo.
In casos whoio only qualilalivo oala is availaLlo, filling oi oplinizing lho
paianolois lo nalch oxpoiinonlal oLsoivalions Loconos noio oifficull. Foi
snall noools il is possiLlo lo solvo lhon analylical ano lhoioLy infoinalion
is gainoo in whal paianoloi iangos lho consiooioo noool shows a coilain
qualilalivo Lohavioi [61, 3c, 1c1[. In aooilion, such infoinalion can lo sono
oxlono Lo liansfoiioo lo Liggoi syslons: soiving as an inilial guoss, paian-
oloi sollings aio aoaploo Ly hano [_/, 1c3[. Foi ovon laigoi syslons oi whon
oiffoionl hypolhosis aio lo Lo losloo, luning Ly hano Loconos infoasiLlo. In
20 Chupter 2 |ooe||ng C|N:
lhis caso, houiislics can Lo usoo [(6–(3, 33, 1c/[ Lul lho spalial conpononl
ano non-linoai ooponooncos involvoo in oovolopnonlal piocossos conpli-
calo lhis lask. In aooilion, whoio foi nanual lochniquos lho fil Lolwoon
noool an oxpoiinonls can Lo oono Ly nanual inspoclion, foi houiislics lhis
conpaiison nooos lo Lo foinalizoo ano quanlifioo. 1his quanlificalion is
oflon achiovoo Ly using lhiosholos lo oisciolizo noool oulpuls in oiooi lo
gol a qualilalivo oosciiplion. 1his oisciolizoo noool oulpul can lhon Lo
conpaioo lo qualilalivo oxpoiinonlal oala on a poi-onlily Laso, o.g., qual-
ilalivo gono oxpiossion piofilos can Lo conpaioo on a poi-gono Lasis ano
lho oissinilaiily is lhon oxpiossoo in nunLois of occuiioncos of oiffoioncos
[(_, 1c/[.
Foinally, a paianoloi solling x ∈ X nininizing lho oiffoionco Lolwoon
noool oulpul g ano oxpoiinonlally ooloininoo qualilalivoly oofinoo pal-
loining p
tar
is soughl using a funclion h quanlifying lhoii oogioo of oissin-
ilaiily:
aignin
x∈X
{
h(g (x) , p
tar
)
}
, (·.¡)
wilh X ⊆ R
n
Loing lho n oinonsional noool paianoloi spaco of in caso of
DL noools usually ioal paianolois. 1ho lopic of paianoloi oplinizalion
of noool paianolois is fuilhoi oiscussoo in lho Chaplois ¸ ano ¸.

Mode|s for Pattern FormatIon In
ßIo|ogIca| 5ystems
Funoanonlal aspocls whon sluoying oovolopnonlal syslons aio lho oslaL-
lishnonl of a spalial oisliiLulion of colls wilh oiffoionl coll lypos, lho noi-
phogonosis ullinaloly iosulling in lho oovolopnonl of oiffoionl lissuos ano
oigans as woll as ils honooslasis. In loins of gono oxpiossion, Lolh aspocls
can Lo oosciiLoo Ly oovolopnonl oi nainlonanco of palloins consisling of
gioups of colls oxhiLiling sinilai oxpiossion piofilos. Whilo oolailoo noch-
anisns unooilying such palloins foi nosl syslons ionain unknown, lhoio
oxisls a iango of pulalivo nochanisns lhal in piinciplo coulo accounl foi
vaiious phononona in oovolopnonlal piocossos. Agiooing on lho facl lhal
infoinalion on oiganisns sloioo in DNA is in piinciplo ioonlical in all colls
of a singlo oiganisn, infoinalion guioing palloin foinalion oiiginalos fion
lho connunicalion Lolwoon colls.
In lho following, ono of lhoso palloin foinalion nochanisns is oosciiLoo
in oolail, lho so calloo ioaclion-oiffusion syslons. In aooilion, sinco lho
22 Chupter : |ooe|: íor |uttern |ormut|on |n 3|o|og|cu| Sy:tem:
iosulling noools lono lo Lo lo conplox lo Lo solvoo analylically, a Liiof
ovoiviow is givon on nolhoos lo nunoiically solvo lhis lypo of noools.
3.1 · ReactIon 0IffusIon 5ystems
1ho iooa of ioaclion-oiffusion (ID) syslons oalo Lack lo 1uiing [1c_[ who
fiisl pioposoo lhal il woulo Lo possiLlo lo gonoialo linoly slaLlo ano spa-
lially holoiogonoous palloins Lasoo on lho inloiaclions Lolwoon lo oiffus-
ing chonicals oi noiphohgons. Guiooo Ly oxpoiinonlal oLsoivalions, ho
showoo nalhonalically lhal spalial infoinalion oxchango Ly oiffusion can
accounl foi lho gonoialion of spalial holoiogonoous palloins in syslons lhal
wilhoul oiffusion ionain spalially honogonoous. 1ho loin spalial oonain
hoioLy iofois lo, o.g., lissuos iopiosonloo Ly aiiays of colls, ano spalial
holoiogonoous palloins on lhoso oonains aio lhon, o.g., oonains of colls
showing oislincl gono oxpiossion palloins liko lhoy aio oLsoivoo in oovol-
opnonlal syslons. ID syslons lhoioLy piovioo a voisalilo nochanisn foi
palloin foinalion [_., _1, _/, 61, /1, 3., 1c3[.
In a gonoial foinIDsyslons aio connonly oosciiLoo Ly oiffoionlial oqualions
(DLs) of lho following foin:
∂c
∂t
= D∆c + f (c) , (¸.¡)
whoio c is a vocloi iopiosonling lho conconlialions of all consiooioo spocios
al lino t, D is a oiagonal naliix of posilivo oiffusion conslanls, ∆ is lho
Laplaco opoialoi, ano f aio lho non-linoai ioaclion kinolics. Hoio, DL
foinalisns iopiosonl a naluial choico sinco lhoy can convonionlly Lo ooiivoo
fion unooilying Lio-chonical ioaclions using lho law of nass aclion ano lhoy
piovioo a suilaLlo lovol of oolail whilo ionaining conpulalionally liaclaLlo.
Whilo oiffusion piocossos connonly aio assunoo lo cancol oul spalial oif-
foioncos in conconlialions, unooi coilain conoilions inclusion of oiffusion
can ooslaLilizo syslons lhal olhoiwiso aio in a slaLlo sloaoy slalo—such
inslaLililios aio calloo oiffusion-oiivon oi 1uiing lypo inslaLililios. Analyl-
ical solulions lo vaiious oiffoionl ID syslons havo shown lhal ospocially
:+ |euct|on 0|ffu:|on Sy:tem: 23
lho iolalion Lolwoon lho oiffoionl oiffusion conslanls in D is ciucial foi oc-
cuiionco of 1uiing palloins as woll as lho inloiaclions Lolwoon lho involvoo
spocios [61, 3c, 1c_[: lhoio nooos lo Lo a oiffoionco Lolwoon lho involvoo
oiffusion conslanls ano lho oosciiLoo kinolics nooo lo aohoio lo sono no-
lion of aclivalion-inhiLilion inloipiolalion, suLsunoo Ly lho piinciplo of
shoil-iango aclivalion ano long-iango inhiLilion [_1, 6_, __[. 1hoioLy, lho
spalial conpononl logolhoi wilh Lounoaiy conoilions inposoo on oonain
Lounoaiios plays a ciucial iolo in oxplaining lho onoigonco of palloins.
In lho nosl sinplo caso, wo consiooi a syslon consisling of lwo spocios in
a spalial oonain. 1ho fiisl spocios a is supposoo lo Lo aulocalalylic ano
aclivoly consuning oi oogiaoing lho socono spocios s which is conslanlly
piooucoo. In lhis sconaiio, a is slowly oiffusing whilo s is fasl oiffusing.
Slailing fion a snall holoiogonoily in lho conconlialion oisliiLulion of a
ovoi lho spalial oonain, lho aulocalalylic piopoilios of a allow foi lho gonoi-
alion of a poak in lho a conconlialion oisliiLulion. Duo lo ils slow oiffusion,
lhis poak ionains locally ano ouiing ils foinalion ano nainlonanco il nog-
alivoly influoncos lho conconlialion lovols of s. Sinco s is fasl oiffusing, lho
conconlialion of s is nol only iooucoo locally Lul in a wiooi aioa oofinoo
Ly lho aLsolulo nagniluoo of ils oiffusion conslanl. 1hoioLy, aiouno lho
a poak, a fiolo is cioaloo whoio s conconlialions aio loo low lo suppoil
anolhoi a poak. 1his inplononlalion of lho piinciplo of shoil-iango acli-
valion ano long-iango inhiLilion is skolchoo in Fig. ¸.¡ ano in iosull, such
a syslon cioalos a slaLlo palloin of conconlialion poaks of a as shown in
Fig. ¸.·. 1his so calloo aclivaloi suLslialo syslon was pioposoo Ly Gioioi
ano Moinhaiol [_1[ ano ils Lohavioi wilh iospocl lo lino t is oosciiLoo Ly
lho following oqualions [61[:
∂a
∂t
= D
a
∆a +ρ
a
a
2
s −µ
a
, (¸.·)
∂s
∂t
= D
s
∆s −ρ
s
a
2
s +σ
s
, (¸.¸)
wilh lho oiffusions conslanls D
a
, D
s
; a spalial ooponooncy iopiosonloo Ly
lho Laplaco opoialoi ∆; lho ioaclion coofficionls ρ
a
, ρ
s
; lho oogiaoalion
24 Chupter : |ooe|: íor |uttern |ormut|on |n 3|o|og|cu| Sy:tem:
FIgure _.± Schemut|c v|ew on the
pr|nc|p|e oí :hort-runge uct|vut|on
uno |ong-runge |nh|o|t|on
space
long-range inhibition
(inhibitory field)
short-range activation possible new
peaks
initial slight
heterogeneity
pattern formation stable pattern
FIgure _.z. ¯|me :er|e: oocument|ng the generut|on oí u ¯ur|ng puttern íor un uct|vutor
:uo:trute :y:tem ¯he top row :how: the concentrut|on o|:tr|out|on oí o (cí Lq _.) íor three
o|:crete t|me po|nt: uno the oottom row :how: the corre:pono|ng concentrut|on o|:tr|out|on
oí s (cí Lq __) /: :put|u| oomu|n u two-o|men:|onu| fie|o w|th _c × _c |nner po|nt: uno
per|oo|c oounoury cono|t|on: |: u:eo
ialo µ
a
; a conslanl pioouclion ialo σ
s
. An analylical solulion lo a sin-
plifioo voision of lhis syslon oocunonling conoilions unooi which 1uiing
inslaLililios occui can Lo founo in Koch ano Moinhaiol [61[.
In aooilion lo lho piosonloo aclivaloi suLslialo syslon, lhoio oxisls a wioo
iango of oiffoionl ID syslons allowing lo gonoialo vaiious palloins Lul al
lhis poinl only lhoso ioaclion oiffusion syslons aio going lo Lo piosonloo
which aio usoo in lhis lhosis; noio conplolo ovoiviows on oiffoionl lypos of
syslons ano lhoii iospoclivo Liological applicalions can Lo founo in Koch
ano Moinhaiol [61[ ano Moinhaiol [/c[.
:+ |euct|on 0|ffu:|on Sy:tem: 25
A syslon in concopl nuch aliko lo lho aclivaloi suLslialo syslon is lho so
calloo Liussolaloi [36[ givon Ly lho following oqualions:
∂x
∂t
= D
x
∆x +a −(b +β) x +cx
2
y, (¸.¸)
∂y
∂t
= D
y
∆y −cx
2
y +bx. (¸.¸)
Sinilai lo lho aclivaloi suLslialo syslon, x is aulocalalylic ano consunos
oi oogiaoos y ouiing ils gonoialion. In offocl, palloins gonoialoo Ly lhoso
lwo syslons lhoiofoio show local ninina in y ano s conconlialion whoio
poaks in x ano a aio foinoo ano in-Lolwoon lhoso poaks, x ano a ioach local
ninina whilo y ano s conconlialions iocovoi (soo Fig. ¸.·). In oiffoionco lo
lho aclivaloi suLslialo syslon lhal incoipoialos jusl lho lwo spocios a ano
s, in aooilion lo x an y lho Liussolaloi conpiisos aooilional spocios a, b, β,
ano c which aio assunoo lo ionain al conslanl conconlialions lhioughoul
lho lino couiso of lho syslon.
A concoplually oiffoionl lypo of syslon is lho aclivaloi inhiLiloi syslon [_1[
oosciiLoo Ly lho following oqualions:
∂a
∂t
= D
a
∆a +ρ
a
a
2
h
−µ
a
,
∂h
∂t
= D
h
∆h −ρ
h
a
2
−µ
h
,
whoio D
a
, D
h
, ρ
a
, ρ
h
, µ
a
, ano µ
h
havo lho sano noaning as in Lqs. ¸.·
ano ¸.¸. In oiffoionco lo a spocios lhal is consunoo oi oogiaooo, hoio, lho
long-iango inhiLilion is inplononloo via an inhiLiloi h which is gonoialoo
logolhoi wilh lho aulocalalylic spocios a. Whoiovoi a lovols slail lo iiso h
lovols iiso as woll. Sinco h oiffusos nuch fasloi lhan a, aiouno local naxina
in a lovols a iogion is gonoialoo inlo which h is oiffusing ano lhal in iosull
shows high h lovols as woll. In offocl, in lhis iogion h lovols aio high onough
lo piovonl now a poaks ano lhoioLy iosulling in a slaLlo spalial palloin (cf.
Fig. ¸.¡).
Whilo so fai only gonoial palloin foinalion capaLililios havo Loon oiscussoo,
consiooiing spalial oonain sizos ano giowlh aoos now aspocls lo Liological
26 Chupter : |ooe|: íor |uttern |ormut|on |n 3|o|og|cu| Sy:tem:
palloin foinalion wilh ID syslons. Fiisl of all, foi a givon ID syslon
lhoio oxisls a ciilical oonain sizo nocossaiy foi inilialion of palloins. In
consoquonco, foi oxanplo in oovolopnonlal syslons palloins onoigo onco
lho syslon ioachos a coilain sizo, i.o., afloi a coilain nunLoi of coll oi-
visions; a facl filling oLsoivalions in onLiyo oovolopnonl. In aooilion,
palloins gonoialoo Ly ID syslons show iogonoialivo piopoilios, o.g., whon
liansplanling iogions of lho spalial oonain, as woll as lho foinoo palloins
can aoapl lo giowing oonains Ly, o.g., in caso of lho aclivaloi suLslialo oi
aclivaloi inhiLiloi syslon Ly splilling oxisling a poaks oi inliooucing now
a poaks iospoclivoly—a facl lhal coulo assisl in oxplaining phyllolaxis, i.o.,
lho aiiangononl of oigans in planls.
3.2· 5Imu|atIon ßy NumerIca| IntegratIon
Allhough noools foi Liological syslons usually nako uso of a iango of sin-
plifying aLsliaclions in oiooi lo allow capluiing coilain piocossos of inloiosl,
lho iosulling noools lono lo ionain conplox. Foi oxanplo ID noools foi
palloin foinalion in oovolopnonlal Liology aio lo conplox lo Lo solvoo
analylically, oonanoing foi nunoiical solulions. Whoio analylical chai-
acloiizalions of noools yiolo infoinalion on, o.g., whal lypos of palloins
a coilain syslon is capaLlo of piooucing foi whal paianoloi sollings, nu-
noiical solulions oi sinulalions follow a oiffoionl ioulo. Lilhoi paianoloi
sollings aio soughl such lhal syslon Lohavioi oxoiloo ouiing nunoiical sin-
ulalion Losl iosonLlos oxpoiinonlally oLsoivoo Lohavioi oi snall vaiialions
aio inposoo on such a caliLialoo noool in oiooi lo piooicl whal influonco
lhis chango nighl havo on ovoiall syslon Lohavioi. In oiffoionco lo iigoious
analylical analysos, nunoiical solulions lhoiofoio highlighl coilain possiLlo
syslon Lohaviois Lul in luin piovioo a full liajocloiy of lho syslon Lohavioi
unooi lho conoilions of lho sinulalion.
Sinco in ID syslons a spalial conpononl nooos lo Lo consiooioo in ao-
oilion lo lino, lho lask of nunoiically solving lho syslon is a Lounoaiy
valuo pioLlon whoio inilial valuos aio givon foi sovoial spalial loci. Duo
lo lho spalial conpononl, lho syslons aio oosciiLoo Ly pailial oiffoionlial
:2 S|mu|ut|on 3y Numer|cu| lntegrut|on 27
oqualions (IDLs) which lypically aio paiaLolic. In oiooi lo solvo lhoso
IDLs nunoiically, infoinalion on ooiivalivos al a coilain poinl wilh io-
spocl lo lino ano spaco aio usoo lo oxliapolalo fuluio syslon slalos. In
offocl, lho conlinuous Lohavioial syslon oosciiplion is oisciolizoo wilh io-
spocl lo Lolh, lino ano spaco, lo conpulo slopwiso appioxinalions. Do-
ponoing on lho chaiacloiislics of lho consiooioo IDLs, lhis piocoss can Lo
noio oi loss oonanoing Lul ospocially lho oiffusion loins in ID syslons
lono lo Lo sliff, noaning colloquial spoaking lhal lho cuivaluio of lho IDLs
unooigoos oiaslic changos. 1hoso changos in cuivaluio iosull in slaLilily
pioLlons foi sono of lho sinploi Lul fasl nolhoos foi nunoiical inlogia-
lion ano lhoiofoio oonano foi sophislicaloo Lul conpulalionally oxponsivo
nolhoos. Sinco conpulalion lino nocossaiy foi nunoiically solving lho con-
siooioo syslons ioachos oioois of nagniluoo in lho iango of ninulos, lho
conpulalion lino nocossaiy foi paianoloi oplinizalion (soo Soclion ·.¸)
nooos lo Lo consiooioo whon choosing a nunoiical inlogialoi.
In lho following wo givo a Liiof ovoiviow on sono of lho noio connon nolh-
oos foi nunoiical inlogialion lhal havo Loon usoo in lhis lhosis, Loginning
wilh fasl Lul sonolinos unslaLlo oxplicil nolhoos, followoo Ly slaLlo Lul
conpulalionally oonanoing inplicil schonos, ano concluoing wilh a con-
Linalion of Lolh, so calloo inplicil-oxplicil schonos. Moio oolailoo ioviows
can Lo founo in Iuulh [_1[ ano Iioss ol al. [3_[.
3.2.1 · Lxp|IcIt 5chemes
Lxplicil nunoiical schonos nako uso of infoinalion of lho ooiivalivos up lo
lho cuiionl lino poinl lo oxliapolalo lho syslon slalo al lho noxl lino poinl.
1ho sol of oxplicil inlogialois can Lo oiviooo inlo lo oiffoionl appioachos,
(i) lhoso which only lako inlo accounl lho cuiionl lino poinl ano nighl
calculalo inloinooialo slops Lolwoon lho cuiionl lino poinl ano lho noxl
poinl ano (ii) ano lho so calloo nulli slop nolhoos which in aooilion lo lho
cuiionl lino poinl nako uso of oailioi lino slops as woll. In aooilion lo lino
oisciolizalion, lho spalial conpononl in lho IDLs nooos lo Lo aooiossoo as
woll; foi oxplicil schonos lho Laplaco opoialoi ∆ foi a funclion a (x, t)
al lino t is connonly oisciolizoo using a spalial giio. Foi oxanplo, a
28 Chupter : |ooe|: íor |uttern |ormut|on |n 3|o|og|cu| Sy:tem:
conlinuous ono-oinonsional oonain x is oiviooo inlo n oquioislanl poinl x
i
wilh 1 ≤ i ≤ n wilh nosh spacing δx. Foi oach of lhoso poinls, lho Laplaco
opoialoi can lhon Lo oisciolizoo as follows:
∆(x
i,j
, t) =
a (x
i−1
, t) +a (x
i+1
, t) −2a (x
i
, t)
(δx)
2
, (¸.6)
a slialogy lhal can Lo oxlonooo in a sliaighl foiwaio nannoi foi oiffoionl
giios as woll as highoi oinonsional spacos.
Runge-Kutta Method
Ono of lho nosl connon oxplicil inlogialoi schonos is lho Iungo-Kulla
fouilh oiooi nolhoo [3_[, Lolonging lo lho fanily of Iungo-Kulla schonos.
Il has an accunulaloo oiioi in lho oiooi of h
4
whoio h is lho slop sizo foi
lino oisciolizalion ano il usos lho lalosl syslon slalo ano aooilional lhioo
inloinooialo slops lo calculalo lho noxl syslon slalo. Il is givon Ly:
y
n+1
= y
n
+
1
6
h(k
1
+ 2k
2
+ 2k
3
+k
4
) ,
t
n+1
= t
n
+h,
k
1
= f (t
n
, y
n
) ,
k
2
= f
(
t
n
+
1
2
h, y
n
+
1
2
hk
1
)
,
k
3
= f
(
t
n
+
1
2
h, y
n
+
1
2
hk
2
)
,
k
4
= f (t
n
+h, y
n
+hk
3
) ,
whoio f (t, y) is lho DL; y
n
ano y
n+1
aio lho cuiionl ano lho noxl syslon
slalo iospoclivoly.
Adams-ßashford
1ho Aoans-Lashfoio inlogialoi [3_[ is a sinplo linoai nulli-slop nolhoo
lhal conpulos lho noxl syslon slalo using infoinalion on a sol of piovious
syslon slalos. In lhis lhosis lho lwo slop Aoans-Lashfoio schono is usoo
which is givon Ly lho following oqualion:
y
n+1
= y
n
+
3
2
hf (t
n
, y
n
) −
1
2
hf (t
n−1
, y
n−1
) ,
:2 S|mu|ut|on 3y Numer|cu| lntegrut|on 29
whoio f (t, y) is lho DL; y
n+1
, y
n
ano y
n−1
aio lho noxl syslon slalo, lho
cuiionl syslon slalo ano lho piovious syslon slalo iospoclivoly.
3.2.2· Imp|IcIt 5chemes
In oiffoionco lo lho alioaoy oosciiLoo oxplicil schonos, inplicil inlogialoi
nako uso of an oslinalo of lho noxl syslon slalo Ly solving lho following
oqualion:
g (y
n
, y
n+1
) = 0,
whoio y
n
is lho cuiionl syslon slalo ano y
n+1
is lho noxl syslon slalo. Al-
lhough solving lhis oqualion inliooucos sono fuilhoi conpulalional ovoi-
hoao, ospocially foi sliff syslons inplicil nolhoos oflon yiolo nuch Lolloi
iosulls.
In lhis lhosis a vaiianl of lho Ciank-Nicolson schono [_3[ is usoo, which is
oosignoo lo solvo IDL syslons ano wo focus on lho spalial oisciolizalion
slop usoo in lhis nolhoo. Il is givon Lo lho following oqualion:
y
i
n+1
−y
i
n
h
=
(
y
i−1
n+1
+y
i+1
n+1
−2y
i
n+1
)
+
(
y
i−1
n
+y
i+1
n
−2y
i
n
)
2 (δx)
2
,
whoio i is lho inoox foi a iogulai spalial giio on a ono oinonsional syslon
ano i − 1 ano i + 1 aio lho noighLoiing inoicos; h is lho lino slop; y
n
ano
y
n+1
aio lho cuiionl syslon slalo ano lho noxl syslon slalo iospoclivoly;
ano δx is lho giio spacing of lho spalial giio.
3.2.3· Imp|IcIt Lxp|IcIt 5cheme
As nonlionoo aLovo, nunoiically solving IDL syslons oiiginaling fion ID
noools ioquiios a liaoo-off Lolwoon conpulalional cosl ano accuiacy. Sinco
in ID syslons only lho oiffusion pails lono lo Lo sliff, il can Lo aovanla-
goous lo uso inplicil-oxplicil (IMLX) schonos lhal uso a fasl oxplicil schono
foi lho ioaclion pail of lho IDLs whilo lho sliff oiffusion loins aio solvoo
using noio accuialo inplicil schonos. 1hoioLy ono has lo lako caio lhal lho
30 Chupter : |ooe|: íor |uttern |ormut|on |n 3|o|og|cu| Sy:tem:
choson lino-slopping nolhoo is al loasl socono oiooi ano oscillaling oiioi
conpononls slonning fion lho oiffusion loins aio offoclivoly oanponoo;
olhoiwiso lho inlogialion piocoss nighl convoigo lo a slaLlo syslon slalo
lhal is qualilalivoly wiong [.3[. Ono nolhoo fulfilling lhoso ioquiiononls
is an IMLX schono Lasoo on a lwo slop Aoans-Lashfoio inlogialoi con-
Linoo wilh a vaiianl of lho Ciank-Nicolson schono [_1[. Il is givon Ly lho
following oqualion:
y
n+1
−y
n
h
=
3
2
f (y
n
) −
1
2
f (y
n−1
)
+D
(
9
16
∆y
n+1
+
3
8
∆y
n
+
1
16
∆y
n−1
)
,
whoio y
n
ano y
n+1
aio lho cuiionl ano lho noxl syslon slalo iospoclivoly;
h is lho lino slop; f (y) is lho ioaclion loin fion Lq. ¸.¡; D is lho oiffusion
conslanl fion Lq. ¸.¡; ano lho Laplaco opoialois ∆ aio oisciolizoo following
Lq. ¸.6.
3.2.4· 0IscussIon
In conclusion, in lhis soclion a iango of oiffoionl nolhoos foi nunoiical
solulion oi sinulalion of DL noools havo Loon piosonloo lhal conslilulo
a liaoo-off Lolwoon conpulalional cosl ano accuiacy. Whilo foi loss con-
plox syslons fasl oxplicil schonos aio sufficionl foi nunoiical inlogialion,
foi noio conplox syslons liko lho pioposoo shool apical noiislon (SAM)
noool (soo Chaploi 6) noio sophislicaloo schonos nooo lo Lo usoo. Slill,
sinco nunoiical solulions only piovioo a local viow on possiLlo syslon Lo-
havioi, ospocially ouiing paianoloi oplinizalion oi caliLialion a significanl
nunLoi of sinulalions is nocossaiy. 1hoiofoio, conpulalional cosls shoulo
Lo iooucoo whoio possiLlo: lho uso of oxponsivo inplicil schonos shoulo Lo
avoiooo, ospocially foi non-linoai loins. In consoquonco, IMLX schonos aio
usoo lhal piovioo lho nocossaiy accuiacy foi lho sliff oiffusion loins apply-
ing inplicil schonos whilo lho non-linoai ioaclion loins aio solvoo using
fasloi oxplicil schonos.

Methods for Mode| Ca|IbratIon:
Cenera| ConsIderatIons
1ho connon noooling lochniquo foi oovolopnonlal syslons ano lhoii un-
ooilying gono iogulalivo nolwoiks (GINs) aio oiffoionlial oqualion foi-
nalisns. 1hoy allow foi a oolailoo napping of Lio-chonical ioaclions con-
sliluling gono iogulalion as woll as coaisoi giainoo suLsunplions of suL-
syslons. Sinulalions of such noools yiolo infoinalion on lino-Lohavioi
of noooloo onlilios liko conconlialions of gono piooucls. In oiooi lo uso
such infoinalion lo valioalo hypolhosis oi nako piooiclions concoining lho
unooilying iogulalion, lho paianoloiizoo oiffoionlial oqualions consliluling
lho noool nooo fiisl lo Lo caliLialoo using oxpoiinonlal oala.
Such caliLialion piocossos aio oifficull foi lho consiooioo syslons. Inloiac-
lions Lolwoon conpononls aio non-linoai ano lhoiofoio appiopiialo paian-
oloi sollings aio haio lo infoi. In aooilion, lho Lohavioi of oovolopnonlal
syslons ooponos on lino as woll as inloiaclions Lolwoon oiffoionl colls of a
lissuo play a ciucial iolo. 1his ciicunslanco aoos a spalial conpononl lo
32 Chupter 4 |ethoo: íor |ooe| Cu||orut|on. Ceneru| Con:|oerut|on:
lho alioaoy lino ooponoonl oiffoionlial oqualions. On lho olhoi hano, spa-
lially high-iosolulion quanlilalivo oala foi lissuo oi oiganisn-lovol syslons
is oifficull lo oLlain; oxpoiinonlal oala concoining such syslons aio noslly
of qualilalivo naluio oiiginaling fion sovoial inaging lochniquos. Foi ox-
anplo Ly using fluoiosconco nicioscopy in conLinalion wilh gonos laggoo
wilh fluoiosconl pioloins, oxpiossion oonains of iospoclivo gonos can Lo vi-
sualizoo. Such infoinalion oosciiLo a palloining of lho consiooioo lissuo
wilh iospocl lo gono oxpiossion lovols.
1o aooioss lho challongos posoo Ly lho lask of noool caliLialion foi lho givon
conloxl of oovolopnonlal syslons il nakos sonso lo oivioo il inlo a sol of
oiffoionl suLlask. (i) A noooling fianowoik as woll as a gonoial nolhoo foi
nininizalion of oiffoioncos Lolwoon noool oulpul ano oxpoiinonlal iosulls
has lo Lo choson. 1ho inplononlalions usoo in lhis lhosis aio piosonloo
in Soclion ¸.¡. (ii) Luiloing on lhis fianowoik, Lofoio noool caliLialion
wilh iospocl lo spocific laigol palloins is puisuoo, lho ioonlificalion of pa-
ianoloi sollings allowing foi lho onoigonco of gonoial palloins has lo Lo
consiooioo. Using ioaclion-oiffusion (ID) syslons as palloin foining noch-
anisn, alioaoy lhis noio gonoial lask is challonging: lho oosiioo spalially
holoiogonoous ano linoly slaLlo palloins aio only foinoo foi snall fiaclions
of lho paianoloi spaco ano lho paianoloi spacos lhonsolvos aio ooninaloo
Ly plaloaus of paianoloi sollings showing qualilalivoly sinilai Lohavioi.
In consoquonco, lhoso plaloaus oLscuio infoinalion allowing a oiiocloo cal-
iLialion piocoss. 1his challongo is aooiossoo in Soclion ¸.¸ whoio foaluios
of oplinizalion ciiloiia aio oxploioo lhal allow lo oscapo lho nonlionoo
plaloaus. Luiloing on lhis woik, lwo fuilhoi aspocls nooo lo Lo consiooioo:
(iii) nalching paianoloi sollings nol only nooo lo Lo ioonlifioo Lul al lho
sano lino syslon piopoilios liko ioLuslnoss oi sonsilivily aio of inloiosl. In
oiooi lo assoss such chaiacloiislics, in Soclion ¸.¸ il is invosligaloo in how
fai oplinizalion ciiloiia can Lo iofoinulaloo lo aio an oxploialion of lho
consiooioo paianoloi spacos wilh iospocl lo such chaiacloiislics. Finally,
(iv) lo allow lho ioonlificalion of paianoloi sollings iosulling in a spocific
palloining ialhoi lhan an aiLiliaiy palloining, nolhoos foi palloin ioonli-
ficalion in noool oulpuls ano quanlificalion of lhoii oogioo of sinilaiily lo
laigol palloins aio oiscussoo in Soclion ¸.¸.
4+ |ounout|on: 33
4.1 · FoundatIons
In lho following a noooling fianowoik foi GINs in nulli coll syslons ano
a ianoonizoo oplinizalion slialogy aio oosciiLoo lhal aio usoo as Lasis foi
lho piosonloo woik on noool caliLialion.
4.1.1 · Framework for 5Imu|atIons of 0eve|opmenta| 5ystems
1ho usoo noooling fianowoik soivos lho lwo goals lo allow foi (i) hypolh-
osis losling ano (ii) hypolhosis oxploialion. On lho ono hano, il shoulo
Lo loslaLlo wholhoi a givon syslon of inloiacling faclois can foin coilain
spalial palloins Ly finoing lho nocossaiy paianoloi sollings ano sinulaling
lho syslon. On lho olhoi hano, Lasoo on a caliLialoo noool piooiclions
on a possiLlo palloining iosulling fion novol inliacollulai ano inloicollulai
inloiaclions shall Lo possiLlo.
1ho pioposoo noool is oofinoo Ly lho following coio conpononls:
Ce||s: 1ho noool consisls of spalially oisciolo unils, lho colls. 1hoy aio
usoo as aulononous unils. Il is assunoo lhal all colls aio sinilai lo oach
olhoi in oosign, in pailiculai iogaioing lho unooilying GIN, ano only
oiffoi in lhoii slalos. Coll volunos as woll as shaioo suifaco aioas aio
assunoo lo Lo of oqual nagniluoo foi all colls.
Cene products: 1ho slalo of a coll v
i
is chaiacloiizoo Ly lho conconlialions
of lho gono piooucls piooucoo in lho coll. 1ho gono piooucl conconlia-
lions aio iopiosonloo Ly a ioal valuoo vocloi. 1ho loin ’gono piooucl’ in
lhis caso nol only iofois lo lho piooucl Lul has lo Lo unooislooo synony-
nous foi gono piooucls, gono oxpiossion lovols ano all piocossos on lho
way fion gono lo gono piooucl. Sinco lhoio oxisls a napping Lolwoon
oxpiossion lovols ano lho iosulling anounl of gono piooucls, lho gono
piooucl conconlialions aio iopiosonling lho gono oxpiossion lovols.
Ce|| structure: 1ho colls aio gioupoo accoioing lo a spalial noighLoihooo
oofining which colls shaio connon coll suifaco aioas. Inloinally lho coll
noighLoihooo is iopiosonloo Ly a giaph G(V, E) consisling of a sol of
colls V . Conlacls oi inloiaclion palhways Lolwoon lho colls aio iopio-
sonloo Ly oogos e = (v
i
, v
j
) ∈ E Lolwoon lwo colls v
i
ano v
j
.
34 Chupter 4 |ethoo: íor |ooe| Cu||orut|on. Ceneru| Con:|oerut|on:
Ce|| communIcatIon: 1o foin spalial holoiogonoous palloins, spalial inloi-
aclions oi coll connunicalion Lolwoon lho consliluling conpononls aio
nanoaloiy. In lhis noool oiffusivo inloiaclions aio consiooioo as noans
of connunicalion ano il lakos placo along lho oogos Lolwoon lho colls.
1hoiofoio inplicilly zoio flux Lounoaiy conoilions aio usoo on lho Louno-
aiios of lho consiooioo spalial oonain.
Using lho fianowoik, syslon oynanics aio oxploioo Ly sinulaling lho io-
sulling noool. Duiing sinulalion lho slalos of lho colls chango accoioing
lo (i) inliacollulai inloiaclion Lolwoon gonos oi gono piooucls ano (ii) lho
inloicollulai connunicalion via oiffusion. In a foinal oosciiplion lho slalo
chango of a coll v
i
follows a liansilion funclion δ (q
i
, N (v
i
)) ooponoing on
lho cuiionl slalo q
i
of lho coll ano lho slalos of ils inloiaclion pailnois
givon Ly lho noighLoiing colls N (v
i
). Lach iloialion in lho sinulalion coi-
iosponos lo calculaling lho liansilions naoo foi ovoiy coll Lasoo on lho
slalus quo. As oiscussoo in Chaplois · ano ¸, foi lho consiooioo lask of
noooling palloin foinalion ano nainlonanco in oovolopnonlal syslons oif-
foionlial oqualion (DL) noools Lasoo on ID syslons aio usoo.
4.2· Method for Mode| Parameter DptImIzatIon
Iopoaling lho foinulalion of lho lask of caliLialing a noool foi lho onoi-
gonco ano nainlonanco of a palloining in oovolopnonlal syslons givon in
Lq. ·.¡ in Chaploi ·, foi noool caliLialion a paianoloi solling x ∈ X
nininizing lho oiffoionco Lolwoon noool oulpul g ano oxpoiinonlally oo-
loininoo qualilalivoly oofinoo palloining p
tar
is soughl using a funclion h
quanlifying lhoii oogioo of oissinilaiily:
aignin
x∈X
{
h(g (x) , p
tar
)
}
, (¸.¡)
wilh X ⊆ R
n
Loing lho n oinonsional noool paianoloi spaco of usually
ioal paianolois.
Foi lhis nininizalion an ovolulion slialogios [._[ is usoo in lhis lhosis. Lvo-
lulion slialogios Lolong lo lho class of ianoonizoo oplinizalion algoiilhns
42 |ethoo íor |ooe| |urumeter 0pt|m|zut|on 35
oosignoo foi ioal-valuoo oplinizalion liko lho paianoloi spacos X ⊆ R
n
consiooioo foi oiffoionlial oqualion noools in oovolopnonlal Liology.
In shoil, ovolulion slialogios nap piinciplos of Daiwinian ovolulion lo foin
an oplinizalion cyclo (soo Fig. ¸.¡): Loginning wilh an inilial guoss on an
appiopiialo soaich oisliiLulion p
X
on lho consiooioo soaich spaco X (hoio
lho noool paianoloi spaco) lho soaich spaco is sanploo λ
SO
linos ano lho
sanplos x
i
wilh 1 ≤ λ
SO
aio ovalualoo using an oLjoclivo oi filnoss funclion
h (hoio lho funclion quanlifying lho oissinilaiily Lolwoon noool oulpul
ano oxpoiinonlally ooloininoo lissuo palloining). Lasoo on lhoii iospoc-
livo oLjoclivo oi filnoss scoios, a suLsol of lho λ
SO
so calloo offspiing voclois
is solocloo lo upoalo lho soaich oisliiLulion p
X
. 1hoso slops aio lhon io-
poaloo unlil a coilain slopping ciiloiion is nol. Slopping ciiloiia lhal aio
connonly usoo aio, o.g., a Louno on lho nunLoi of oLjoclivo funclion oval-
ualions oi a filnoss lhiosholo which onco oxcooooo Ly ono of lho sanplo
voclois loininalos lho oplinizalion piocoss. As soaich oisliiLulion, con-
nonly noinal oisliiLulions N
(
m, s
2
C
)
aio usoo, wilh oisliiLulion noan
m, a covaiianco naliix C, ano a scaling facloi s.
In oolail, lho CMA-LS oosignoo Ly Hanson ano Osloinoioi [(([ is usoo. In
oach iloialion of ils oplinizalion cyclo il usos infoinalion on lho solocloo
x
i
lo infoi ooponooncios Lolwoon lho oiffoionl oinonsions of X. 1hoioLy,
il aoapls lho shapo of C. In aooilion, lho scaling facloi s is upoaloo. 1ho
offspiing aio oiawn accoioing lo:
x
i
∼ m+sN (0, C) .
Lolh, C ano s aio upoaloo in such a way lhal lho likolihooo of sanpling a
poinl x

lhal is Lolloi in loins of lho filnoss funclion lhan lho pioviously
oiawn sanplos is incioasing.
1ho CMA-LS shows a sol of invaiianco piopoilios lhal in offocl nako il a
ioLusl oplinizalion nolhoo: (i) sinco lho soloclion of lho λ
SO
offspiing oui-
ing oach cyclo oi gonoialion is oono using a ianking of lho sanploo poinls
x
i
wilh iospocl lo h, CMA-LS is invaiianl lo oiooi piosoiving liansfoina-
lions on h; (ii) aoaplion of C is capaLlo of infoiiing iolalions wilh iospocl
36 Chupter 4 |ethoo: íor |ooe| Cu||orut|on. Ceneru| Con:|oerut|on:
FIgure µ.± lterut|ve opt|m|zut|on
cyc|e oí the C|/-LS ¯o |oen-
t|íy u :ett|ng :o|v|ng the con:|o-
ereo opt|m|zut|on tu:|, u :eurch
o|:tr|out|on |: fir:t :ump|eo, írom
the :ump|e:, the oe:t cuno|oute:
|n term: oí the oo¦ect|ve ure :e-
|ecteo, u:|ng the :e|ecteo :um-
p|e:, the :eurch o|:tr|out|on |:
uoupteo |ere, the ootteo ||ne:
ure ||ne: repre:ent|ng equu| oo-
¦ect|ve vu|ue: uno the opt|mum
oí the :|etcheo proo|em |: |o-
cuteo |n the oottom |eſt corner
¯he ou:heo ||ne: repre:ent ||ne: oí
equu| proouo|||ty oen:|ty to :um-
p|e u vector íor the con:|oereo
:eurch o|:tr|out|on:
Initial Search
Distribution
Sampled Search
Distribution
Chosen
Samples
Adapted Search
Distribution
O
p
t
im
u
m
O
p
t
im
u
m
O
p
t
im
u
m
O
p
t
im
u
m
lo soaich spaco axos, iosulling in an invaiianco lo iolalions; (iii) aoaplion
of s allows foi sono invaiianco lo ovoiall scaling of lho paianoloi spaco,
givon lhal inilial C ano s aio choson appiopiialoly. In conLinalion, lhoso
piopoilios nako CMA-LS a soaich houiislic lhal has piovon ils valuo in a
iango of ioal valuoo oplinizalion lasks [_, (6, (_, //, 3/[.
In lho oosciiLoo foin lho CMA-LS is spocializoo lo ooal wilh oplinizalion
lasks whoio only a singlo oLjoclivo is consiooioo. On lho olhoi hano, in
lho conloxl of noool caliLialion oflon a sol of oLjoclivos has lo Lo con-
siooioo, o.g., oiffoioncos Lolwoon sinulaloo palloining ano oxpoiinonlally
ooloininoo palloining wilh iospocl lo a nunLoi of gonos. 1hoiofoio, slialo-
gios lo ooal wilh nulliplo oLjoclivos nooo lo Lo consiooioo. In lhis caso, lho
solulion lo lho pioLlon slaloo in Lq. ¸.¡ Loconos lho sol:
{
x ∈ X|∄ x

∈ X : x

≼ x ∧ x ̸≼ x

}
, (¸.·)
42 |ethoo íor |ooe| |urumeter 0pt|m|zut|on 37
whoio x, x

aio canoioalo solulions in lho paianoloi spaco X ⊆ R
n
ano
‘≼’ oonolos lho woak Iaiolo-ooninanco iolalion wilh iospocl lo lho vocloi
valuoo funclion h(x). Foi lwo voclois x, x

∈ R
n
, x is saio lo woakly oon-
inalo x

(x ≼ x

) wilh iospocl lo h(x) = (h
1
(x) , . . . , h
m
(x)) iff h
i
(x) ≤
h
i
(x

) ∀ i ∈ {1, . . . , m}. 1hoioLy, Lq. ¸.· iopiosonls lho sol of all opli-
nal solulions oi Iaiolo-sol of lho nullioLjoclivo oplinizalion pioLlon; lho
inago of lho Iaiolo-sol in lho oLjoclivo spaco is calloo lho Iaiolo-fionl.
Connonly, lhoio aio al loasl lwo oiffoionl appioachos lo ioonlify solulions
in lhis sol: (i) nolhoos whoio all oLjoclivo funclions aio aggiogaloo inlo a
singlo oLjoclivo, ano (ii) nolhoos lhal consiooi all oLjoclivos sinullanoously.
Wilh iospocl lo (i) possiLlo aggiogalions aio woighloo sun appioachos oi
scalaiizalions liko ChoLyshov scalaiizalion [/([. Wilh iospocl lo (ii) nulliplo
oLjoclivos aio consiooioo sinullanoously Ly conpaiing oiffoionl canoioalo
solulions using inoicalois Lasoo on lho concopl of Iaiolo ooninanco [.c[.
In conpaiison, appioachos oxplicilly consiooiing all oLjoclivos sinullano-
ously havo lho aovanlago lhal lhoy can ioonlify a sol of solulions conlainoo
in lho sol oofinoo Ly Lq. ¸.· whilo aggiogalion appioachos lono lo show loss
oivoisily. Allhough in piinciplo a singlo filling paianoloi solling nighl Lo
onough lo solvo lho lask of noool caliLialion, a sol of sollings can piovioo
fuilhoi infoinalion wilh iospocl lo, o.g., ioLuslnoss of lho pioposoo noool.
In aooilion, foi a iango of oiffoionl oplinizalion lasks sluoios havo shown
lhal consiooiing nullioLjoclivo foinulalions can havo a Lonoficial iosliuc-
luiing offocl on lho pioLlon lanoscapo, facililaling lho oplinizalion piocoss
[1(, (1–(_, __, __, 3_[.
Novoilholoss, singlooLjoclivo appioachos havo lho aovanlago lhal lhoy in-
poso a lolal oiooi on lho paianoloi spaco wilh iospocl lo lho opliniza-
lion ciiloiion which sinplifios soloclion piocossos ouiing oplinizalion. Ap-
pioachos Lasoo on lho concopl of Iaiolo ooninanco in luin only inposo a
pailial oiooi, inliooucing possiLlo anLiguilios ouiing oplinizalion. 1o io-
solvo lhis nalloi, slalo of lho ail nullioLjoclivo appioachos uso iofinononls
of lho Iaiolo ooninanco iosolving lhoso anLiguilios ano oslaLlishing a lo-
lal oiooi, o.g., iofinononls liko lho hypoivoluno [11c–11.[. Foi hypoivoluno
calculalion, a iofoionco poinl is inliooucoo in lho oLjoclivo spaco ano lho
38 Chupter 4 |ethoo: íor |ooe| Cu||orut|on. Ceneru| Con:|oerut|on:
FIgure µ.z |ypervo|ume |no|cutor íor u m|n|m|zut|on proo-
|em w|th two oo¦ect|ve: ¯he hypervo|ume íor u po|nt µ |n the
oo¦ect|ve :puce |: oefineo oy the vo|ume oí the hyper-cuoe
:punneo oy the po|nt uno u reíerence po|nt ¯he hypervo|ume
:punneo oy the po|nt µ
1
|: :hown |n gruy 0ur|ng :e|ect|on,
the hypervo|ume |no|cutor vu|ue: |
|
cun oe u:eo to ou||o u
run||ng on o|fferent cuno|oute vector: thut |: u totu| oroer
uno comp||unt w|th the concept oí |ureto oom|nunce
Reference
Point
<<
1
h
2
h
<
<
2
( ) 29.90
H
I p =
1
( ) 216.38
H
I p =
FIgure µ._ 0ur|ng the opt|m|zu-
t|on cyc|e oí the |0-C|/-LS
euch oí the C|/-LS |n the popu|u-
t|on generute: u :|ng|e off:pr|ng
Como|n|ng the current popu|ut|on
w|th the off:pr|ng, the new popu-
|ut|on |: :e|ecteo
current
Population
new Population
combined Sets
Offspring
qualily of a givon canoioalo solulion is ovalualoo Lasoo on lho voluno on-
closoo Ly lho hypoi-cuLo spannoo Ly a canoioalo solulion ano lho iofoionco
poinl (soo Fig. ¸.·).
1o gain floxiLilily in loins of nunLois of consiooioo oLjoclivos, lhoio oxisls
a nullioLjoclivo oxlonsion of lho CMA-LS, lho MullioLjoclivo Covaiianco
Maliix Aoaplion Lvolulion Slialogy (MO-CMA-LS) [_.[: in oach gonoi-
alion a sol oi populalion of CMA-LSs is usoo, wilh a populalion sizo of
λ
MO
. 1o gonoialo a now populalion, oach of lho λ
MO
CMA-LSs of lho cui-
ionl populalion gonoialos a singlo offspiing. Insloao of a soloclion jusl on
lho offspiing, foi oach CMA-LS lho soloclion is oono on lho olo CMA-LS
ano ils offspiing. 1hoioLy λ
MO
offspiing CMA-LS aio gonoialoo ano lho
populalion of CMA-LSs foi lho noxl gonoialion is solocloo fion lho cui-
ionl populalion ano lho offspiing gonoialoo lhoioof. A singlo cyclo of lho
MO-CMA-LS is skolchoo in Fig. ¸.¸.
4: |ooe| |urumeter 0pt|m|zut|on on |0 :y:tem:. Lmergence oí Sput|u| |uttern|ng 39
FIgure µ.µ ¯wo :|mu|ut|on: íor
u one o|men:|onu| 3ru::e|utor
uct|vutor (:o||o ||ne:) :uo:trute
(ou:heo ||ne:) :y:tem (:ee Lq: _(
uno __) |urumeter :ett|ng:
ure :|m||ur |n ooth :|mu|ut|on:
(o·c1, !·c., β·c1, c·c1, 0
.
·c1),
on|y one o|ffu:|on con:tunt 0
,
|:
:||ght|y perturoeo /. 0
,
·c6_, 3.
0
,
·c/
11 11 20 20 1 1
0.8 0.8
1.2 1.2
1.6 1.6
2.0 2.0
2.4 2.4
C
o
n
c
e
n
t
r
a
t
i
o
n
s
C
o
n
c
e
n
t
r
a
t
i
o
n
s
Cells Cells
A B
FIgure µ._ ||tne:: |uno:cupe íor
the purumeter :puce oí the 3ru::e-
|utor (:ee Lq: _( uno __) w|th re-
:pect to the purumeter: 0
.
uno 0
,
íor the oo¦ect|ve íunct|on Lq (_ 0
.
uno 0
,
ure :ump|eo |n the |ntervu|
[cc_, 1__] u:|ng :tep: δ·cc_ wh||e
the other purumeter: ure fi·eo |or
the u:eo oo¦ect|ve íunct|on, vu|ue:
oí c corre:pono to :put|u||y het-
erogeneou: puttern|ng wh||e vu|ue:
c|o:e to 1 repre:ent :put|u||y ho-
mogeneou: puttern|ng ¯he:e two
reg|on: ure o|v|oeo oy u r|oge-|||e
trun:|t|on ureu
0
0.5
1.0
1.5
0
0.4
0.8
1.2
1.6
2
0
1
O
b
j
e
c
t
i
v
e

F
u
n
c
t
i
o
n

V
a
l
u
e
2.0
x
D
y
D
4.3· Mode| Parameter DptImIzatIon on R0 systems: Lmergence of
5patIa| PatternIng
Allhough ID syslons can oxplain a wioo iango of oiffoionl palloining in
Liological syslons, caliLialion of such noools wilh only qualilalivo oala is
a oifficull lask. Duo lo lho non-linoai loins in lhoso syslons, liansilions
Lolwoon qualilalivo syslon Lohavioi lono lo occui iapioly onco coilain pa-
ianolois cioss ciilical valuos (soo Fig. ¸.¸) whilo lho syslons show consio-
oiaLlo ioLuslnoss wilh iospocl lo paianoloi poiluiLalions olhoiwiso (soo
Fig. ¸.¸). 1hoioLy, alioaoy lho lask of ioonlifying paianoloi sols foi which
insloao of spalially honogonoous palloins, spalially holoiogonoous palloins
onoigo can Lo haio lo fino.
40 Chupter 4 |ethoo: íor |ooe| Cu||orut|on. Ceneru| Con:|oerut|on:
Tab|e µ.±. ln|t|u| :ett|ng: íor C|/-LS
|urumeter vu|ue
ln|t|u| |urumeter: [o, !, β, c, 0
.
, 0
,
] [c(_, c(_, c(_, c(_, c3, c3]
ln|t|u| Stunouro oev|ut|on íor |urumeter: [c._, c._, c._, c._, c), c)]
|u·|mu| Numoer oí 0o¦ect|ve |unct|on Lvu|uut|on: 1ccc
Using lho Liussolaloi ID syslon (soo Lqs. ¸.¸ ano ¸.¸ in Chaploi ¸) as an
oxanplo syslon, lhis soclion invosligalos whal chaiacloiislics an oLjoclivo
funclion foi lho singlooLjoclivo CMA-LS nooos lo show in oiooi lo allow foi
lho ioonlificalion of paianoloi sollings iosulling in lho onoigonco of spa-
lially holoiogonoous palloins. 1hoioLy, foining palloins aio ovalualoo wilh
iospocl lo (i) slaLilily of ovolving palloining ovoi lino ano (ii) significanco
of lho holoiogonoily of lho iosulling palloining.
1hoso chaiacloiislics ano lhoii coiiosponoing oLjoclivo funclions havo Loon
ovalualoo Lasoo on ¡¡ iuns wilh oach iun laking ¸ houis on a singlo CIU
of a lwo chip AMD Oploion 2.6GHz ¸·-Lil nachino wilh 4GB IAM using
lho inilial sollings shown in 1aL. ¸.¡.
4.3.1 · ßase|Ine Approach
Foi lho Lasolino appioach, Lolh, spalial holoiogonoily of lho iosulling gono
piooucl conconlialion oisliiLulion ano convoigonco of lho gono piooucl
conconlialions ovoi lino aio scoioo ano aggiogaloo inlo a singlo oLjoclivo
h(x) as follows:
h(x) =

i∈gp
(nax(δ
t
−∆
s
i
, 0) + ∆
t
i
), (¸.¸)
whoio gp aio all gono piooucls, ∆
s
i
is lho naxinal oiffoionco in gono piooucl
i noasuioo ovoi all colls al lho ono of lho sinulalion, δ
t
is a lhiosholo valuo
which is usoo lo oocioo if a givon spalial holoiogonoily is significanl, ano ∆
t
i
is lho laigosl chango in gono piooucl conconlialion i in lho lasl inlogialion
slop. Hoio, δ
t
= u.¸ was usoo.
4: |ooe| |urumeter 0pt|m|zut|on on |0 :y:tem:. Lmergence oí Sput|u| |uttern|ng 41
In offocl, lho fiisl loin in lhis oLjoclivo funclion can Lo soon as a ponally
loin on paianoloi sollings lhal fail lo gonoialo a slaLlo palloin. 1ho
socono loin ponalizos sollings foi which lho sinulalion ooos nol convoigo
wilhin lho givon nunLoi of inlogialion slops.
4.3.2· IntegratIon of 0omaIn Know|edge
Consiooiing lho oifficullios in oplinizing lho paianolois wilhoul oonain
knowloogo, oiffoionl sconaiios lo incluoo oonain knowloogo inlo lho op-
linizalion piocoss aio consiooioo. Sinco sanpling lho paianoloi spaco
iovoaloo a filnoss lanoscapo wil iospocl lo Lq. ¸.¸ lhal is ooninaloo Ly
plaloaus (soo Fig. ¸.¸), foi lho oplinizalion piocoss haioly any soaich oi-
ioclion is pioviooo. 1hoiofoio, oonain knowloogo is usoo lo gonoialo soaich
oiioclion in lho iogions whoio olhoiwiso only ianoon soaich coulo Lo poi-
foinoo. In oolail, lho pioposoo lo vaiianls aio:
¡. Inliooucing a loin poinling lo a iogion lhal il is known lo Lo pionising
ano lhoioLy gonoialing Lias lowaios lhis iogion,
·. consliaining lho paianolois consiooiing known ooponooncios Lolwoon
paianolois liko lho iolalion Lolwoon oiffusion conslanls.
Foi lho fiisl vaiianl infoinalion on pionising iogions in paianoloi spaco,
o.g., slonning fion analylical invosligalions on conpaiaLlo syslons, aio
inliooucoo in foin of an aooilional loin lo Lq. ¸.¸ lhal ponalizos oislanco
lo such a known pionising iogion. 1ho iosulling oLjoclivo funclion ioaos
as follows:
f(x) =




i∈gp
(nax(δ
t
−∆
s
i
, 0) + ∆
t
i
) +∥x −x
t
∥ if ∥x −x
t
∥ > δ
d
,

i∈gp
(nax(δ
t
−∆
s
i
, 0) + ∆
t
i
) olso,
whoio x
t
is a vocloi iopiosonling lho laigol iogion of lho paianoloi spaco
ano δ
d
is a nininal longlh of lho oiffoionco vocloi of x ano x
t
.
1ho socono vaiianl follows a noio gonoial iooa: il oxploils lho knowloogo
aLoul lho nocossaiy iolalion Lolwoon lho lwo oiffusion conslanls D
x
ano
D
y
. Whonovoi lho iolalion Lolwoon Lolh conslanls oxcooos a lhiosholo of
42 Chupter 4 |ethoo: íor |ooe| Cu||orut|on. Ceneru| Con:|oerut|on:
u.¡, lho aclual iolalion is aoooo lo lho funclion valuo. In offocl, lho soaich
spaco is sofl consliainoo. 1ho iosulling oLjoclivo funclion ioaos as follows:
f(x) =




i∈gp
(nax(δ
t
−∆
s
i
, 0) + ∆
t
i
) +
D
x
D
y
if
D
x
D
y
> 0.1,

i∈gp
(nax(δ
t
−∆
s
i
, 0) + ∆
t
i
) olso.
(¸.¸)
4.3.3· Resu|ts
1ho oplinizalion iuns unooilakon foi lho Lasolino vaiianl failoo lo convoigo
lo an oplinun wilhin ¡uuu oLjoclivo funclion ovalualions. Afloi invosli-
galing which pails of lho paianoloi spaco hao Loon oxploioo ouiing lho
oplinizalion iuns, il luinoo oul lhal only ¸ poiconl of lho losloo sollings
hao iolalions Lolwoon lho oiffusion conslanls D
x
ano D
y
of
D
x
/D
y

1
/7.
Allhough il is known fion liloialuio lhal palloin foinalion using ID sys-
lons only lakos placo if foi lho iolalion of lho oiffusion conslanls
D
x
/D
y

1
/7
holos.
Using lho paianoloi vocloi (a=u.¡, b=u.·, β=u.¡, c=u.¡, D
x
=u.¡, D
y
=¡.¸)
as a laigol vocloi gonoialing soaich oiioclion lowaios a gooo iogion in pa-
ianoloi spaco, lho oLlainoo iosulls woio ioasonaLlo Lul lho iuns oio nol
convoigo lo a solling wilh an oLjoclivo valuo Lolow ¡u
-¡¸
, lho convoigonco
lhiosholo usoo Ly lho CMA-LS. 1his has lo Lo alliiLuloo lo lho facl lhal
Ly laking lho Lucliooan oislanco Lolwoon lho paianoloi vocloi oosciiLing
lho oosiioo paianoloi iogion ano lho aclual paianoloi vocloi, all paiano-
lois oqually conliiLulo lo lho oislanco Lolwoon lho lwo voclois. Sinco D
x
is
an inpoilanl paianoloi lhal lypically lakos nuch snalloi aLsolulo valuos
lhan lho olhoi paianolois, ils conliiLulion lo lho soaich oiioclion is ovoi-
iuloo Ly lho olhois ano lho gonoialoo signal is Lluiioo. In facl, onphasizing
lho conliiLulion of lho oiffusion conslanls inpiovos convoigonco piopoilios.
Aooiossing lhis pioLlon Ly oiioclly consiooiing lho iolalions Lolwoon D
x
ano D
y
in oiooi lo guioo lho oplinizalion piocoss, lhis vaiianl oulpoifoins
lho piovious lwo appioachos as shown in Fig. ¸.6. A iopiosonlalivo pal-
loining iosulling fion lhis oplinizalion piocoss is shown in Fig. ¸.¸.
44 |urumeter Spuce L·p|orut|on íor |0 |ooe|: 43
FIgure µ.6 |e:u|t: oí conoucteo run: u: oo·p|ot: ’3u:e-
||ne’ reíer: to the fir:t vur|unt not |ncorporut|ng uny oo-
mu|n |now|eoge, ’¯urget’ reíer: to the vur|unt where the
oomu|n |now|eoge wu: |ntegruteo oy gu|o|ng the :eurch
to u prom|:|ng reg|on, ’¯urget, emph on 0|ff’ reíer: the
run: gu|oeo to u prom|:|ng reg|on w|th u :put|u| emphu:|:
on the o|ffu:|on con:tunt:, uno ’Con:tru|nt’ reíer: to the
vur|unt where |now|eoge on the re|ut|on oí the o|ffu:|on
con:tunt: wu: u:eo
0
0.5
1
B
a
s
e
l
i
n
e
T
a
r
g
e
t
T
a
r
g
e
t
,
e
m
p
h
.

o
n

D
i

.
C
o
n
s
t
r
a
i
n
t
F
i
t
n
e
s
s
FIgure µ.) |uttern|ng generuteo
oy the 3ru::e|utor |0 :y:tem on
u two o|men:|onu| ce|| p|une w|th
u he·ugonu| |utt|ce Luch verte·
repre:ent: u ce|| Ce||: ure co|oreo
uccoro|ng to the|r concentrut|on:
w|th re:pect to the concentrut|on:
oí the :pec|e: . uno , Concentru-
t|on |eve|: ure re|ut|ve uno runge
írom |ow (||ght co|or) to h|gh (our|
co|or)
Species x Species y
4.4· Parameter 5pace Lxp|oratIon for R0 Mode|s
Whilo foi hypolhosis valioalion wilh iospocl lo GINs Lasoo on noooling
ono is piinaiily inloiosloo in lho ioonlificalion of a paianoloi solling foi
which sinulaloo noool oulpul is ioasonaLlo closo lo oxpoiinonlal oala, in
aooilion, syslon piopoilios liko ioLuslnoss of lho consiooioo syslon aio of
inloiosl. Insloao of jusl a singlo filling paianoloi solling, in lhis caso ono
is inloiosloo in a noio iigoious oxploialion of lho paianoloi spaco of a
givon noool. In lhis conloxl, lho oxploialion capaLililios of lho pioposoo
ovolulionaiy appioach foi paianoloi oslinalion aio invosligaloo. 1ho focus
lhoioLy is on lho oosign of suilaLlo oLjoclivo funclions foi paianoloi spaco
oxploialion, Lasoo on lho sognonl polaiily GIN in Drosophila melanogaster
as oxanplo syslon.
44 Chupter 4 |ethoo: íor |ooe| Cu||orut|on. Ceneru| Con:|oerut|on:
FIgure µ.8 / :|etch oí the :eg-
ment po|ur|ty C|N (uoopteo írom
¦1c/¦). e|||p:e: repre:ent m|N/::,
rectung|e: repre:ent prote|n:,
the he·ugon repre:ent: u prote|n
comp|e· uno the ‘+’ repre:ent:
ou:u| e·pre::|on ¯he |nteruct|on:
oetween the o|fferent con:|oereo
:pec|e: ure g|ven oy urrow:
(po:|t|ve |nteruct|on:) uno urrow
:tuo: (negut|ve |nteruct|on:) ¯o
reflect the :put|u| component oí
the C|N, the |nteríuce oetween
two ne|ghoor|ng ce||: |: :hown
CN
en en
hh
wg
ptc
cid PH PH CID
PTC PTC
HH HH
EN
WG WG
+
intracellular
space
intracellular
space
extracellular
space
4.4.1 · 5egment Po|arIty Network
1ho sognonl polaiily nolwoik is a suL-nolwoik lo lho sognonlalion GIN io-
sponsiLlo foi Looy sognonlalion lhal plays a ciucial iolo ouiing Drosophila
oovolopnonl. 1ho foinalion of lho Looy sognonls onconpassos ¸ oiffoionl
gioups of gonos which aio aclivo ouiing oiffoionl slagos. Fiisl, infoinalion
on lho localion of lho anloiioi,posloiioi Looy axis of Drosophila is lakon up
ano a fiisl ciuoo oivision of lho Looy is oslaLlishoo Ly lho gap gonos. 1his
oivision is iofinoo lo lho ¡¸ Looy sognonls following lho palloin foinoo Ly
lho paii-iulo gonos. Finally, lho polaiily of lho Looy sognonls is oofinoo
ouo lo a palloin foinoo Ly lho sognonl polaiily nolwoik.
1ho sognonl polaiily nolwoik usos lho paii-iulo gono palloin as inpul
slinulus ano oslaLlishos an asynnoliic, slaLlo palloining foi lho piinci-
plo oulpuls, i.o., lho gono piooucl oisliiLulions of lho gonos wingless (WG),
hedgehog (HH), ano engrailed (EN) [1c/[. 1ho cuiionl knowloogo on lho
gono iogulalivo piocossos Lolwoon lho sognonl polaiily gonos is suLsunoo
Ly a GIN noool Ly von Dassow ol al. [1c/[, naoo up Ly a sol of ¡¸ oiffoi-
onlial oqualions ano onconpassing noaily ¸u fioo paianolois such as ialo
conslanls ano olhoi kinolic conslanls, cf. supplononlaiy infoinalion of
[1c/[ foi noool oolails. A skolch of lho sognonl polaiily GIN is shown in
Fig. ¸.S.
44 |urumeter Spuce L·p|orut|on íor |0 |ooe|: 45
4.4.2· Prob|em Formu|atIon
1his soclion ains al losling lho inpacl of nullioLjoclivizalion on paianoloi
spaco oxploialion of lho sognonl polaiily GIN noool of Drosophila. 1ho
consiooioo GIN is a gooo oxanplo nolwoik ouo lo ils Liological iolovanco
ano al lho sano lino Loing inloiosling foi noooling ouo lo ils sizo whilo io-
naining liaclaLlo foi paianoloi oslinalion. In conloxl of paianoloi spaco
oxploialion, paianoloi sollings iosulling in a palloining of lho Drosophila
Looy sognonls as known fion oxpoiinonlal sluoios aio lo Lo ioonlifioo. 1ho
laigol palloin is oofinoo Ly lho spalial oisliiLulion of lho gono piooucls of
¸ sognonl polaiily gonos EN, WG, ano HH which aio supposoo lo foin a
linoly slaLlo ano spalially holoiogonoous palloin. Sinco lhoio oxisls a sol
of oiffoionl paianoloi sollings iosulling in lho oosiioo palloin [1c/[, oxplo-
ialion ains al ioonlifying a iopiosonlalivo sol of filling paianoloi sollings,
i.o., a sol of paianoloi sollings lhal iosull in lho oosiioo laigol palloin
whilo Loing as oivoiso as possiLlo wilh iospocl lo lho paianoloi spaco. 1his
oxploialion lask is foinally oosciiLoo Ly lho following oxpiossion:
aignin
x∈X
{h(x)}.
Whoio x is a paianoloi solling in lho paianoloi spaco X ⊆ R
n
ano
h : X →R is a scoiing funclion noasuiing lho oovialion Lolwoon lho oosiioo
oulcono ano lho oulcono iosulling fion lho paianoloi solling x. An opli-
nal paianoloi solling x
opt
lhoiofoio has lho nininal scoio of h(x
opt
) = 0.
Insloao of consiooiing lho singlo-oLjoclivo lask, il nighl Lo aovanlagoous lo
ooconposo lho funclion h inlo a sol of funclions h(x) = (h
1
(x), . . . , h
m
(x)).
1his nullioLjoclivizalion is a sliaighlfoiwaio piocoouio foi lho givon op-
linizalion pioLlon: as nonlionoo Lofoio, h alioaoy ooponos on a sol of ¸
oiffoionl gonos (EN, WG, HH) ano foi oach of lhoso on · oiffoionl chaiac-
loiislics (palloin slaLilily, palloin nalch) allowing lo suLoivioo h in a sol
of up lo 6 oiffoionl oLjoclivos. 1ho aovanlago of such a ooconposilion is
anlicipaloo lo Lo lwofolo: fiisl, lho nullioLjoclivizalion polonlially aios lho
oplinizalion piocoss [1(, (1–(_, __, __, 3_[. Socono, in oxploialion sconaiios
ono is inloiosloo in a sol of oplinal solulions ialhoi lhan a singlo solulion
(as usually pioviooo Ly singlooLjoclivo nolhoos). 1hoiofoio iofoinulaling
46 Chupter 4 |ethoo: íor |ooe| Cu||orut|on. Ceneru| Con:|oerut|on:
lho lask as a nullioLjoclivo pioLlon coulo allow lo ioonlify a sol of oiffoionl
oplinal solulions wilhin a singlo iun ano lhoioLy nako a noio officionl uso
of lho availaLlo conpulalion lino. 1ho nullioLjoclivo pioLlon is foinally
oosciiLoo Ly Lq. ¸.·:
4.4.3· Approach
In lhis soclion fiisl lho usoo algoiilhns is oosciiLoo, followoo Ly lho pio-
posoo oLjoclivo funclions, onoing wilh a oosciiplion of lho inplononlalion
of lho GIN lhal is usoo lo gonoialo lho oala nocossaiy foi lho ovalualion
of lho oLjoclivos.
A|gorIthms
1o conliasl lho ianoon sanpling appioach usoo in [1c/[ ano lo aooioss
lho foinoi oplinizalion lasks (soo Lqs. ¸.¡ ano ¸.·) lho MO-CMA-LS is
usoo. A slighl vaiialion is inliooucoo lo lho MO-CMA-LS: insloao of
lho oxacl hypoivoluno inoicaloi [11c[, foi lho onviionnonlal soloclion slop
lho hypoivoluno is appioxinaloo using a nolhoo Lasoo on Monlo Cailo
sanpling, HypL [([. 1his chango is inliooucoo sinco lho conpulalion of lho
hypoivoluno is shown lo Lo =P-haio [1_[ ano lho faslosl known algoiilhn
has a iun lino conploxily of O
(
p
m
/2
)
[_[ (wilh p lho nunLoi of inoiviouals
ano m lho nunLoi of oLjoclivos). In consoquonco, conpulalion of lho oxacl
hypoivoluno inoicaloi is piaclically infoasiLlo alioaoy foi sollings wilh ¸
oLjoclivos ano aLoul ¸u inoiviouals—a sconaiio lhal has lo Lo consiooioo
hoio sinco noio lhan ¸ oLjoclivos aio usoo.
Db|ectIve FunctIon
As oiscussoo in lho supplononlaiy infoinalion of [1c/[, a singlo-oLjoclivo
funclion can Lo usoo foi lho oplinizalion of noool paianolois: il oncon-
passos olononls scoiing palloin nalch of lho gono piooucl oisliiLulions of
lho lhioo gonos EN, WG, HH as woll as lho slaLilily scoios foi lho sin-
ulaloo lino of lho palloin oofinoo Ly lho ¸ gonos. In olhoi woios, lhis
filnoss funclion is a woighloo sun of slaLilily noasuios ano palloin nalch
scoios—oLjoclivo conpononls lhal aio oxplainoo in oolail in lho following.
44 |urumeter Spuce L·p|orut|on íor |0 |ooe|: 47
1his conposilion of oiffoionl conpononls allows foi a sliaighlfoiwaio oo-
conposilion Ly consiooiing lho singlo conpononls as sopaialo oLjoclivos—a
ioulo lhal is followoo foi lho nullioLjoclivizalion appioach. In aooilion, an
oLjoclivo oxplicilly noasuiing lho oivoisily of lho paianoloi sollings in lho
paianoloi spaco is pioposoo. 1his is a plausiLlo aooilion sinco lho lask of
paianoloi oslinalion of lho consiooioo GIN oxplicilly onconpassos nax-
inizing lho oivoisily of lho founo oplinal paianoloi sollings wilh iospocl
lo lho paianoloi spaco.
Pattern 5corIng Following lho suggoslion of von Dassow ol al. [1c/[ (supplo-
nonlaiy infoinalion) lho foining palloin is ovalualoo Ly conpaiing lho
sinulalion oulpul lo a nask oofining lho laigol palloin p
tar
ent
= {on, off}
|T|
(wilh T Loing lho sol of colls foining lho consiooioo oonain ano |T| Loing
ils caioinalily), inoicaling which gonos aio aclivo in which coll. Hoio lho
lhioo gonos oi onlilios ent ∈ {EN, WG, HH} aio consiooioo. 1o assoss lho
nalch Lolwoon sinulaloo palloin ano laigol palloin lho sinulaloo oala is
oisciolizoo. Foi lhis oosciolizalion a lhiosholo of δ
t
=u.¡ is usoo: whonovoi
a conconlialion [c
i
] ≥ δ
t
(1 ≤ i ≤ |T|) lho coiiosponoing gono is consiooioo
lo Lo aclivo in coll i, iosulling in anolhoi nask p
sim
ent
= {on, off}
|T|
. 1ho
palloin scoio h
ent
lhon is a oisciolo funclion counling lho poi-coll oiffoionco
in lho sinulaloo palloin ano lho laigol palloin foi a gono. Il is givon Ly
lho following oqualion:
h
ent
(p
tar
ent
, p
sim
ent
) =

p
sim
ent,i
̸=p
tar
ent,i
1, wilh 1 ≤ i ≤ |T| . (¸.¸)
5tabI|Ity 5corIng 1o assoss lho slaLilily of lho iosulling palloins, a oiffoi-
onl appioach is choson lhan Ly von Dassow ol al. [1c/[; lhoy usoo a slioing
winoow on lho lino-couiso oala of lhoii sinulalions in oiooi lo oolocl os-
cillalions aonilling lhal lho oscillalion ooloclion was lhoii nain ioason foi
falso scoiing of palloins (poisonal connunicalion). Novoilholoss, lho nun-
Loi of falso oocisions was ialhoi snall. Hoio, a ciiloiion Lasoo on Fouiioi
analysis is usoo, lho spoclial onvolopo [__, 1cc[. 1ho spoclial onvolopo pio-
vioos a way lo nap lho vaiianco in a lino-soiios signal lo a sol of fioquoncy
inooxoo oscillaling conpononls (sinos ano cosinos). 1ho spoclial onvolopo
48 Chupter 4 |ethoo: íor |ooe| Cu||orut|on. Ceneru| Con:|oerut|on:
lhon givos a noasuio lo which piopoilion lho vaiianco in lho signal can Lo
alliiLuloo lo a coilain oscillaling conpononl. Hoio, lho inplononlalion of
lho spoclial onvolopo nolhoo pioposoo in [__[ is choson: 1ho lino soiios
oala X

t
of all colls wilh iospocl lo a singlo gono is consiooioo. Il is givon
as a naliix whoio lho conconlialions of lho colls aio oiooioo in iows ano
lho colunns iopiosonl lho lino couiso foi lho lino poinls t = 1, . . . , k. 1ho
oala is fiisl noan-conloioo ano naoo unil vaiianl. Using lho noinalizoo
oala X, lho fioquoncy oisciolizoo poiiooogian
ˆ
I
k
(ω) is appioxinaloo Ly:
ˆ
I
k

j
) =

1
k
[
k−1

t=0
x(t) oxp (−2πiω
j
t)
] [
k−1

t=0
x(t) oxp (−2πiω
j
t)
]

,
whoio lho fioquoncios ω
j
=
j
k
, j = 1, . . . ,

k
2

aio consiooioo, x(t) oonolos lho
conconlialions in all colls al lino t, i
2
= −1, ano ‘

’ oonolos lho conjugalo
liansposo. 1ho iosulling poiiooogian is snoolhoo using a slioing winoow
wilh iospocl lo lho fioquoncios:
ˆ
P
X

j
) =
1
4
ˆ
I
k

j−1
) +
1
2
ˆ
I
k

j
) +
1
4
ˆ
I
k

j+1
) .
1ho spoclial onvolopo
ˆ
λ(ω
j
) can lhon Lo oslinaloo Ly laking lho laigosl
oigonvaluos of
ˆ
P
X

j
) iloialing ovoi all fioquoncios ω
j
. Foi oolails on lho
ooiivalion soo [__, 1cc[.
Givon a noisy signal conlaining an oscillalion, lho spoclial onvolopo shows a
poak foi lho fioquoncios oxplaining lho nosl vaiianco in lho oiiginal signal.
Foi a signal lhal is flal apail fion lho oscillalion lho poak shoulo Lo naiiow
(cf. Fig. ¸ in Jiang ol al. [__[). Sinco lho sinulalion oala galhoioo Ly
nunoiical inlogialion of lho oiffoionlial oqualion noool is noiso-fioo Lul lho
sinulalions incluoo a liansionl pail whoio conconlialions vaiy sliongly, hoio
a slighlly oiffoionl appioach has lo Lo lakon in oiooi lo ioonlify oscillalions
in lho spoclial onvolopo. In a lypical spoclial onvolopo of lho sinulaloo oala
(soo Fig. ¸.¸), ono oLsoivos a Lulgo foi lho lowoi fioquoncios lhal is quasi-
nonolonically oocioasing wilh giowing fioquoncios. Now, a lino couiso is
iogaiooo as oscillaling as soon as lho onvolopo
ˆ
λ(ω) is golling laigoi Ly
al loasl δ
osc
=¡u

foi incioasing fioquoncios ω. 1ho oscillalion scoio h
osc
is
44 |urumeter Spuce L·p|orut|on íor |0 |ooe|: 49
FIgure µ.§ Spectru| enve|ope:
generuteo írom :|mu|ut|on outu
íor the :egment po|ur|ty C|N
mooe| ¯he :o||o ||ne :how: the
enve|ope íor u typ|cu| :tuo|e t|me
cour:e oí the gene hh wh||e the
ou:heo ||ne :how: the enve|ope
íor un o:c|||ut|ng t|me cour:e íor
the :ume gene
0
10⁰ 10¹ 10²
200
400
600
800
s
p
e
c
t
r
a
l

e
n
v
e
l
o
p
e
ˆλ
frequency ω
conpuloo using Lq. ¸.6. Il has lo Lo nininizoo ano has ils oplinun al
h
osc
=u. 1ho usoo δ
osc
has Loon ooloininoo oxpoiinonlally ano lho ciiloiion
ilsolf was losloo on a sol of sanplo lino couisos fion lho sognonl polaiily
GIN noool.
h
osc
(
ˆ
λ) = nax
j=2,...,⌊
k
2

{

nin
{
ˆ
λ(ω
j−1
) −
ˆ
λ(ω
j
) +δ
osc
, 0
}

}
. (¸.6)
0IversIty 5corIng In oiooi lo assoss oocision spaco oivoisily lho following cii-
loiion is usoo: a ianking on a givon sol of paianoloi voclois
{
x
1
, . . . , x
k
}

X is ooloininoo whoio X ⊆ R
n
is lho n oinonsional paianoloi spaco. 1ho
ianking is Luilo using a Monlo Cailo piocoouio: sanplo paianoloi voclois
{
s
1
, . . . , s
j
}
∈ X aio unifoinly oiawn ano foi oach of lho sanploo voc-
lois s
h
(h = 1, . . . , j) ils Lucliooan oislanco lo all paianoloi voclois x
i
(i = 1, . . . , k) is conpuloo. 1hon, foi oach of lho j sanplo voclois a iank-
ing on lho x
i
is gonoialoo whoio lho Losl iank r = 1 is assignoo lo lho x
i
wilh lho nininal oislanco lo s
h
. 1ho woisl iank r = k is assignoo lo lho
paianoloi vocloi x
i
wilh lho naxinal Lucliooan oislanco lo s
h
. Afloi all
sanplo iankings havo Loon Luill lho final iankings aio ooloininoo: foi oach
vocloi x
i
all ils j iankings aio sunnoo up ano lho final ianking is givon Ly
lho asconoing oiooi on lho sunnoo ianks foi ovoiy x
i
.
Foi lho final ianking j=¸S¡u sanplos aio oiawn—following Hooffoing’s in-
oqualily [(_[ using ¸S¡u sanplos iosulls in a pioLaLilily of u.¸u of iosulling
in an oiioi in covoiago conpulalion of err ≤u.¡·¸. Foi lhis calculalion,
lho oxpocloo oislanco of lwo paianoloi sollings in lho paianoloi spaco
X = [u, ¡]
¸¸
is appioxinaloo wilh lho woisl-caso oislanco of ¸.
50 Chupter 4 |ethoo: íor |ooe| Cu||orut|on. Ceneru| Con:|oerut|on:
FIgure µ.±o Schemut|c v|ew on
the :|mu|uteo ce|| oomu|n :how-
|ng the pre-puttern u:eo u: |n|t|u|
cono|t|on to the numer|cu| |nte-
grut|on. |n ce||: hutcheo w|th hor-
|zontu| ||ne: wC |eve|: uno tho:e
oí the encooeo prote|n ure :et to
1 wh||e |n ce||: hutcheo w|th vert|-
cu| ||ne: f| |eve|: uno tho:e oí the
encooeo prote|n ure :et to 1 |or
u|| other gene: uno ce||: the |n|t|u|
concentrut|on: ure :et to c
Mode| Imp|ementatIon
1ho noool oosciiLoo in lho supplononlaiy infoinalion of von Dassow ol al.
[1c/[ is io-inplononloo in MA1LAL
¯
. In agioononl wilh lho piosonloo
noool, as sinulaloo oonain · iows of S hoxagonal colls (soo Fig. ¸.¡u) aio
usoo. 1ho colls aio connocloo wilh oach olhoi via aojaconl coll facos allowing
foi coll-coll connunicalion Ly oxchango of gono piooucls. Liko von Dassow
ol al. [1c/[, poiiooic Lounoaiy conoilions aio usoo foi lho sinulaloo oonain.
Sinulalions of lho GIN aio conoucloo Ly nunoiical inlogialion of lho ¡¸
oiffoionlial oqualions conposing lho noool. Foi lho nunoiical inlogialion
of lho iosulling syslon lho inplicil-oxplicil (IMLX) schono consisling of
a nooifioo Ciank-Nicolson schono ano an Aoan-Lashfoio schono [_1[ is
usoo wilh a lino slop ∆
t
=u.· nin ano a spalial oisciolizalion in collulai
iosolulion. As sinulaloo lino inloival a winoow of ¡uuu nin is choson in
conplianco wilh lho woik Ly von Dassow ol al. [1c/[.
As inilial conoilions foi lho nunoiical sinulalion lho sano conoilions as
pioposoo Ly von Dassow ol al. [1c/[ aio usoo: all conconlialions foi all
gonos aio sol lo u oxcopl foi lho INA ano lho lhoioLy oncoooo pioloin of
EN in lho colls of lho ·
no
ano 6
lh
colunn as woll as lhoso of WG in lho
colls of lho ¡
sl
ano ¸
lh
colunn. In lhoso colls lho conconlialions aio sol
lo ¡. Aooilionally, lho Lasal oxpiossion lovol foi lho INA of CID in Lq. h
(supplononlaiy infoinalion of [1c/[) is sol lo u.¸. 1ho iosulling pio-palloin
foi EN ano WG is shown in Fig. ¸.¡u.
44 |urumeter Spuce L·p|orut|on íor |0 |ooe|: 51
Tab|e µ.z. 0etu||: íor the hypervo|ume cu|cu|ut|on:. íor euch oí the con:|oereo |0-C|/-LS
:etup: (u:|ng írom . to / oo¦ect|ve:) the reíerence po|nt: uno the oroer|ng oí the oo¦ect|ve:
ure g|ven |ere ‘uggr :core’ |: un uggreguteo :core íor :tuo|||ty uno puttern mutch íor u g|ven
:et oí gene:, ‘:tuo :core’ |: the :tuo|||ty :core íor u :|ng|e gene, ‘puttern :core’ |: the puttern
mutch :core íor u :|ng|e gene, uno ‘o|v :core’ |: the o|ver:|ty :core íor u :et oí purumeter
vector:
0pt|m|zer |eíerence po|nt 0o¦ect|ve oroer
C|/-LS – uggr :core over u|| gene:
|0 . oo¦ (1.6c, 1_) uggr :core over u|| gene:, o|v :core
|0 _ oo¦ ((.c, (.c, (.c) uggr :core :epurute|y íor f|, wC, ||
|0 ( oo¦ ((.c, (.c, (.c, 1_)
uggr :core :epurute|y íor f|, wC, ||, o|v
:core
|0 6 oo¦ ((cc, (cc, (cc, .c, .c, .c)
:tuo :core íor f|, wC, ||, puttern :core
íor f|, wC, ||
|0 ) oo¦ ((cc, (cc, (cc, .c, .c, .c, 1_)
:tuo :core íor f|, wC, ||, puttern :core
íor f|, wC, ||, o|v :core
4.4.4· 5Imu|atIons and Resu|ts
In lhis soclion fiisl lho poifoinanco noliics usoo foi ovalualion aio oo-
sciiLoo, followoo Ly a oosciiplion of lho sinulalion solup, ano finally pio-
sonling iosulls foi lho sinulalion iuns.
Performance MetrIcs
1ho CMA-LS ano MO-CMA-LS appioachos aio conpaioo lo ianoon san-
pling (as iopoiloo in von Dassow ol al. [1c/[). 1ho conpaiison is oono wilh
iospocl lo · oiffoionl poifoinanco inoicalois: (i) lho noan nunLoi of ois-
lincl oplina founo wilhin ¸uuu ovalualions, (ii) lho noan invoiso covoiago
of lho paianoloi spaco achiovoo wilhin ¸uuu ovalualions. Whoioas lho fiisl
noliic is sliaighlfoiwaio, a Liiof oxplanalion how lo assos lho invoiso cov-
oiago is givon: foi a sol of oplinal paianoloi voclois x
i
∈ {x
1
, . . . , x
k
} lho
invoiso covoiago is iopiosonloo Ly lho oxpocloo nininal oislanco of any of
lho voclois x
i
lo any ianoon vocloi in lho paianoloi spaco X. 1his ox-
pocloo valuo is appioxinaloo using Monlo Cailo sanpling. A sol of sanplo
voclois s
h
∈ {s
1
, . . . , s
j
} is gonoialoo ano foi oach of lho s
h
lho nininal
Lucliooan oislanco lo lho x
i
is calculaloo. 1ho avoiago of lhoso j nininal
52 Chupter 4 |ethoo: íor |ooe| Cu||orut|on. Ceneru| Con:|oerut|on:
oislancos is usoo as appioxinalion of lho invoiso covoiago. ¸S¡uuu san-
plos aio oiawn foi lhis appioxinalion which using Hoofoing’s inoqualily
[(_[ iosulls in a pioLaLilily of u.¸u of iosulling in an appioxinalion oiioi
err ≤u.u¡·¸. In Hoofoing’s inoqualily, lho oxpocloo oislanco of voclois
in lho paianoloi spaco X = [u, ¡]
¸¸
is appioxinaloo wilh ils woisl-caso
oislanco of ¸.
5Imu|atIon 5etup
Whilo foi ianoon sanpling lho iopoiloo valuo of in avoiago ¡ hil poi ·uu
sanplos in ioonlifying an oplinal paianoloi solling is lakon, lho valuos
foi lho CMA-LS ano lho oiffoionl MO-CMA-LS aio ooloininoo Ly sinu-
lalion. Foi lho singlo-oLjoclivo CMA-LS lho slanoaio paianolois oxcopl
lho following aio usoo: naxinal nunLoi of ovalualions of ¸uuu, populalion
sizo of ¸u, laigol filnoss of ¡u
-S
. Aooilionally, a ioslail slialogy is usoo:
afloi loininalion ano as long as lhoio aio ovalualions lofl, lho CMA-LS
is ioslailoo wilh a now inilial vocloi ano lho sano paianolois. Foi lho
nullioLjoclivo MO-CMA-LS ¸ oiffoionl sols of oLjoclivo funclions aio usoo:
(i) lho oivoisily funclion (soo Soclion ¸.¸.¸) ano lho oLjoclivo funclion foi
lho singlo-oLjoclivo caso, aggiogaling slaLilily scoios (soo Soclion ¸.¸.¸) ano
palloin scoios (soo Soclion ¸.¸.¸) foi all gonos; (ii) an aggiogalion of slaLil-
ily scoio ano palloin scoio foi oach gono iosulling in ¸ oLjoclivo funclions
(iii) lho ¸ afoio nonlionoo oLjoclivo funclions plus lho oivoisily funclion;
(iv) lho slaLilily scoio ano palloin scoio sopaialoly foi oach gono iosulling
in 6 oLjoclivo funclions; (v) lho 6 afoio nonlionoo oLjoclivo funclions plus
lho oivoisily funclion. Foi lho MO-CMA-LS a populalion sizo of ¡uu is usoo
ano ¸uuu ovalualions aio poi iun. Foi lho HypL piocoouio ¡uuuu sanplos
ano iofoionco poinls as shown in 1aL. ¸.· aio usoo. Foi oach CMA-LS ano
MO-CMA-LS solup ·¡ iuns aio oono wilh oach iun laking appioxinaloly
a oay on a lwo chip oual coio AMD Oploion ·.6GHz 6¸-Lil nachino wilh
SGB IAM using MA1LAL
¯
¸.6 (I·uuSa).
Resu|ts
1ho iopoiloo hil ialo foi ianoon sanpling iosulls on avoiago in ¡¸ opli-
nal paianoloi sollings founo in ¸uuu ovalualions, lho CMA-LS founo on
44 |urumeter Spuce L·p|orut|on íor |0 |ooe|: 53
Tab|e µ._. |e:u|t: íor :ump||ng, C|/-LS, uno |0-C|/-LS run:. íor u|| con:|oereo como|-
nut|on: oí oo¦ect|ve: the meun numoer oí íouno opt|mu (∅(r opt)) uno the meun |nver:e
coveruge vu|ue: (∅(|nv cov)) ure g|ven, e·cept íor the :ump||ng upprouch. íor :ump||ng on|y
the meun numoer oí íouno opt|mu| purumeter :ett|ng: |: g|ven wh|ch |: cu|cu|uteo ou:eo on
|níormut|on g|ven |n ¦1c/¦ ln uoo|t|on, íor euch con:|oereo :cenur|o the numoer oí :|gn|ficunt|y
oetter (ío||ow|ng Conover-lnmun) :cenur|o: ure g|ven íor the coveruge vu|ue: (run| cov) uno
the numoer: oí íouno opt|mu (run| opt) u: we|| u: the coveruge vu|ue: (cov)
S
u
m
p
|
|
n
g
C
|
/
-
L
S
|
0
.
o
o
¦

|
0
_
o
o
¦

|
0
(
o
o
¦

|
0
6
o
o
¦

|
0
)
o
o
¦

∅(+ opt) 1_ 6_). .3___ .__). .__31 .3___ .661_
∅(|nv cov) – c_6_( c_(.. c_(_6 c_((. c_(_1 c_(_1
run| opt _ 6 c c c c c
run| cov – _ c c c c c
avoiago aLoul 6 oplinal paianoloi sollings in ¸uuu ovalualions, ano lho
MO-CMA-LS founo on avoiago noio lhan ·¸ oiffoionl oplinal paianoloi
sollings foi any of lho consiooioo sol of oLjoclivos (soo 1aL. ¸.¸). 1ho facl
lhal ianoon sanpling piooucos Lolloi iosulls lhan lho CMA-LS is suipiis-
ing on lho fiisl glanco Lul has lo Lo iolalivizoo: lho consiooioo paianoloi
oplinizalion lask is conpaiaLly oasy which is oocunonloo Ly lho facl lhal
ianoon sanpling is lhal succossful. Foi lho CMA-LS lhis facl iosulls in
a pioLlon sinco lho oplinizalion piocoss woulo nooo lo convoigo wilhin ¸
gonoialions in oiooi lo koop up wilh ianoon sanpling—ianoon sanpling
ioonlifios an oplinun ovoiy ·uu sanplos which conpaios lo ¸ gonoialion
wilh ¸u ovalualions poi gonoialion foi lho CMA-LS. 1o oononslialo ils full
polonlial, lho CMA-LS woulo nooo a noio oifficull lask. Novoilholoss, lho
MO-CMA-LS in avoiago founo noio lhan ·¸ oplinal paianoloi sollings
cloaily inpioving lho iosulls of Lolh, CMA-LS ano ianoon sanpling. 1his
can Lo soon as sliong inoicaloi foi lho offoclivonoss of lho nullioLjocliviza-
lion appioach ano lho foasiLilily of applying ovolulionaiy algoiilhns liko
lho MO-CMA-LS lo lho consiooioo oplinizalion lask in lho fiisl placo. 1ho
supoiioiily of lho MO-CMA-LS is oocunonloo Ly lho invoiso covoiago noa-
suio as woll: all losloo MO-CMA-LS vaiianls inpiovo lho invoiso covoiago
conpaioo lo lho CMA-LS Ly aLoul ¸/ (soo 1aL. ¸.¸). 1hoso iosulls aio
54 Chupter 4 |ethoo: íor |ooe| Cu||orut|on. Ceneru| Con:|oerut|on:
losloo foi slalislical significanco, fiisl using lho Kiuskal-Wallis losl [13[ al
a significanco lovol of α =u.u¸. Il was possiLlo lo iojocl lho H
0
hypolhosis
lhal lhoio is no significanl oiffoionco in nooian wilh iospocl lo nunLoi of
founo oplina ano covoiago Lolwoon lho nullioLjoclivo sconaiios, lho singlo
oLjoclivo CMA-LS ano ianoon sanpling. 1hoioafloi, foi all paiis of algo-
iilhns lho oiffoionco in lho nunLoi of founo oplina ano covoiago valuos
is conpaioo using lho Conovoi-Innan piocoouio [13[ wilh lho sano α lovol
as in lho Kiuskal-Wallis losl. In iosull lho slalislical losling shows lhal
lho nullioLjoclivizalion slialogios aio significanlly Lolloi lhan Lolh, singlo
oLjoclivo CMA-LS ano ianoon sanpling, ianoon sanpling is significanlly
Lolloi lhan lho singlo oLjoclivo CMA-LS, ano lhoio is no significanl oiffoi-
onco Lolwoon lho oiffoionl nullioLjoclivo sconaiios. Suipiising aLoul lhis
iosull is lhal lhoio is no cloai oiffoionco Lolwoon lho oiffoionl nullioLjoc-
livizalion solups. Al loasl Lolwoon lhoso nullioLjoclivo vaiianls using lho
oivoisily ciiloiion ano lhoso only using slaLilily ano palloin nalch a oif-
foionco woulo havo Loon oxpocloo: whilo slaLilily ano palloin nalch oofino
lho oiiginal ciiloiia foi lho oplinizalion, oocision spaco oivoisily is con-
plololy uniolaloo ano incluoing il in lho oplinizalion piocoss shoulo iosull
in a iosliucluiing of lho filnoss lanoscapo. Il woulo havo Loon oxpocloo
lhal lhis iosliucluiing causos an offocl visiLlo in lho iosulls. 1ho facl lhal
lho iosulls oo nol ioflocl lhis in pail nighl again slon fion lho facl lhal
lho paianoloi oplinizalion lask foi lho consiooioo nolwoik is conpaiaLly
oasy Lul as woll coulo Lo an inhoionl piopoily of lho consiooioo GIN oi
lho consiooioo laigol palloin.
4.5· Automated QuantIficatIon of 5ImI|arIty between Qua|ItatIve
Patterns
Whilo in lho piovious soclion lho palloin iocognilion was oono using nasks,
lhis soclion pioposos a noio floxiLlo appioach foi palloin iocognilion ano
sinilaiily quanlificalion Lolwoon sinulalions ano qualilalivo laigol palloin.
4: /utomuteo (uunt|ficut|on oí S|m||ur|ty oetween (uu||tut|ve |uttern: 55
4.5.1 · 5ImI|arIty Measure
Lasoo on lho sinulalion fianowoik oosciiLoo in Soclion ¸.¡.¡ lho nolion of
a laigol palloin nooos lo Lo foinalizoo ano palloin conpononls nooo lo Lo
ioonlifioo in a givon picluio in oiooi lo quanlify palloin sinilaiily.
Qualilalivo spalial gono oxpiossion palloins liko lho ono shown in Fig. ¸.¡¡A
ano Fig. ¸.¡¡L can Lo ooconposoo inlo a nunLoi of Lasic goonoliic shapos
liko ioclanglos, oisks ano liianglos (Fig. ¸.¡¡C). Foi sako of sinplicily, in
lho following lho focus of lhis soclion is iosliicloo lo a singlo class of shapos,
nanoly ioclangulai palloin conpononls. Slill, lho sano appioach can Lo
usoo foi olhoi shapos oi conLinalions of shapos as woll. 1o allow foi ioli-
aLlo iocognilion of sliipos il is nocossaiy lo chooso a iopiosonlalion lhal is
invaiianl againsl isoliopic changos in sizo, lianslalion ano iolalion. In lhis
way, o.g., whon oxanining sliipo foinalion in Diosophila nolanogasloi [6c[,
foinoo sliipos alignoo wilh lho wiong Looy axis oi oovialing slighlly in sizo
can Lo oolocloo; solulions lhal show pionising Lohavioi which olhoiwiso
coulo nol Lo ioonlifioo. Such an invaiianl oosciiplion can Lo achiovoo Ly
oosciiLing a sliipo Ly a ioclanglo onconpassing lho colls lho sliipo consisls
of. 1o allow foi invaiianco againsl isoliopic changos in sizo, insloao of sloi-
ing aLsolulo valuos foi Lioaolh, longlh, ano ooplh, lho ialio Lolwoon lhoso
lhioo axos is sloioo; a valuo slaying conslanl foi isoliopic liansfoinalions.
Aooilionally, sinco il is nol assunoo lhal gono oxpiossion oonains occui al
a spocific localion in lho lissuo Lul ialhoi il is analyzoo whoio in lho lissuo
an oxpiossion oonain has foinoo, lho oosciiplion is invaiianl againsl lians-
lalions of oonains. Lasl, sinco lho oosciiplion of a ioclanglo Ly lho ialio
Lolwoon ils axos ignoios lho oiionlalion of lho ioclanglo, lho oosciiplion is
invaiianl againsl iolalions. Aooilionally, Ly consliaining lho allowoo sizos,
iocognilion of ailifacls of snall sizo Lul coiiocl piopoilions is avoiooo.
In oiooi lo ioonlify a sliipo in lho sinulalion oulpul, a lhioo-slop piocoss
is usoo:
¡. Ioonlificalion of connocloo colls on lho sano oxpiossion lovol, laloi on
calloo connocloo conpononl (CC). Following lho inluilion lhal oxpios-
56 Chupter 4 |ethoo: íor |ooe| Cu||orut|on. Ceneru| Con:|oerut|on:
A
CLV3
B
FM
IM
IM
FM FM
FM
WUS
Stem
OC
SCD
C
FIgure µ.±±. L·pre::|on puttern: oí C|v uno wJS |n (/) Cup:e||u ruoe||u uno (3) / rho!|ono
uno u :|etch oí the re:u|t|ng S/| puttern|ng oer|veo írom the:e |muge: (C) l|. |nflore:cence
mer|:tem ||. floru| mer|:tem Scu|e · _c µm (|N/ |n :|tu hyor|o|zut|on: prov|oeo oy |u|í
|u||er, l||S, ¯he Un|ver:|ty oí Lo|nourgh)
sion oonains foinulaloo in lho laigol palloins aio conposoo of a con-
linuous coll iogion, CCs aio ooonoo a gooo iopiosonlalion foi oonains.
·. Calculalion of lho piincipal axis foi lho ioonlifioo CCs.
¸. Filling of lho laigol shapo onlo lho CCs.
Following lhis schono (soo. Fig. ¸.¡· foi a schonalic ovoiviow on lho pio-
coss), fiisl lho colls of lho noool syslon aio assignoo lo oisciolo classos
accoioing lo lhoii oxpiossion piofilo. Using lhiosholo valuos, lho conlinu-
ous gono piooucl conconlialions (soo Fig. ¸.¡·A) oLlainoo fion lho lissuo
noool aio oisciolizoo (soo socono pail of Fig. ¸.¡·). Afloiwaios lho sols of
connocloo colls assignoo lo lho sano oxpiossion class aio ooloininoo ano
conLinoo lo a CC (soo oaik colls in Fig. ¸.¡·L). Foi all CCs assignoo lo
gonos ano oxpiossion lovols piosonl in lho laigol palloin, lhoii sinilaiily
in shapo is noasuioo. Fiisl, lho CC’s piincipal axos (soo Llack aiiows
Fig. ¸.¡·L) aio ooloininoo Ly laking lho fiisl oigonvoclois calculaloo using
a piincipal conpononl analysis. Slailing fion a ioclanglo alignoo lo lho
piincipal axos of lho CC ano onconpassing lho wholo lissuo (soo ouloinosl
ioclanglo in Fig. ¸.¡·C), a gioooy houiislic iloialivoly shiinking lho iocl-
anglo is applioo. Fiisl, slicos of lho lissuo aio ionovoo foi which all colls
aio nol assignoo lo lho CC. Whon all lhoso slicos aio ionovoo, in a socono
slop slicos aio ionovoo foi which lho oiffoionco Lolwoon colls nol assignoo
lo lho CC insioo lho ioclanglo ano colls assignoo lo lho CC oulsioo lho
4: /utomuteo (uunt|ficut|on oí S|m||ur|ty oetween (uu||tut|ve |uttern: 57
FIgure µ.±z / :chemut|c
overv|ew on the |oent|ficut|on
uno quunt|ficut|on proce:: oí the
turget puttern íormeo oy ou:|c
geometr|c :hupe: |rom |eſt
to r|ght, (/) the o|:tr|out|on oí
gene proouct concentrut|on: over
the :y:tem, (3) the oeterm|neo
CC uno |t: pr|nc|pu| u·e:, (C)
rectung|e: con:|oereo our|ng
puttern oetect|on, uno (0) the
re:u|t|ng :core (:ee Lq (/) |:
:hown ln (C), the outermo:t rect-
ung|e repre:ent: the rectung|e
con:|oereo when :turt|ng the
:hr|n|uge proce:: uno the |nner
two rectung|e: v|:uu||ze the |u:t
:tep oí the :hr|n|uge proce::
0ur|ng th|: |u:t :tep, the three
ce||: thut ure |ocuteo |n the o|gger
oí the two rectung|e: on|y, ure
om|tteo
A
C D
B
Rectangle Size: 11 cells
Inside: 0 wrong cells
Outside: 2 wrong cells
Resulting Score: 0.18
ioclanglo is golling Lolloi, i.o., in lho consiooioo slico lho nunLoi of wiong
classifioo colls is laigoi lhan lho nunLoi of iighl classifioo colls. Using lhis
piocoouio lho ioclanglo is shiunkon unlil no fuilhoi inpiovononl can Lo
achiovoo (soo Fig. ¸.¡·C). Hoio, il has lo Lo nonlionoo lhal lho iosulling
ioclanglo nol nocossaiily iopiosonls lho Losl ioclanglo wilh iospocl lo lho
nonlionoo coll ialio Lul piovioos a ioasonaLly gooo appioxinalion. Sinco
lho syslons consiooioo hoio only pioouco sliipos paiallol lo lho axis of lho
ioclangulai lissuo, lho alignnonl slop can Lo onilloo.
Afloi ioonlifying lho ioclanglo conlaining lho CC, il is chockoo if lho ioclan-
glo aohoios lo lho piincipal axis ialio ano if longlh ano Lioaolh aio wilhin
lho oofinoo inloivals. If yos, lho scaloo oiffoionco g(S
tis
) Lolwoon colls coi-
ioclly classifioo Ly lho ioclanglo ano lhoso wiongly classifioo is usoo lo scoio
58 Chupter 4 |ethoo: íor |ooe| Cu||orut|on. Ceneru| Con:|oerut|on:
lho sinilaiily Lolwoon lho palloin foinoo foi paianoloi sol x ano lho laigol
palloin. 1ho sinilaiily scoio h
sim
(x) is givon Ly:
h
sim
(x) =



1 −g(S
tis
) if g(S
tis
) ≥ 0,
1 olso.
(¸.¸)
whoio,
g(S
tis
) =

i∈S
rec
I
S
CC
(i) −
(

i∈S
rec
I
S
C
CC
(i) +

i∈S
C
rec
I
S
CC
(i)
)
|S
rec
|
Hoio, lho sol S
tis
oonolos all colls in lho noool, S
rec
⊆ S
tis
iofois lo all colls
wilhin lho filloo ioclanglo (soo Fig. ¸.¡·), S
CC
⊆ S
tis
iofois lo all colls in
lho consiooioo CC. S
C
rec
ano S
C
CC
oonolo lho conplononls of S
rec
ano S
CC
wilh iospocl lo S
tis
. 1ho inoicaloi funclion I
S
is oofinoo as follows:
I
S
(i) =



1 if i ∈ S,
0 olso.
4.5.2· va|IdatIon of Proposed Approach
In oiooi lo valioalo lho pioposoo palloin ioonlificalion nolhoo ano sini-
laiily noasuio, lhoy aio inlogialoo inlo lho CMA-LS foi noool paianoloi
oplinizalion using Lq. ¸.¸ as oLjoclivo which is oxlonooo Ly Lq. ¸.¸. 1ho
iosulling filnoss funclion is:
f(x) =








i∈gp
(
nax(δ
t
−∆
s
i
, 0) + ∆
t
i
)
+f
sim
(x) +
D
c
1
D
c
2
if
D
c
1
D
c
2
< δ
D
,

i∈gp
(
nax(δ
t
−∆
s
i
, 0) + ∆
t
i
)
+f
sim
(x) olso.
(¸.S)
4: /utomuteo (uunt|ficut|on oí S|m||ur|ty oetween (uu||tut|ve |uttern: 59
Test 5ystems
1o ovalualo lho pioposoo appioach, lwo ID syslons which aio known lo Lo
aLlo lo foin sliipos [_c, /.[ aio usoo. Duiing lho paianoloi oplinizalion
piocoss, lho Lolo paianolois woio consiooioo.
¡. An aclivaloi (a soo Lq. ¸.¸) inhiLiloi (h soo Lq. ¸.¡u) syslon in a lwo
oinonsional plano conpiisoo of ¡uuסu colls wilh isoliopic oiffusion.
1ho plano is inilializoo wilh ianoon slailing gono piooucl conconlialion
lovols gp
i
∈ [u.u, u.¡]:
∂a
∂t

a
a
2
(1 +κ
a
a
2
)h
−µ
a
a +σ
a
+ D
a
∆a (¸.¸)
∂h
∂h

h
a
2
−µ
h
h +σ
h
+ D
h
∆h (¸.¡u)
Hoio, ∆ is lho Laplaco opoialoi, D
i
is lho oiffusion ialo of gono piooucl
i, σ
i
is a Laso oxpiossion of gono i, µ
i
is lho oogiaoalion ialo foi gono
piooucl i, κ is a saluialion conslanl ano ρ a cioss-ioaclion coofficionl
[61[.
·. A ID syslon consisling of lwo inooponoonl aclivaloi (a
1
, a
2
) inhiLiloi
(h
1
, h
2
) syslons liko lho ono oosciiLoo Ly Lqs. ¸.¸ ano ¸.¡u in a lwo oi-
nonsional plano conpiisoo of ¸u׸u colls wilh anisoliopic oiffusion—ono
of lho inhiLilois oiffusos lon linos slowoi in y oiioclion lhan in x oiioc-
lion ano lho olhoi inhiLiloi oiffusos lon linos slowoi in x oiioclion lhan
in y oiioclion. Aooilionally, lho syslon usos an offocloi gono v [_/[ oo-
ponoing on Lolh aclivalois (a
1
, a
2
). Il is givon Ly lho following Lq. ¸.¡¡:
˙ v =
1
τ
u(σv +ρa
1
+ρa
2
) −µ
v
v (¸.¡¡)
u(x) =
1
2
(
1 +
x

1 +x
2
)
Hoio, τ oonolos lho invoiso naxinal ialo of gono v, µ
v
is lho oogiaoalion
ialo of v ano u(x) is a signoio funclion noooling lho swilch Lohavioi of
lho iosponso gono. 1ho aclivaloi ano inhiLiloi gono piooucl conconlia-
lions foi lhis syslon aio inilializoo wilh a linoai giaoionl gp
i
∈ [u.u, u.¡],
foi lho fiisl of lho lwo inooponoonl syslons lho giaoionl is oiiocloo along
60 Chupter 4 |ethoo: íor |ooe| Cu||orut|on. Ceneru| Con:|oerut|on:
Tab|e µ.µ. Str|pe oe:cr|o|ng purumeter:
|urumeter vu|ue
3reuoth lntervu| :pun _-1_ ce||:
Length lntervu| :pun _c¹-1cc¹ oí one :put|u| o|men:|on
Con:|oereo L·pre::|on Cene uct|vutor
Con:|oereo L·pre::|on Leve|
e·pre::|on >3c¹ oí the m|n|mum uo¦u:teo
mu·|mu| e·pre::|on uſter :|mu|ut|on
lho x axis wilh ils naxinun on lho lofl Loiooi ano foi lho socono syslon
in y oiioclion wilh ils naxinun on lho lop Loiooi. 1ho inilial offocloi
gono piooucl conconlialions aio sol lo zoio. Foi Lq. ¸.¡¡, lho following
fixoo paianoloi sollings woio usoo: τ =·u, σ =u, ρ =¡u, µ
v
=u.¡.
Resu|ts
Foi Lolh losl syslons a sol of lwolvo sopaialo oplinizalion iuns is con-
oucloo. Lach of lhoso iuns losloo ¡uuu paianoloi voclois ano consunoo
appioxinaloly ¸uh of conpulalion lino on ono coio of a lwo chip oual coio
AMD Oploion ·.6GHz 6¸-Lil nachino wilh SGB IAM. Duiing lho paian-
oloi oplinizalion piocoss, lho Lolo paianolois in Lqs. ¸.¸ ano ¸.¡u woio
consiooioo. All iuns nanagoo lo ioonlify a sliipo palloin nalching lho iop-
iosonlalion givon in 1aL. ¸.¸ ano lhoiofoio iosulling in a filnoss closo lo zoio.
Foi lho fiisl syslon, lho laigol palloin consisloo of ono sliipo foinoo Ly
lho aclivaloi gono whoioas foi lho socono syslon oach of lho inooponoonl
aclivaloi gonos hao lo foin a sliipo. Sinco lho socono syslon is oosignoo
in such a way lhal ono of lho aclivaloi inhiLiloi paiis can foin voilical
sliipos whilo lho olhoi can foin hoiizonlal sliipos, lho offocloi gono shows
a cioss-liko palloin oi if lho sliipos aio localoo on lho Loioois of lho coll
plano, an ’L’-shapoo palloin. Sinco lho offocloi gono v ooponos on Lolh a
1
ano a
2
, in lho iogion whoio Lolh conconlialions aio high lho cioss oi ’L’ can
oogonoialo lo a oianono oi liiangulai-shapoo fiaclion of a oianono. 1ho
iosulling palloins foi ono paianoloi vocloi foi oach losl syslon aio shown
in Fig. ¸.¡¸ ano Fig. ¸.¡¸. Allhough lho paianoloi oplinizalion piocoss
founo appiopiialo paianoloi voclois foi Lolh syslons in alnosl all iuns,
nono of lho iuns convoigoo lo lho lhooiolical oplinun of zoio (noan filnoss
4: /utomuteo (uunt|ficut|on oí S|m||ur|ty oetween (uu||tut|ve |uttern: 61
A B
FIgure µ.±_. |or the fir:t te:t :y:tem ure :hown, /. gene proouct concentrut|on o|:tr|out|on
ootu|neo our|ng :|mu|ut|on, 3. the :tr|pe thut wu: |oent|fieo |n (/) ln the p|cture, ||ght co|or:
repre:ent |ow gene proouct concentrut|on: uno our| co|or: repre:ent h|gh concentrut|on:
FIgure µ.±µ Cene proouct concentrut|on ootu|neo our-
|ng :|mu|ut|on: íor the :econo :y:tem ln the p|cture,
||ght co|or: repre:ent |ow gene proouct concentrut|on:
uno our| co|or: repre:ent h|gh concentrut|on:
ovoi all iuns u.¡S foi syslon (¡) ano u.¸6¸ foi syslon (·) wilh a slanoaio
oovialion of u.·¸ foi syslon (¡) ano u.¡6 foi syslon (·)). 1ho facl lhal
nono of lho iuns convoigoo lo zoio iosulls fion a ponally foi nol ioaching
a significanco lhiosholo lovol of δ
t
=u.¸ in Lq. ¸.S. Sinco lhis lhiosholo was
only inliooucoo lo nako suio lhal lho oLsoivoo gono piooucl conconlialion
oiffoionco is ouo lo lho oynanics ano ooos nol slon fion nunoiical insla-
Lililios in lho inlogialion piocoss, lho lhiosholo can Lo lowoioo in fuluio
filnoss funclions. 1hoiofoio in offocl, lho palloin oosciiplion ano sinilaiily
scoiing woikoo ioasonaLly woll. An oxonplaiy lino couiso of lho ovolulion
62 Chupter 4 |ethoo: íor |ooe| Cu||orut|on. Ceneru| Con:|oerut|on:
FIgure µ.±_ ¯|me cour:e outu
uoout the opt|m|zut|on proce::
íor two e·emp|ury run:, one íor
:y:tem (1) uno one íor :y:tem (.),
:how|ng u c|eur treno towuro:
oetter ruteo purumeter vector:
our|ng the m|n|m|zut|on proce::
||otteo ure the meun fitne::
vu|ue: íor the :e|ecteo off:pr|ng
purumeter vector: generuteo
our|ng euch C|/-LS |terut|on
wor:en|ng |n fitne:: cun occur
:|nce no e||t|:t :trutegy |: u:eo
Objective Value Evolution 1st System
Objective Value Evolution 2nd System
10
1
10
-1
10
0
10
2
10
-2
0 200 400 600 800 1000
Number of Evaluations
M
e
a
n

F
i
t
n
e
s
s

V
a
l
u
e
of lho noan filnoss of lho populalions gonoialoo ouiing lho oplinizalion is
showoo in Fig. ¸.¡¸.
4.6· Conc|usIons
1his chaploi pioviooo an ovoiviow on lho usoo noooling ano noool cali-
Lialion fianowoik foi GINs in lho conloxl of oovolopnonlal Liology lhal
aio Lasoo on ID syslons. Using lhis fianowoik il has Loon invosligalo how
lo foinulalo oLjoclivo funclions lhal aio suilaLlo lo guioo lho paianoloi
caliLialion piocoss foi such syslons wilhoul iolying on noslly unavailaLlo
quanlilalivo oala Lul only qualilalivo oala. Diffoionl aspocls of lhis lask
havo Loon oxploioo: (i) foaluios lhal aio capaLlo lo allow ioonlificalion of
paianoloi sollings iosulling in spalially holoiogonoous ano linoly slaLlo
palloins, (ii) foaluios lhal allow assossing piopoilios liko sonsilivily oi io-
Luslnoss ano aio Lasoo on paianoloi spaco oxploialion, ano (iii) nolhoos
foi palloin ioonlificalion in sinulalion oulpul as woll as suilaLlo funclions
foi quanlificalion of palloin sinilaiilios Lolwoon oxpoiinonlally ooloininoo
laigol palloins ano sinulaloo palloins.
Whilo lho nolhoos piosonloo in lhis chaploi woio concoivoo as Laso lino ap-
pioach ano lhoiofoio liioo lo avoio inclusion of oonain knowloogo, il luinoo
oul lhal lho pioLlon sliucluio unooilying lho caliLialion piocoss nakos lhis
4c Conc|u:|on: 63
lask oifficull. Lspocially iiogo-liko liansilions Lolwoon qualilalivo oiffoionl
syslon Lohaviois foi snall changos of paianoloi valuos in coilain paianoloi
spaco iogions opposoo Ly plaloaus lhal show no iocognizaLlo changos foi lho
ionaining pails of lho paianoloi spaco conplicalo lho caliLialion piocoss.
Fiisl losls incluoing oonain knowloogo in luin inoicalo lhal such inclusions
has lho polonlial lo gioally facililalo lho piocoss. 1hoiofoio, in Chaploi ¸
lwo oiffoionl lochniquos lo incluoo such knowloogo aio pioposoo ano losloo.
Slill, lho iosulls piosonloo in lhis chaploi piovo lho gonoial foasiLilily of lho
choson appioach lo noool caliLialion ano lho piosonloo nolhoos aio usoo
ouiing lho oailioi slagos of oovoloping a noool foi lho SAM of A. thaliana
in Chaploi 6.

Methods for Mode| Ca|IbratIon:
IncorporatIng 0omaIn Know|edge
1ho piovious chaploi piosonloo fiisl iosulls concoining lho paianoloi cal-
iLialion lask foi noools of oovolopnonlal syslons using only qualilalivo
oala Lul il showoo linilalions as woll. 1hoso linilalions noslly slon fion
lho highly non-linoai inloiaclions Lolwoon noooloo conpononls ano nani-
fosl lhonsolvos in foin of a pioLlon sliucluio lhal is ooninaloo Ly plaloaus
of inoislinguishaLlo paianoloi sollings in loins of iospoclivo noool fil. In
consoquonco, lho oplinizalion nolhoo usoo foi caliLialion haioly iocoivos
soaich foooLack lowaios pionising iogion whal iosulls in ialhoi inofficionl
ianoon sanpling Lohavioi on lho plaloaus.
Hoio, lhis linilalion is aooiossos Ly gonoialing aooilional foooLack foi
lho oplinizalion nolhoo Ly incoipoialing lwo oiffoionl souicos of oonain
knowloogo. (i) Alioaoy in lho piovious chaploi il was liioo lo incluoo
knowloogo concoining coilain conoilions lhal aio nocossaiy foi ioaclion-
oiffusion (ID) syslons in oiooi lo gonoialo a oosiioo palloining: using
knowloogo on lho iolalion Lolwoon lho oiffusion conslanls of lho oiffoionl
66 Chupter : |ethoo: íor |ooe| Cu||orut|on. lncorporut|ng 0omu|n Know|eoge
spocios, lho oplinizalion piocoss coulo cloaily Lo inpiovoo. Following lhis
iooa of incluoing analylical iosulls concoining lho palloin gonoialion noch-
anisn ID syslon, in a noio iigoious appioach nachino loaining lochniquos
aio usoo lo oxliacl gonoial foaluios chaiacloiizing ID syslons. 1hoso foa-
luios iovoal sliucluio of lho paianoloi spaco foi an unknown ID syslon
ano lhoioLy assisl in guioing lho oplinizalion piocoss lowaios pionising
iogions. (ii) In lho socono appioach, oLsoivalions concoining lho oovolop-
nonlal liajocloiios aio incoipoialoo inlo lho caliLialion piocoss insloao of
knowloogo concoining lho palloin gonoialion nochanisn. Whilo solling up
lho noool foi lho shool apical noiislon (SAM) of Arabidopsis thaliana (A.
thaliana) oosciiLoo in lho noxl chaploi, il occuiioo lhal ouiing oovolopnonl
of such syslons a soiios of liansionl slalos aio visiloo Lofoio lho final sloaoy
slalo is ioachoo. 1his facl was oxploiloo in foin of a hioiaichical oocon-
posilion of lho oovolopnonlal liajocloiy lhal was usoo ouiing lho nanual
paianoloi caliLialion piocoss al lho lino lho noool was sol up. 1aking up
lhis iooa, an aulonaloo appioach foi paianoloi caliLialion incoipoialing
infoinalion on lho oovolopnonlal liajocloiy is piosonloo.
5.1 · Lxp|oItatIon of Cenera| Ana|ytIca| Resu|ts ConcernIng Pattern
FormatIon CapabI|ItIes of R0 5ystems
Lncouiagoo Ly lho facl lhal inclusion of knowloogo on analylical iosulls
concoining lho usoo noool lypos can consiooiaLly facililalo lho paianoloi
caliLialion lask (soo Soclion ¸.¸), hoio an appioach gonoializing lhis iooa
is piosonloo. Whoio in lho piovious chaploi syslon spocific infoinalion
havo Loon usoo lhal aio only availaLlo foi snall syslons, lhoso analylical
iosulls aio usoo in oiooi lo liain a piooicloi iovoaling infoinalion concoin-
ing lho sliucluio of lho consiooioo paianoloi spacos of now syslons. In
oolail, lho piooicloi is usoo lo oslinalo lho oislanco of a givon paiano-
loi solling fion a Lounoaiy in paianoloi spaco lhal oisciininalos Lolwoon
qualilalivoly oiffoionl syslon Lohaviois. 1his piooicloi lhon guioos an op-
linizalion nolhoo lo ioonlify a woll oisliiLuloo sol of paianoloi sollings
consliluling such Lounoaiios. Knowloogo on such Lounoaiios in luin can Lo
:+ L·p|o|tut|on oí Ceneru| /nu|yt|cu| |e:u|t: 67
usoo lo conconlialo lho soaich piocoss on spocific pionising iogions. Sinco
lho consiooioo noools foi palloin foinalion in Liological syslons aio Lasoo
on lho sano gonoial piinciplos of local solf-aclivalion ano long iango inhi-
Lilion [_1, 6_[ unooilying ID syslons, lho piooicloi liainoo on oala foi a
sinplo ID syslon is supposoo lo gonoializo woll foi olhoi ID syslons.
5.1.1 · Approach
Sunnaiizing lho concopl unooilying lho appioach, analylical iosulls con-
coining a slaLilily analysis of a sinplo ID syslon aio usoo lo annolalo
coiiosponoing nunoiical oala wilh iospocl lo qualilalivo syslon Lohavioi.
IossiLlo qualilalivo lypos of syslon Lohavioi aio shown in Fig. fig:concopl.
1his annolaloo oala sol is lhon usoo lo liain a piooicloi lo oslinalo lho clos-
osl oislanco in paianoloi spaco of a givon paianoloi solling lo a Lounoaiy
lhal oolinils iogions in paianoloi spaco iosulling in qualilalivoly oiffoionl
syslon Lohavioi. Foi lhis puiposo lho nunoiical oala is piocossoo in oiooi
lo ioouco il lo sono nola chaiacloiislics lhal capluio inpoilanl foaluios lo
ooloinino lo which qualilalivo iogion a givon paianoloi solling Lolongs—a
nocossaiy slop lo allow lhal lho consiooioo chaiacloiislics Locono invaii-
anl lo lho oxacl spocificalion of lho consiooioo ID syslon ano lhoiofoio
allow foi gonoializalion. Using lhis piooicloi, in lho following il is usoo lo
guioo lho oplinizalion nolhoo on ils lask lo oxploio lho paianoloi spaco
lo localo lhoso Lounoaiios. In offocl, lhis appioach is oiviooo inlo lwo
phasos, (i) oala gonoialion ano liaining of lho piooicloi, ano (ii) paiano-
loi spaco oxploialion. Hoio, as piooicloi ailificial nouial nolwoiks (ANNs)
aio choson ano lho MullioLjoclivo Covaiianco Maliix Aoaplion Lvolulion
Slialogy (MO-CMA-LS) (soo Soclion ¸.·) is usoo foi paianoloi spaco ox-
ploialion. 1ho iosulling schono is skolchoo in Fig. ¸.·.
TraInIng 0ata CeneratIon
1o gonoialo lho liaining oala foi lho ANN nunoiical oala has lo Lo anno-
laloo wilh analylical iosulls foi an analylically liaclaLlo ano lhoiofoio sin-
plo ID syslon. Hoio, a sinplifioo vaiianl of lho aclivaloi-inhiLiloi syslon
68 Chupter : |ethoo: íor |ooe| Cu||orut|on. lncorporut|ng 0omu|n Know|eoge
Simulated Time
0 200 400 600 800 1000
10⁴
10²
10⁰
10²
10⁴
10⁶
C
o
n
c
e
n
t
r
a
t
i
o
n
10⁴
10²
10⁰
10²
10⁴
10⁶
0 200 400 600 800 1000
C
o
n
c
e
n
t
r
a
t
i
o
n
Simulated Time
A B
FIgure _.±. ¯|me cour:e: repre:ent|ng the
three quu||tut|ve|y o|fferent oehuv|or: oí the
one o|men:|onu| uct|vutor |nh|o|tor :y:tem
¯he y-u·|: oí euch p|ot :how: the reucheo
concentrut|on: wh||e the ·-u·|: repre:ent:
t|me uno euch oí the 1cc curve: per p|ot rep-
re:ent: the t|me oehuv|or oí the uct|vutor oí
u :|ng|e ce|| oí the :y:tem /. u typ|cu| o:c||-
|ut|ng :y:tem, 3. u :put|u||y heterogeneou:
puttern, C. u :put|u||y homogeneou: oehuv-
|or
0 200 400 600 800 1000
C
o
n
c
e
n
t
r
a
t
i
o
n
Simulated Time
10⁴
10²
10⁰
10²
10⁴
10⁶
C
FIgure _.z S|etch oí the tru|n-
|ng phu:e oí the urt|fic|u| neuru|
networ| u: u preo|ctor íor the o|:-
tunce oetween u purumeter :et-
t|ng uno the c|o:e:t oounoury |n
purumeter :puce oe||m|t|ng re-
g|on: re:u|t|ng |n quu||tut|ve|y o|í-
íerent oehuv|or (|eſt) uno the |níor-
mut|on flow |n the C|/-LS thut |:
oev|:eo to |oent|íy po|nt: on :uch
u oounoury íor un un|nown reuc-
t|on o|ffu:|on :y:tem, ou||o|ng on
the urt|fic|u| neuru| networ| (r|ght)
Phase 1:
Learning
Phase 2:
Parameter Space Exploration
Analytical Data
Numerical Data
Training Data
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:+ L·p|o|tut|on oí Ceneru| /nu|yt|cu| |e:u|t: 69
is usoo lhal was alioaoy analylically invosligaloo Ly Koch ano Moinhaiol
[61[. Il is givon Ly lho following oqualions:
∂a
∂t
= D∆a +ξ
a
2
h
−a +σ,
∂h
∂t
= ∆h +ξµ(a
2
−h).
1his syslon consisls of lwo inloilinkoo spocios, an aclivaloi a ano an in-
hiLiloi h. 1hoii iospoclivo lino Lohavioi is oosciiLoo Ly pailial oiffoionlial
oqualions (IDLs) lhal in aooilion lo lino oopono on spalial infoinalion:
a oiffusion loin iopiosonloo Ly lho Laplaco opoialoi ∆ ano a oiffusion con-
slanl D. Lolh spocios onconpass a ioaclion loin, poiluiLoo Ly a unifoinly
ianoon valuo ξ ∈ [u.¸¸, ¡.u¸], ano a oocay loin. 1ho ioaclion- ano oocay
loin of lho inhiLiloi aio quanlifioo wilh a conslanl µ. In aooilion, lho
aclivaloi conlains lho loin σ lhal iopiosonls Lasal oxpiossion. 1his syslon
ooponos on lhioo conslanls: D, σ, ano µ.
1o gonoialo nunoiical oala foi lhis syslon, an inplononlalion of lhis sys-
lon in a ono-oinonsional spalial oonain consisling of ¡uu colls wilh poiiooic
Lounoaiy conoilions is consiooioo. 1ho paianoloi spaco is sanploo using
an oquioislanl giio of ¸uuu paianoloi sollings on lho paianoloi suL-spaco
spannoo Ly (D, µ). 1ho Lasal oxpiossion loin is sol conslanl lo σ=u.uu¡
ano as inilial conoilions (a
i
, h
i
) = (u.u¡, u.u¡) is usoo foi all colls ¡≤ i ≤¡uu
foi Lolh spocios a ano h. 1ho giio spans (D, µ) = [u.uu6, u.¸] × [u.u¸, ¸]
wilh iospoclivo slop sizos of (u.uu6, u.u¸). Foi nunoiical inlogialion lho in-
loival [u, ¡uuu] of oinonsionloss lino is consiooioo ano lho inplicil-oxplicil
(IMLX) schono consisling of a nooifioo Ciank-Nicolson inlogialoi ano an
Aoans-Lashfoio inlogialoi [_1[ is usoo. 1ino is oisciolizoo Lasoo on an
oquioislanl giio wilh slop sizo δ
t
=u.¡·¸ ano foi spaco oisciolizalion a spa-
lial giio in collulai iosolulion is applioo.
Afloi ioonlifying lho analylically ooloininoo Lounoaiios in (D, µ) paian-
oloi spaco in lho nunoiical oala, lho shoilosl Lucliooan oislanco foi oach
sinulaloo paianoloi solling lo lhoso Lounoaiios is conpuloo ano noinal-
izoo: lho (D, µ) = [u, u.¸]×[u, ¸] paianoloi spaco is ioscaloo lo [u, ¡]×[u, ¡].
70 Chupter : |ethoo: íor |ooe| Cu||orut|on. lncorporut|ng 0omu|n Know|eoge
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µ µ
D
FIgure _._. Normu||zeo o|:tunce: oí euch purumeter :ett|ng |n the (0, µ) = [c, c_] ×[c, (]
purumeter :puce u: oeterm|neo írom the :|mu|ut|on outu (/) uno preo|cteo oy the /NN (3)
1ho iosulling oislancos aio shown in Fig. ¸.¸A. Following lho gonoialion of
lho oulpuls usoo foi liaining lho ANN, in a lasl slop lho inlogialion oala
(poi paianoloi solling an n × m naliix X wilh n Loing lho nunLoi of
colls ano m Loing lho nunLoi of consiooioo lino poinls) is iooucoo lo a sol
of nola chaiacloiislics lhal capluio syslon invaiianl foaluios. 1hoy allow
lho ANN lo loain lho napping Lolwoon paianoloi solling (iopiosonloo Ly
lho foaluios) ano lho shoilosl oislanco lo a Lounoaiy in paianoloi spaco.
Analyzing lho availaLlo lino couiso oala il luinoo oul lhal in piinciplo lwo
chaiacloiislics shoulo Lo sufficionl lo chaiacloiizo lho oiffoionl paianoloi
sollings: (i) lho spalial oiffoionco occuiiing Lolwoon all colls ouiing a lalo
inlogialion slop ano (ii) lho ooninaling oscillalion poiioo oslinaloo fion
lho oala (foi non-oscillaling lino couisos il can Lo sol lo a voiy snall pos-
ilivo valuo, hoio ¡ue
-¡¸
). 1hoso lwo chaiacloiislics havo lho aovanlago lhal
lhoy aio invaiianl wilh iospocl lo vaiialions of lho sinulaloo oonain, Lolh
in nunLois of colls ano changos of oinonsionalily. Slill, lhoso lwo chai-
acloiislics allow lo capluio foaluios oisciininaling Lolwoon oscillaloiy ano
slaLlo syslon Lohavioi ano spalially honogonoous oi holoiogonoous slalos.
Whon in aooilion consiooiing lhoso lwo chaiacloiislics only foi lho acliva-
loi, invaiianco wilh iospocl lo possiLlo olhoi ioalizalions of an inhiLilion is
gainoo, o.g., insloao of a oiiocl inhiLilion Ly an inhiLiloi, inhiLilion coulo
Lo ioalizoo Ly ooploling a suLslialo.
:+ L·p|o|tut|on oí Ceneru| /nu|yt|cu| |e:u|t: 71
Whilo lho conpulalion of lho spalial oiffoionco is a sliaighl foiwaio pioco-
ouio, il is Liiofly oxplainoo how lho ooninanl oscillalion poiioo is oslinaloo.
In a fiisl slop, lho oxisling lino couiso oala X is iooucoo lo a consonsus
lino couiso X
max
Ly laking lho naxinun ovoi all colls foi oach lino poinl.
1his has lho aovanlago of gonoialing a noio iogulai signal sinco ouo lo lho
slochaslic ξ loins lho consiooioo lino couiso nighl show sono iiiogulaii-
lios in singlo colls. In a socono slop lho oala is oisciolizoo using a lhiosholo
δ
thresh
=
1
/2noan(X
max
). Foi all lino poinls whoio X
max
≥ δ
thresh
, lho ois-
ciolizoo lino couiso oala X
disc
is sol lo ¡ ano u olhoiwiso. 1hon, lho poiioos
Lolwoon ‘¡’ poaks aio ooloininoo ano galhoioo in a hislogian wilh Luckols
onconpassing ¸ lino slops. Using a slioing winoow covoiing ¸ consoculivo
Luckols, lho poiioo wilh lho nosl occuiioncos is ooloininoo whoio in caso
of oqual occuiioncos wo havo a piofoionco foi shoiloi poiioos. 1ho piocoss
of ooloinining lho ooninanl poiioo is skolchoo in Fig. ¸.¸.
ArtIficIa| Neura| Networks
1o loain lho napping Lolwoon inpuls oxliacloo fion lho lino couiso oala
of lho nunoiical inlogialion lo lho oislanco of lho iospoclivo paianoloi sol-
ling lo a Lounoaiy in paianoloi spaco ooliniling paililions of qualilalivoly
oiffoionl syslon Lohavioi, ANNs aio usoo [6[. Sinco loaining lho oosciiLoo
napping is a iogiossion pioLlon, fooo foiwaio nulli-layoi poicoplions wilh
lwo layois of aoaplivo woighls ano in lolal lhioo layois aio usoo: an inpul
layoi wilh lwo nouions, a hiooon layoi of ¸u nouions wilh hypoiLolic lan-
gonl funclions as aclivalion funclions, ano an oulpul layoi wilh a singlo
nouion ano a linoai aclivalion funclion. 1o fuilhoi onhanco lho piooiclivo
capaLililios of lho ANN, insloao of a singlo ANN an onsonLlo of ANNs [_6[
is liainoo. In oolail lho W-SLCA piocoouio pioposoo Ly Gianillo ol al.
[_6[ is usoo lo consliucl lho ANN onsonLlo whoio lho onsonLlo piooiclion
is lho woighloo noan of all ANNs in lho onsonLlo. Il is conpuloo using lho
following woighling funclion w
i
foi oach onsonLlo nonLoi i [_6[:
w
i
=
e
−2
i

j
e
−2
j
.
Hoio, e is lho piooiclion oiioi of an onsonLlo nonLoi wilh iospocl lo lho
oala sol conlaining all ¸uuu oala poinls ano j iloialos ovoi all onsonLlo
72 Chupter : |ethoo: íor |ooe| Cu||orut|on. lncorporut|ng 0omu|n Know|eoge
Period
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10²
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10²
10⁴
10⁶
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FIgure _.µ. / :|etch oí the proce:: u:eo to e:t|mute the oom|nunt o:c|||ut|on per|oo |n t|me
cour:e outu /. t|me cour:e outu oí the uct|vutor íor u 1cc ce|| uct|vutor |nh|o|tor :y:tem, 3.
t|me cour:e: ure reouceo to u :|ng|e t|me cour:e thut repre:ent: the mu·|mum íor euch t|me
po|nt over the 1cc ce||: (:o||o curve) uno the thre:ho|o δ
rhrcsh
u:eo íor o|:cret|zut|on (ou:heo
||ne), C. o|:cret|zeo t|me cour:e outu íor wh|ch the per|oo: oetween ‘1’ peu|: ure computeo, 0.
h|:togrum oí the cu|cu|uteo per|oo: uno the :||o|ng w|noow u:eo to oeterm|ne the oom|nunt
per|oo |n term: oí occurrence:
:+ L·p|o|tut|on oí Ceneru| /nu|yt|cu| |e:u|t: 73
nonLois. Sinco lho singlo inpul valuos can Locono ialhoi laigo, lo facili-
lalo liaining lhoy aio liansfoin Ly laking lhoii logaiilhn. Lach onsonLlo
nonLoi is liainoo using lho scaloo conjugalo giaoionls algoiilhn [6[. Foi
liaining, lho availaLlo oala is oiviooo in a liaining sol ano a valioalion sol
using Loolsliapping: lho liaining sol consisls of ¸uuu Loolsliap sanplos
whilo lho nol-sanploo poinls aio usoo as valioalion sol. 1ho ANNs aio
liainoo using lho liaining sol unlil lho piooiclion oiioi foi lho valioalion
sol in succossivo liaining opochs gols woiso. LnsonLlo piooiclions of lho
onsonLlo usoo in lho following aio shown in Fig. ¸.¸.
DptImIzatIon A|gorIthm
Aining al lho ioonlificalion of a iopiosonlalivo sol of paianoloi sollings
ooliniling iogions in paianoloi spaco iosulling in qualilalivoly oiffoionl
syslon Lohavioi, lho oplinizalion ciiloiion of nininizing lho oislanco lo a
Lounoaiy is conplononloo Ly a socono oLjoclivo: lho covoiago of lho paian-
oloi spaco Ly ioonlifioo paianoloi sollings. 1ho covoiago of lho paianoloi
spaco is assossoo Ly ianking lho paianoloi sollings x
i
in a populalion G
of lho MO-CMA-LS using lhoii oislanco lo unifoinly ianoon paianoloi
sollings x
j
∈ S as oosciiLoo alioaoy in Soclion ¸.¸.¸. In lolal|S|=·¸¸¸S
ianoon paianoloi sollings aio oiawn; following Hooffoing’s inoqualily [(_[
lhis iosulls in a pioLaLilily of u.¸¸ of piooucing in an oiioi in covoiago
conpulalion err≤u.u¡ foi lho consiooioo lwo oinonsional noinoo paiano-
loi spaco [u, ¡]
2
. In oiooi lo ioonlify liaoo-offs Lolwoon lhoso lwo oLjoclivos
lho MO-CMA-LS [_.[ is usoo.
5.1.2· 5Imu|atIons and Resu|ts
In lho following iosulls foi lhis appioach losloo on lhioo syslons aio shown.
As a pioof of piinciplo lho aclivaloi-inhiLiloi syslon foi which lho liaining
oala was gonoialoo is usoo. 1o losl lho gonoializaLilily lwo aooilional,
concoplually oiffoionl syslons aio consiooioo; Lolh ioalizo lho long-iango
74 Chupter : |ethoo: íor |ooe| Cu||orut|on. lncorporut|ng 0omu|n Know|eoge
inhiLilion Ly sono soil of ooploling suLslialo. Lqualions ¸.¡ ano ¸.· lhoioLy
conslilulo a sinplifioo vaiianl of lho aclivaloi-suLslialo syslon [_1, 61, 6_[.
∂a
∂t
= D∆a +ξa
2
s −a +σ (¸.¡)
∂s
∂t
= ∆s +ξµ(1 −sa
2
) (¸.·)
Sinilai lo lho aclivaloi inhiLiloi syslon usoo foi liaining, lho Lasal ox-
piossion loin is sol conslanl (σ=u.uu¡) ano lho lhoioLy iooucoo (D, µ) pa-
ianoloi spaco is oxploioo. 1ho ionaining lwo Lqs. ¸.¸ ano ¸.¸ conslilulo
a sinplifioo vaiianl of lho Liussolaloi [36[ foi which lho lhioo-oinonsional
paianoloi spaco (D, x, y) is consiooioo.
∂x
∂t
= D∆x +a −(b + 1)x +ξx
2
y +σ (¸.¸)
∂y
∂t
= ∆y +bx −ξx
2
y (¸.¸)
In all foui oqualions ξ iopiosonls a ianoon poiluiLalion unifoinly oiawn
fion lho inloival [u.¸¸, ¡.u¸]. Again, ∆ oonolos lho Laplaco opoialoi iopio-
sonling lho spalial conpononl, D is a oiffusion conslanl, σ iopiosonls Lasal
oxpiossion, µ is a oogiaoalion ialo, ano a ano b aio aooilional spocios, lho
conconlialions of which aio assunoo lo ionain conslanl.
Lofoio iosulls concoining lhoso lhioo syslons aio piosonloo, lho usoo oxpoi-
inonlal solup as woll as lho noans of valioalion foi lho founo sollings aio
Liiofly oosciiLoo.
Methodo|ogy
Foi lho oplinizalion piocoss, on oach syslon lho sano ANN onsonLlo is
usoo ano lho MO-CMA-LS is iun ¡u linos. Foi oach iun, a naxinun of
·¸uu funclion ovalualions is usoo wilh a populalion sizo of ¸u. 1ho hypoi-
voluno is calculaloo foi lho iofoionco poinl (¡, ¡uu) foi lho lwo oLjoclivos
(i) oislanco lo Lounoaiy ano (ii) covoiago of lho paianoloi spaco. Lach of
lho iuns look appioxinaloly · oays on a lwo chip oual coio AMD Oploion
:+ L·p|o|tut|on oí Ceneru| /nu|yt|cu| |e:u|t: 75
·.6GHz 6¸-Lil nachino wilh SGL IAM using MA1LAL
¯
¸.6 (I·uuSa)
ano lho NL1LAL [31[ inplononlalion foi ANNs ano iolaloo algoiilhns.
Foi lho ovalualion of lho iuns lwo oiffoionl faclois aio consiooioo: (i) lho
iopioouciLilily of lho ioonlifioo sols of paianoloi sollings ovoi all iuns foi
oach syslon, ano (ii) lho gooonoss of lho ioonlifioo Lounoaiios. Allhough
lho iopioouciLilily of lho founo sols of paianoloi sollings is oifficull lo assos
quanlilalivoly, novoilholoss, visual inspoclion of lho sols cloaily showoo lhal
coilain suL spacos conlainoo no ioonlifioo paianoloi sollings whilo olhois
woio woll-populaloo foi all iuns; an oLsoivalion lhal is ooonoo lo Lo suffi-
cionl lo oocunonl iopioouciLilily. In oiooi lo valioalo lho ioonlifioo Louno-
aiios, lwo oiffoionl appioachos aio usoo: sinco foi lho aclivaloi-inhiLiloi
syslon lho Lounoaiios aio known, lho ioonlifioo paianoloi sollings aio con-
paioo visually lo lho known Lounoaiios. Foi lho ionaining lwo syslons lho
pulalivo Lounoaiios infoiioo fion lho ioonlifioo paianoloi sollings aio val-
ioaloo Ly pioLing lho Lohavioi aiouno lho pulalivo Lounoaiios: paianoloi
sollings iosioing on voclois oilhogonal lo lho assunoo Lounoaiios aio sin-
ulaloo in oiooi lo losl if a qualilalivo chango of syslon Lohavioi occuis in
lho vicinily of lho pulalivo Lounoaiios. In aooilion, using lho sano pioLing
lochniquo il is losloo if paianoloi sollings localoo in iogions foi which no
Lounoaiy is oolocloo oxhiLil qualilalivoly sinilai Lohavioi.
Proof of PrIncIp|e
1ho pioposoo nolhoo is usoo lo ioonlify Lounoaiios paililioning lho pa-
ianoloi spaco in iogions iosulling in qualilalivo oiffoionl syslon Lohavioi
foi lho aclivaloi-inhiLiloi syslon (Lqs. ¸.¡.¡–¸.¡.¡) lhal was usoo foi liain-
ing lho ANN onsonLlo. Duiing piolininaiy iuns il was oLsoivoo lhal lho
covoiago of lho paianoloi spaco Locano woiso ouiing lho oplinizalions
piocoss coiiosponoing wilh a ioouclion in nunLoi of oislincl paianoloi
sollings consliluling lho oslinaloo Lounoaiios. Lvonlually, lho algoiilhn
convoigoo onoing up wilh only ono oi lwo paianoloi sollings. Whon ana-
lyzing lho lanoscapo of oislancos piooicloo Ly lho ANN onsonLlo, il luinoo
oul lhal allhough lho gonoial oislanco lanoscapo is in gooo agioononl wilh
lho calculaloo oislancos (soo Fig ¸.¸) nol all Lounoaiy consliluling paian-
oloi sollings aio nappoo lo lho sano gloLally oplinal valuo: foi oxanplo in
76 Chupter : |ethoo: íor |ooe| Cu||orut|on. lncorporut|ng 0omu|n Know|eoge
lho iogion wilh snall D-valuos ano laigo µ-valuos lho piooicloo oislancos
Locono nogalivo ano in loins of nininizalion Lolloi lhan lhoso foi olhoi
Lounoaiy poinls. 1hoioLy, lho appioach liaooo off covoiago foi conconlial-
ing on lho iogions conlaining nogalivo valuos. In oiooi lo piovonl lhoso falso
gloLal oplina fion ooninaling lho oplinizalion piocoss, a nininun valuo
of u foi lho piooicloo oislancos is inliooucoo. 1hoioLy il is achiovoo lhal
nosl Lounoaiy consliluling paianoloi sollings aio nappoo lo lho gloL-
ally oplinal valuo of u Lul al lho sano lino sono falso posilivo Lounoaiy
poinls aio inliooucoo, o.g., again in lho iogion wilh snall D-valuos ano
laigo µ-valuos. Using lhis nooificalion lho Lounoaiy ooloininoo Ly lho
appioach is in gooo agioononl wilh lho known Lounoaiy (soo Fig. ¸.¸).
Slill, lho (D, µ) ∈ [u, u.¸] × [u, ¡.¸6] iogino coiiosponoing lo oscillaling
syslon Lohavioi conlains a consiooiaLlo nunLoi of falso posilivo sollings.
Whon again chocking lho piooicloo oislancos (soo Fig. ¸.¸L) il can Lo soon
lhal lhoso falso posilivo sollings coiiospono lo naiiow spikos in lho pio-
oicloo lanoscapo—a facl lhal coulo Lo aooiossoo oilhoi Ly consiooiing lho
ioLuslnoss of lho piooicloo oislanco lo a Lounoaiy wilh iospocl lo sono
soil of noighLoihooo aiouno lho consiooioo paianoloi solling oi Ly fuilhoi
iofining lho liaining piocoss of lho ANNs, o.g., Ly incluoing iogulaiiza-
lion loins lo snoolhon ANN oulpuls Ly piovonling possiLlo ovoi filling.
Novoilholoss, allhough a nunLoi of paianoloi sollings coiiosponos lo falso
posilivo Lounoaiy poinls, lho appioach in ils cuiionl foin alioaoy cloaily
shows lhal laigo pails of lho paianoloi spaco Lolong lo qualilalivoly sinilai
iogions ano lhoiofoio can Lo noglocloo.
Test of Cenera|IzabI|Ity
Afloi lhis pioof of piinciplo, lho gonoializalion capaLililios of lho appioach
havo Loon losloo Ly applying il lo lho ionaining lwo losl syslons. Whon
chocking lho oala foi a sinplifioo vaiianl of an aclivaloi-suLslialo syslon
(Lqs. ¸.¡–¸.·), lho ioonlifioo paianoloi sollings cloaily oullino a Lounoaiy
fion snall D-valuos ano laigo µ-valuos lowaios laigo D-valuos ano snall
µ-valuos. 1o valioalo if lhoso sollings conslilulo a liuo Lounoaiy Lolwoon
qualilalivoly oiffoionlly Lohaving paianoloi spaco iogions lho Lohavioi in
a noighLoihooo aiouno lho pulalivo Lounoaiy was pioLoo using lho voc-
:+ L·p|o|tut|on oí Ceneru| /nu|yt|cu| |e:u|t: 77
0 0.1 0.2 0.3
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3
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0 0.1 0.2 0.3
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2
3
4
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B A
µ µ
FIgure _._. 3ounoury oe||m|t-
|ng purumeter :ett|ng: |oent|-
fieo íor the three te:t :y:tem:
/. |oent|fieo purumeter :ett|ng:
(c|rc|e:) uno unu|yt|cu||y oeter-
m|neo oounoury po|nt: (:quure:)
íor the uct|vutor |nh|o|tor :y:tem,
3. |oent|fieo purumeter :ett|ng:
íor the uct|vutor :uo:trute :y:-
tem uno the u:eo proo|ng vec-
tor:, C. |oent|fieo purumeter :et-
t|ng: íor the 3ru::e|utor u: we||
u: the u:eo proo|ng vector: uno
the hyperp|une out||n|ng un u:-
:umeo oounoury
0
2
4
C
0
0.2
0.4
0
2
4
D
a
b
lois shown in Fig. ¸.¸L. Lvalualing lho coiiosponoing sinulalions il was
confiinoo lhal on lho lowoi Loaiooi of lho ioonlifioo Lounoaiy lho syslon
shows a chango in Lohavioi fion a spalially holoiogonoous palloin (lowoi
iogion in Fig. ¸.¸L) lo a spalial honogonoous palloin (uppoi iogion in
Fig. ¸.¸L). In aooilion, along lho pioLing voclois localoo in iogions foi
which no Lounoaiy was piooicloo, inoooo no qualilalivo chango in syslon
Lohavioi was oLsoivoo.
78 Chupter : |ethoo: íor |ooe| Cu||orut|on. lncorporut|ng 0omu|n Know|eoge
Whon looking al lho pulalivo Lounoaiy consliluling paianoloi sollings
ioonlifioo foi lho Liussolaloi (soo Fig. ¸.¸C), ono iocognizos lhal ioonlifying
Lounoaiios Loconos incioasingly noio oifficull whon ooaling wilh highoi
oinonsional soaich spacos ospocially whon lho Lounoaiios slon fion non-
linoai iolalions Lolwoon paianolois. Slill, il was possiLlo lo ioonlify a
hypoiplano oullinoo Ly founo paianoloi sollings. Using lho sano pioLing
appioach (soo Fig. ¸.¸C foi oxacl localion of hypoi plano ano pioLing vocloi)
lo valioalo lhis pulalivo Lounoaiy, a chango fion spalially honogonoous
linoly slaLlo solulions lo linoly oscillalions was oLsoivoo whon following
lho pioLing vocloi in oiioclion of incioasing b valuos. Again, pioLing iogions
lhal accoioing lo lho appioach woio nol supposoo lo conlain Lounoaiios
showoo no qualilalivo chango in syslon Lohavioi.
5.2· HIerarchIca| Approach to Mode| Ca|IbratIon
Foi lho caliLialion of noools foi oovolopnonlal syslons foi which only qual-
ilalivo oala is availaLlo, connonly infoinalion on a finally onoiging slaLlo
qualilalivo palloining of lho consiooioo lissuo is usoo lo ooloinino lho oo-
gioo of fil Lolwoon oala ano noool. Hoio, an appioach is pioposoo lhal
oxploils lho facl lhal oovolopnonlal syslons iun lhiough a soiios of inloi-
nooialo slalos Lofoio lho syslon ioachos ils final slaLlo slalo. 1hoioLy, oach
of lho liansionl slagos involvos only pails oi loosoly connocloo suLsyslons
of lho conplolo syslon unooi invosligalion, o.g., gap gonos, paii iulo gonos,
oi sognonl polaiily gonos in Drosophila oovolopnonl [1c/[. In oolail, lho
appioach incluoos knowloogo of lhoso oiffoionl slagos lo ooconposo lho op-
linizalion lask inlo a sol of oplinizalion lasks foi lho known inloinooialo
slalos lhal aio concoinoo wilh paianolois foi suLsyslons only. Ly consio-
oiing lho inloinooialo slalos as woll, noio infoinalion Loconos availaLlo
foi lho oiiginal oplinizalion lask. In aooilion, lho paianoloi spacos lhal
havo lo Lo consiooioo foi lho now oplinizalion suLlasks conslilulo only suL-
spacos of lho oiiginal paianoloi spacos whal polonlially fuilhoi facililalos
lho oplinizalion piocoss.
:2 ||erurch|cu| /pprouch to |ooe| Cu||orut|on 79
In lhis conloxl, lwo hypolhosos aio invosligaloo: such a ooconposilion (i)
inpiovos lho convoigonco of houiislics foi paianoloi oplinizalion ano (ii)
iosulls in savings in nocossaiy conpulalional cosl ouo lo lho facl lhal foi
oaily slagos only suLsyslons nooo lo Lo consiooioo which aio choapoi in
loins of conpulalional cosl. As losl syslon, lho oiffoionlial oqualion (DL)
noool foi oovolopnonl ano nainlonanco of lho palloining in lho SAM of
A. thaliana piosonloo in Chaploi 6 is usoo.
5.2.1 · Approach
Invosligaling oovolopnonlal piocossos liko giowlh of a planl, ono oLsoivos
lhal lhoy lako placo in conlinuous lino ano involvo changos in oxpiossion
of a nulliluoo of gonos, ullinaloly iosponsiLlo foi lho oLsoivoo phonolypo.
1hoioLy, oxpiossion is pinpoinloo Lasoo on conconlialions of liansciiLoo
INA oi gono piooucls, again living in a conlinuous scalo. Slill, slalos
of such syslon aio connonly oosciiLoo involving oisciolizalions: insloao
of lho oovolopnonlal liajocloiy a coilain lino poinl is consiooioo, oflon
naiking an oquiliLiiun slalo, ano conconlialions aio iooucoo lo lovols liko
high ano low. 1hoioLy, ospocially lho iosliiclion lo a singlo poinl in lino
iosulls in a loss of infoinalion concoining lho oovolopnonl. 1hoiofoio, lho
appioach pioposoo hoio is oosignoo lo allow lo incoipoialo infoinalion on
lho oovolopnonlal liajocloiy in foin of a sol of slalos lhal aio consiooioo
foi noool caliLialion.
LntIty 0IscretIzatIon
Wilh iospocl lo lino, connonly lho oxpoiinonlally ooloininoo lasl sla-
Llo syslon slalo is usoo as laigol palloin p
tar
foi noool caliLialion. Sinco
lho focus of lhis soclion is on lho incoipoialion of aooilional infoinalion
wilh iospocl lo lino, hoio oxpiossion palloins aio iopiosonloo in a sin-
plo foin using qualilalivo nasks. 1hoso nasks aio gonoialoo foi lho oif-
foionl noool onlilios foi coilain poinls in lino using lhiosholos; in caso
of lho consiooioo SAM noool, foi oach of lho fivo noool onlilios ent ∈
{[WUS] , [FacX] , [WUS
oxl
] , [sl] , [CLV¸]} lhis iosulls in a palloin p
sim
ent
=
{on, off}
|T|
(wilh T Loing lho sol of noooloo colls of caioinalily |T|). Masks
80 Chupter : |ethoo: íor |ooe| Cu||orut|on. lncorporut|ng 0omu|n Know|eoge
oooucoo fion noool sinulalions can lhon gol conpaioo lo qualilalivo ox-
piossion palloins Ly counling oiffoioncos in gono oxpiossion slalos Lolwoon
lho lwo on a poi onlily ano coll Lasis. In caso of lho SAM, p
tar
consisls
of lhioo nasks, ono foi oach of lho onlilios [WUS], [sl], ano [CLV¸]. Foi
noool caliLialion lhoso nasks aio usoo lo oofino lhioo oiffoionco funclions
h
3
WUS
, h
3
sl
, ano h
3
CLV¸
lhal aio inslanlialions of Lq. ¸.¸ lhal is iopoaloo
hoio:
h
ent
(
p
sim
ent
, p
tar
ent
)
=

p
sim
ent,i
̸=p
tar
ent,i
1, wilh 1 ≤ i ≤ |T| .
TIme 0IscretIzatIon
Aooing fuilhoi lino infoinalion nighl piovioo usoful infoinalion foi lho
quanlificalion of oiffoioncos Lolwoon sinulalions ano oxpoiinonls. Hoio,
lho facl lhal oovolopnonlal piocossos aio oflon oiganizoo hioiaichical ano
in offocl iun lhiough a soiios of known liansionl slalos can Lo oxploiloo. Foi
lho oxanplo syslon SAM in A. thaliana such a ooconposilion inlo liansionl
slalos looks as follows: lho sliucluio of a wilo lypo SAM can Lo oosciiLoo
as palloin consisling of lwo spalially confinoo oonains, slon coll oonain
(SCD) ano oiganizing conloi (OC) (soo Chaploi 6). Duiing SAM oo novo
assonLly, fiisl colls oxpiossing WUSCHEL (WUS) Locono visiLlo, lhoioLy
inoicaling foinalion of an OC. Inilialoo Ly WUSCHLL (WUS), slon coll
ioonlily is inilialoo oocunonloo Ly lho onsol of CLAVATA (CLV) oxpios-
sion [__, _3[. Il is ooconposoo inlo lho slalos (i) onoigonco of an OC ano
(ii) foinalion of a coiiosponoing SCD. Fion a noooling poispoclivo lho
foinalion of lho SCD can Lo fuilhoi ooconposoo: allhough hioiaichically
sliucluioo, SAM iogulalion incluoos foooLack of CLAVA1A¸ (CLV¸) on
WUS oxpiossion, lhoiofoio inliooucing a ciiculai conpononl lo SAM oovol-
opnonl. In oiooi lo ioonlify suilaLlo noool paianoloi sollings, il is holpful
lo fuilhoi oisiupl lhis cyclo Ly inliooucing an ailificial inloinooialo slop
ouiing which (iii) foooLack of CLV¸ on WUS is ignoioo.
1hoso lhioo oiffoionl slagos iosull in lho coiiosponoing laigol palloins wilh
iospocl lo lho noool onlilios [WUS], [sl], ano [CLV¸] shown in Fig. ¸.6.
Foi lho fiisl slago lho laigol palloin capluios lho foinalion of a spalially
:2 ||erurch|cu| /pprouch to |ooe| Cu||orut|on 81
FIgure _.6 |uttern|ng oí the S/|
u:eo our|ng purumeter cu||orut|on
íor o|fferent :tuge: w|th re:pect to
the :pec|e: [wUS], [:t], uno [CLv_]
íor u one-o|men:|onu| :y:tem
WUS
stemness
CLV3
Stage 1 Stage 2 Stage 3
confinoo OC al a ianoon localion in lho noooloo oonain. Lnoigonco
of lhis oonain only ooponos on a suLsyslon of lho usoo noool oncon-
passing lho noool onlilios {[WUS] , [FacX]}. 1ho palloining foi lho socono
slago, on lop of an OC, capluios lho onoigonco of a spalially confinoo SCD.
Sinco foi lho socono slago only {[WUS] , [FacX] , [WUS
sig
] , [sl]} aio consio-
oioo ano lho nogalivo foooLack Lolwoon SCD ano OC via CLV¸ signaling
is noglocloo, lhoio aio no consliainls inposoo on lhoii iolalivo aiiangononl
naking il nosl likoly lhal Lolh oonains ovoilap: lho nogalivo foooLack
iopolling Lolh oonains is nissing ano lho pionoling influonco of lho OC
on SCD is sliongosl al lho localion of lho OC. In luin, lho sloaoy slalo
palloining of a wilolypo noiislon is usoo foi slago lhioo. In lhis palloin,
Lolh funclional oonains fion slago lwo aio slill piosonl, lhis lino focus-
ing on lhoii iolalivo aiiangononl: juxlaposilion of Lolh oonains ano a
slaLlo foooLack Lolwoon Lolh wilh iospocl lo pionoling (WUS signaling)
ano inhiLiling (CLV¸ signaling) influoncos. Foi lhis slago, lho full noool is
consiooioo.
Conplononling lho oiffoionco funclions h
3
WUS
, h
3
sl
, ano h
3
CLV¸
foi lho
lhiio ano final slago, foi lho liansionl slagos ano coiiosponoing slago noools
(soo Apponoix L) now oiffoionco funclions aio aoooo: (i) foi lho fiisl slago,
h
1
WUS
ovalualing lho fil of an onoiging OC, ano (ii) foi lho socono slago,
h
2
WUS
ano h
2
sl
noasuiing lho fil of oovoloping OC ano SCD.
1ho sinplosl way lo incoipoialo lhoso slagos is lo always sinulalo all slagos
sinullanoously. Whilo such an appioach in piinciplo shoulo havo a nax-
inun of infoinalion availaLlo in oach slago, sinulaling all slagos ouiing
ovoiy ovalualion of a paianoloi solling inliooucos consiooiaLlo ovoihoao
in loins of conpulalion lino. 1o avoio lhis ovoihoao, il nakos sonso lo
consiooi lho oiffoionl slagos in a soquonlial nannoi, an appioach lhal is in-
82 Chupter : |ethoo: íor |ooe| Cu||orut|on. lncorporut|ng 0omu|n Know|eoge
spiioo Ly slialogios foi nullilovol oplinizalion [_c, /_[. 1hoioLy, foi ovoiy
ovalualion of a paianoloi slolling only ono noooloo slago nooos lo Lo sin-
ulaloo. In aooilion lho facl lhal slagos aio oiooioo in a hioiaichical nannoi
can Lo oxploiloo: laloi slagos conlain lho suLsyslons ano lhoioLy alioaoy
caliLialoo paianolois fion oaily slagos ano il coulo Lo possiLlo lo lians-
foi fuilhoi infoinalion Lolwoon lho oplinizalion piocossos foi consoculivo
slagos, o.g., ooponooncios Lolwoon involvoo paianolois oi gonoial infoina-
lion on pioLlon sliucluio. In consoquonco, lho pioLlon of caliLialing lho
noool wilh iospocl lo lho final slago is ooconposoo in snalloi suLpioLlons,
lho sun of which coulo Lo oasioi lo oplinizo lhan lho oiiginal pioLlon liko
in oynanic piogianning appioachos.
Imp|ementatIon
Hoio, lho MO-CMA-LS (soo Soclion ¸.·) is usoo foi paianoloi caliLialion.
Wilh such a slialogy foi ioal-valuoo nullioLjoclivo oplinizalion al hano,
foi lho pioposoo soquonlial oplinizalion appioach lho quoslion aiisos whal
ciiloiion can Lo usoo lo ooloinino whon lho swilchos Lolwoon lho oiffoionl
slagos shoulo Lo oono. Sinco piolosls showoo lhal foi a succossful soquon-
lial oplinizalion il is nocossaiy lhal lho slago chango only occuis whon a
suilaLlo oivoisily of sufficionlly gooo paianoloi sollings is accunulaloo foi
a givon slago, slago chango occuis onco al loasl ¸u/ of lho λ
MO
CMA-LS in
lho populalion of lho MO-CMA-LS havo ioonlifioo a uniquo paianoloi sol-
ling wilh an oplinal filnoss of u foi all consiooioo ciiloiia in lho iospoclivo
slago.
As oiscussoo aLovo, il coulo Lo Lonoficial foi lho oplinizalion piocoss lo
liansfoi infoinalion on pioLlon sliucluio oi ooponooncios of paianolois
Lolwoon consoculivo slagos ano lho oosign of lho MO-CMA-LS naluially
suppoils such liansfois: on lop of a paianoloi solling iopiosonling lho
Losl guoss of lho houiislic foi lho consiooioo oplinizalion lask, lho usoi is
pioviooo wilh fuilhoi infoinalion on lho lasl soaich oisliiLulion N fion
which lho final paianoloi solling was sanploo. 1hoioLy, lho usoi gols a
hano on infoinalion concoining conoilioning (C) ano ovoiall scaling (s) of
lho soclion of lho paianoloi spaco conlaining pionising solulions. Whilo
lho CMA-LS lypically aio slailoo using lho ioonlily naliix as slailing
:2 ||erurch|cu| /pprouch to |ooe| Cu||orut|on 83
covaiianco naliix C
new
, in lho oosciiLoo sconaiio il is possiLlo lo ioplaco
suL-naliicos of C
new
Ly onliios lakon fion a covaiianco naliix gonoialoo
foi an oailioi slago C
prev
. In aooilion, infoinalion on scaling can Lo incoi-
poialoo as woll whon conpaiing lho scaling s
prev
iosulling fion oplinizing
an oailioi slago lo lho inilial scaling s
new
: using lho quolionl (
s
prev
/s
new
)
2
as
a facloi lo scalo onliios lakon fion C
prev
.
In aooilion lo lhoso oolails on oplinizalion nolhooology, lho quoslion how
lho soaich spaco X ⊆ R
n
is Losl iopiosonloo in lho oplinizalion piocoss
shoulo Lo aooiossoo: whilo lho MO-CMA-LS is oosignoo lo hanolo ioal-
valuoo spacos, consiooioo noool paianolois liko ioaclion ialos, Lasal ox-
piossion loins, oogiaoalion ialos, kinolic conslanls as woll as oiffusion con-
slanls lono lo livo in a logaiilhnic scalo wilhin coilain inloivals naiking a
foasiLlo iogion. 1o facililalo hanoling paianolois in lho ovolulion slialogy,
lho ioal-valuoo paianoloi spaco X is nappoo lo log-scalo ano noinalizoo lo
[u, ¡] Lofoio il is hanooo ovoi lo oplinizalion. In caso of lho consiooioo SAM
noool, lho paianoloi spaco consiooioo ouiing oplinizalion is X = [u, ¡]
¡¸
ano only ouiing lho lhiio slago lho full oinonsional paianoloi spaco nooos
lo Lo consiooioo: lwo of lhoso fifloon paianolois aio oxclusivoly usoo foi lho
lhiio slago. In lho socono slago, lhiiloon paianolois aio consiooioo, wilh
fivo of lhoso nowly inliooucoo in conpaiison lo lho fiisl slago; iosulling in
oighl paianolois usoo ouiing lho fiisl slago.
5.2.2· Resu|ts and 0IscussIon
Il is invosligalo how oxpoiinonlal oala can Lo usoo in lho piocoss of noool
caliLialion oi noool paianoloi oplinizalion. In lhis iogaio hypolhosos
aio losloo lhal inclusion of infoinalion on inloinooialo syslon slalos can
facililalo paianoloi oplinizalion foi gono iogulalivo nolwoik (GIN) noools
in oovolopnonlal Liology foi which noslly qualilalivo oala is availaLlo. As
oxanplo syslon lho noool foi onoigonco ano nainlonanco of lho SAM in
A. thaliana piosonloo in Chaploi 6 is usoo.
84 Chupter : |ethoo: íor |ooe| Cu||orut|on. lncorporut|ng 0omu|n Know|eoge
Test 5ystem
1ho oovolopnonlal liajocloiy of lho SAM can Lo hioiaichically ooconposoo
inlo lhioo oiffoionl slagos wilh iospocl lo lino:
¡. Foinalion of a spalially confinoo oonain of colls oxpiossing lho WUS,
lho so calloo OC.
·. Foinalion of a spalially confinoo oonain of colls laking up slon coll
ioonlily, lho SCD.
¸. Iolalivo spalially aiiangononl of lho lwo funclional oonains.
Foi oach slago lhoio oxisls a laigol palloining wilh iospocl lo lho consiooioo
Liological onlilios (soo Fig. ¸.6), lho onoigonco of which is lo Lo iopiooucoo
wilh lho noool. Duiing lho lhioo slagos lho following oiffoionco funclions
aio lakon inlo accounl:
5tage ±: h
1
WUS
noasuiing lho fil of a oovoloping OC,
5tage z: h
2
WUS
ano h
2
sl
noasuiing lho fil of oovoloping OC ano SCD,
5tage _: h
3
WUS
, h
3
sl
, ano h
3
CLV¸
noasuiing lho nalch of oovoloping OC,
SCD, ano aioa unooi CLV¸ influonco.
Test 5etup
As alioaoy oosciiLoo, lhoio is a iango of possiLililios lo consiooi infoinalion
on lho oovolopnonlal liajocloiy ouiing noool caliLialion: (i) a Lasolino
appioach using only lho final syslon slalo ouiing noool caliLialion, (ii) an
appioach lhal sinullanoously consioois all lhioo slagos, (iii) appioachos lhal
consiooi lho slagos in a soquonlial nannoi. Hoio, lho soquonlial appioachos
aio oiffoionlialoo Ly lho anounl of infoinalion lhal is liansfoiioo Lolwoon
lho caliLialion piocoss of suLsoquonl slagos:
• only lhoso paianolois nowly inliooucoo lo lho noool in lho iospoclivo
slago aio oplinizoo ano all pioviously caliLialoo paianolois ionain fixoo
(fix),
• appioachos whoio in oach slago all iospoclivo paianolois aio oplinizoo
Lul no infoinalion liansfoi lakos placo (new),
• appioachos whoio Lolwoon slagos covaiianco naliicos C of iospoclivo
soaich oisliiLulions aio liansfoiioo (adapt-I),
:2 ||erurch|cu| /pprouch to |ooe| Cu||orut|on 85
• appioachos whoio Lolwoon slagos covaiianco naliicos C ano scaling fac-
lois s of iospoclivo soaich oisliiLulions aio liansfoiioo (adapt-II).
Sinco in all lhoso appioachos a sol of oiffoionco funclions nooos lo Lo con-
siooioo sinullanoously al loasl ouiing coilain phasos, lwo vaiianls of oach
appioach aio consiooioo: (i) a singlooLjoclivo vaiianl woio all oiffoionco
funclions aio sunnoo up lo foin an aggiogaloo oiffoionco funclion, ano
(ii) a vaiianl lhal consioois all oLjoclivos sinullanoously using a hypoivol-
uno Lasoo appioach (soo Soclion ¸.·). A lisl of all appioachos is givon in
1aL. ¸.¡.
1ho oiffoionl slialogios lo incluoo lhoso infoinalion aio losloo using lho
MO-CMA-LS as nolhoo foi paianoloi oplinizalion. IossiLlo gains aio
ovalualoo wilh iospocl lo convoigonco of lho oplinizalion piocoss ano sav-
ings in nocossaiy ovoiall conpulalion lino foi noool sinulalions. 1hoioLy,
foi lho lalloi ciiloiion ono has lo Loai in nino lhal lho conpulalional cosl
ouiing paianoloi oslinalion slons fion sinulalion lino whilo lho opli-
nizalion lochniquo ilsolf inliooucos only nogligiLlo conpulalional ovoihoao.
1hoiofoio, whon foi sono noool ovalualions insloao of lho conplolo noo-
oloo syslon il is sufficionl lo sinulalo only a suLsyslon, lhis can iosull in
consiooiaLlo conpulalional savings. In caso of lho consiooioo SAM noool,
conpulalional cosl scalos linoaily wilh lho nunLoi of sinulaloo spocios (soo
1aL. ¸.·)—lhoioLy polonlially piovioing significanl savings whon consiooi-
ing lhal paianoloi oplinizalion iuns on slalo of lho ail conpulois slill iun
in lho oiooi of oays.
Iosulls foi lho oiffoionl slialogios aio losloo foi slalislical significanco, fiisl
using lho Kiuskal-Wallis losl [13[ al a significanco lovol of α=u.u¸. In lhoso
paiiwiso losls as H
u
hypolhosis is losloo if lhoio is no significanl oiffoionco
in nooian wilh iospocl lo:
convergence capaLilily lo ioonlify a paianoloi solling showing no oiffoionco
Lolwoon sinulaloo palloin ano laigol palloin,
qua|Ity aggiogaloo scoio ioachoo al lho ono of an oplinizalion iun,
86 Chupter : |ethoo: íor |ooe| Cu||orut|on. lncorporut|ng 0omu|n Know|eoge
Tab|e _.±. 0verv|ew on computut|onu| upprouche: (top purt) thut ure con:|oereo |n two vur|-
unt: (oottom purt)
!osc 0n|y the |u:t :tuge oí the oeve|opmentu| proce:: |: con:|oereo íor mooe|
cu||orut|on
µoro /|| :tuge: oí the oeve|opmentu| proce:: ure con:|oereo |n puru||e| íor mooe|
cu||orut|on
fi. /|| :tuge: oí the oeve|opmentu| proce:: ure con:|oereo íor mooe| cu||orut|on
out |n u :equent|u| munner |ere, no |níormut|on |: trun:íerreo oetween the
o|fferent phu:e: oí the cu||orut|on proce:: uno purumeter: u|reuoy opt|m|zeo
our|ng eur||er :tuge: ure fi·eo
nc. /|| :tuge: oí the oeve|opmentu| proce:: ure con:|oereo íor mooe| cu||orut|on
out |n u :equent|u| munner |ere, no |níormut|on |: trun:íerreo oetween the
o|fferent phu:e: oí the cu||orut|on proce:: uno u|| con:|oereo purumeter:
remu|n íree
oJoµr-| /nother :equent|u| upprouch thut trun:íer: |níormut|on on the |u:t u:eo
covur|unce mutr|· C oetween phu:e: w|th u|| con:|oereo purumeter: remu|n|ng
íree
oJoµr-|| /nother :equent|u| upprouch thut trun:íer: |níormut|on on the |u:t u:eo
covur|unce mutr|· C uno the :cu||ng: s oetween phu:e: w|th u|| con:|oereo
purumeter: remu|n|ng íree
SD S|ng|eoo¦ect|ve vur|unt where u|| o|fference íunct|on: h ure uggreguteo
to íorm u :|ng|e oo¦ect|ve vu|ue
|D |u|t|oo¦ect|ve vur|unt thut |n cu:e oí the ou:e||ne upprouch !osc uno
the :equent|u| upprouche: con:|oer: u|| o|fference íunct|on: h :|mu|tuneou:|y
ln cu:e oí the puru||e| upprouch µoro, the o|fference íunct|on: oí the :tuge:
ure uggreguteo |nto one oo¦ect|ve íor euch :tuge, re:u|t|ng |n three
:|mu|tuneou:|y con:|oereo oo¦ect|ve:
runtIme usoo conpulalion lino foi a iun whoio a sinulalion foi lho fiisl
slago piooucos conpulalional cosls c=u.¸, lho socono slago of c=u.S,
ano lho lhiio slago of c=¡.
1hoioafloi, foi all paiis of algoiilhns lho oiffoioncos aio conpaioo using lho
Conovoi-Innan piocoouio [13[ wilh lho sano α lovol as in lho Kiuskal-Wallis
losl (soo 1aL. ¸.¸), iosulling in a ianking of lho slialogios (soo 1aL. ¸.¸).
:2 ||erurch|cu| /pprouch to |ooe| Cu||orut|on 87
Tab|e _.z. 0verv|ew on computut|onu| co:t: íor :|mu|ut|on: oí o|fferent :tuge: |or euch
:tuge _c :|mu|ut|on: on the one o|men:|onu| 1c ce|| :y:tem íor repre:entut|ve purumeter
:ett|ng: huve oeen oone uno the|r re:pect|ve runt|me |n :econo: huve oeen recoroeo |re-
:enteo ure the meun computut|on t|me: uno the|r re:pect|ve :tunouro oev|ut|on: (srJ) per
:tuge u: we|| u: per :tuge runt|me normu||zeo w|th the numoer oí con:|oereo :pec|e:
1
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meun |n :ec 13..66 _6_1__ (_((.( _11__ _1.3_ _c33_
srJ |n :ec c1___ c_.c_ c(__. cc))c cc1_c1 cc3)c
Tab|e _._. |u|rw|:e compur|:on re:u|t: oetween o|fferent :truteg|e: to |nc|uoe |níormut|on
on trun:|ent :tuge: |nto the purumeter opt|m|zut|on proce:: |or euch te:teo :trutegy, the
pu|rw|:e :|gn|ficunce te:t re:u|t: ure :hown w|th re:pect to convergence (c), quu||ty (¸), uno
runt|me (r) ¯hereoy, the row: :how entr|e: |n u co|umn whenever the methoo oep|cteo |n u
row :how: :|gn|ficunt|y oetter períormunce w|th re:pect to one oí the períormunce |no|cu-
tor: S|gn|ficunce te:t|ng |: oone u:|ng Kru:|u|-wu|||: te:t: como|neo w|th the Conover-lnmun
proceoure
!
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!osc
SD
--- --- --- --- --- --- --- --- --- --- ---
!osc
|D
--- --- --- -¸- --- --- --- --- --- --- ---
µoro
SD
c¸- c-- --r c¸- c¸- --- --- c-- --- --- ---
µoro
|D
--- --- --- -¸- --- --- --- --- --- --- ---
fi.
SD
--r --r --- -r- --- --- --- --- --- --- ---
fi.
|D
--r --r --- -r- --- --- --- --- --- --- ---
oJoµr-||
SD
c¸r -¸r --r -¸r c¸r c¸r --- c-r --- --- ---
oJoµr-||
|D
c¸r c¸r --r c¸r c¸r c¸r --- c¸r --- --- ---
oJoµr-|
SD
C --r --r --r --r -¸- --- --- --- --- --- ---
oJoµr-|
|D
c¸r c¸r c¸r c¸r c¸r c¸r --- --- c¸r --- -¸-
nc.
SD
C c¸r --r --r --r c¸- c¸- --- --- --- --- ---
nc.
|D
c¸r --r --r --r c¸- c-r --- --- --- --- ---
88 Chupter : |ethoo: íor |ooe| Cu||orut|on. lncorporut|ng 0omu|n Know|eoge
Tab|e _.µ. |un||ng on :|gn|ficunce re:u|t: oí the o|fferent :truteg|e: to |nc|uoe |níormut|on
on trun:|ent :tuge: |nto the purumeter opt|m|zut|on proce:: |or euch oí the te:teo :truteg|e:
uno u|| three períormunce |no|cutor:, convergence (c), quu||ty (¸), uno runt|me (r), the numoer oí
:truteg|e: :|gn|ficunt|y oe:t|ng the re:pect|ve :trutegy (-) u: we|| u: the numoer oí :truteg|e:
:|gn|ficunt|y oe:teo oy the re:pect|ve :trutegy (-) ure g|ven u: pu|r ’-/-’
!
o
s
c
S
D
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c 6/c _/c c/_ ./c 6/c 6/c c/( c/6 (/c c/3 1/_ 1/_
¸ 6/c _/1 c/_ _/1 _/c _/c c/_ c/6 ./1 c/) c/_ 1/.
r 3/c 3/c 6/1 _/c _/_ (/c c/) c/) _/( c/) c/( c/_
1ho losling is oono on Lasis of ¡· iuns foi oach slialogy, allowing up lo ¸uuu
sinulalions oi ¸uu gonoialions of lho MO-CMA-LS using a populalion sizo
of λ
mo
=¡u.
In aooilion, foi lhis sluoy wo oociooo lo ciicunvonl sono of lho conpula-
lion lino nocossaiy foi sinulalions: insloao of consiooiing lho lwo oinon-
sional ailificial longiluoinal soclion lhiough lho SAM as spalial oonain, il
is iosliicloo lo a ono oinonsional syslon conlaining ¡u colls (soo Fig. ¸.6).
ComparIson
Wilh lho conpaiison of lho pioposoo appioachos, lho lwo lho hypolhosis
aio valioaloo lhal (i) inclusion of infoinalion on liansionl lissuo palloining
inpiovos lho ovoiall convoigonco of noool caliLialion piocossos ano (ii) lhal
oxploiling such infoinalion is capaLlo of iooucing lho nocossaiy conpula-
lion lino.
Resu|ts: Convergence PropertIes In a fiisl go ano aooiossing lho fiisl hy-
polhosis, lho Lasolino appioachos base
SO
ano base
MO
aio conpaioo lo slialo-
gios whoio foi ovoiy paianoloi solling lhal is consiooioo ouiing lho cali-
Lialion piocoss all lhioo slagos aio sinulaloo, nanoly para
SO
ano para
MO
.
Inoooo, inclusion of lhoso infoinalion inpiovos lho convoigonco of lho pa-
ianoloi oplinizalion piocoss significanlly (soo 1aL. ¸.¸): para
SO
shows Lol-
:2 ||erurch|cu| /pprouch to |ooe| Cu||orut|on 89
loi convoigonco piopoilios lhan Lolh, base
SO
ano base
MO
. Al lho sano lino,
para
MO
, base
SO
, ano base
MO
aio inoiffoionl wilh iospocl lo convoigonco.
Incluoing lho soquonlial appioachos inlo lho conpaiison, convoigonco ano
qualily piopoilios aio fuilhoi inpiovoo: adapt-II
SO
, adapt-II
MO
, ano adapt-
I
MO
show significanl inpiovononls conpaioo lo base
SO
, base
MO
, ano para
MO
.
1his finoing pioLaLly has lo Lo alliiLuloo lo lho facl lhal lho ooponoonco
Lolwoon lho oiffoionl slagos ouiing oovolopnonl can Lo oxploiloo whon
infoinalion on succossful soaich oisliiLulions foi lho paianoloi suLspacos
fion piovious slagos is liansfoiioo lo laloi slagos. An iooa lhal is suppoiloo
Ly lho facl lhal lho slialogios lhal oo nol liansfoi such infoinalion Lul al-
ways slail of wilh a now soaich oisliiLulion (new
SO
ano new
MO
) aio nol
significanlly Lolloi lhan oilhoi para
SO
oi para
MO
(soo 1aL. ¸.¸). Allhough il
is Lonoficial lo liansfoi infoinalion on soaich oisliiLulions Lolwoon slagos,
lho oaily slagos soon lo Lo insufficionl lo alioaoy ioonlify oofinilivo sollings
foi lho involvoo paianolois lhal ionain fixoo ouiing laloi slagos. Iospoc-
livo slialogios fix
SO
ano fix
MO
aio Lolh significanlly woiso lhan nosl of lho
appioachos whoio paianolois ionain fioo.
1hoioLy, lho iosulls suppoil lho fiisl hypolhosis lhal inclusion of infoina-
lion on liansionl lissuo palloining inpiovos lho ovoiall convoigonco of lho
noool caliLialion piocossos.
Resu|ts: ComputatIona| Cost Wilh iospocl lo lho socono hypolhosis lhal
oxploilalion of infoinalion on liansionl lissuo palloining is capaLlo of io-
oucing lho nocossaiy conpulalion lino, again fiisl lho Lasolino appioachos
base
SO
ano base
MO
aio conpaioo lo lho paiallol appioachos para
SO
ano
para
MO
. Whilo lho paiallol appioachos havo accoss lo a naxinun of in-
foinalion, sinulaling always ovoiy slago inliooucos consiooiaLlo aooilional
conpulalional cosl. In caso of lho SAM noool whoio foi lho fiisl slago lwo
spocios, foi lho socono slago foui spocios, ano foi lho final slago ¸ spocios
aio consiooioo, lhis anounl lo ·.· linos lho conpulalional offoil.
Novoilholoss, in loins of iunlino lho foui slialogios aio inoislinguishaLlo
oospilo lho oxlia in conpulalional cosl (soo 1aL. ¸.¸). 1his can Lo oxplainoo
Ly lho slighlly Lolloi convoigonco piopoilios of lho lalloi lwo appioachos
90 Chupter : |ethoo: íor |ooe| Cu||orut|on. lncorporut|ng 0omu|n Know|eoge
(ovon whon nol significanl in caso of para
MO
): sono of lho iuns convoigo
alioaoy quilo fasl using nuch loss conpulalion lino lhan lho Lasolino ap-
pioachos.
Consiooiing lho soquonlial appioachos as woll, all of lhoso piovioo a signifi-
canl inpiovononl in nocossaiy conpulalion lino whon conpaioo lo base
SO
,
base
MO
, para
SO
, ano para
MO
(soo 1aL. ¸.¸). 1hoioLy, lho socono hypolhosis
is valioaloo.
Only lho influonco of using nullioLjoclivo vaiianls conpaioo lo singlooL-
joclivo vaiianls is loss cloai: apail fion lho vaiianls whoio all slagos aio
consiooioo sinullanoously, lho nullioLjoclivo appioachos aio supoiioi lo lho
singlooLjoclivo onos (soo 1aL. ¸.¸). Sinco a pio-sluoy has shown lhal oivoi-
sily in lho founo paianoloi solling is ciucial foi a succossful oplinizalion
piocoss, lhis can Lo oxplainoo wilh lho facl lhal nullioLjoclivo appioachos
in gonoial suppoil oivoisily whilo ovon sol Lasoo singlooLjoclivo appioachos
lono lo show loss oivoisily. Slill, in caso of para ano new, lho singlooLjoclivo
vaiianls soon lo Lo supoiioi. A possiLlo oxplanalion foi lhis finoing nighl
Lo lhal in lhoso casos lho nullioLjoclivo appioach in conLinalion wilh ois-
ciolo filnoss funclions inlioouco anLiguilios lhal cannol Lo iosolvoo using
lho hypoivoluno ano in consoquonco oLscuio lho oplinizalion piocoss.
5.3· Conc|usIons
1his chaploi piosonloo lwo oiffoionl slialogios lo incluoo oonain knowloogo
in lho piocoss of noool caliLialion. 1ho lwo appioachos followoo oiffoionl
ioulos lo achiovo lhis goal: (i) infoinalion concoining analylical iosulls
wilh iospocl lo lho usoo palloin foinalion nochanisn ID syslons havo
Loon usoo ano (ii) infoinalion concoining lho couiso of lho oovolopnonlal
liajocloiy of lho syslons unooi consiooialion havo Loon usoo.
In lho fiisl appioach, lho MO-CMA-LS was usoo lo ioonlify paianoloi sol-
lings lhal conslilulo Lounoaiios lhal paililion lho paianoloi spaco of ID
syslons in iogions showing qualilalivoly oiffoionl syslon Lohavioi. 1his
soaich piocoss was guiooo Ly an ANN onsonLlo which was liainoo using
:: Conc|u:|on: 91
nunoiical oala gonoialoo foi a sinplo ioaclion oiffusion syslon ano an-
nolaloo wilh analylical iosulls. 1his solup was losloo on lhioo oiffoionl
ID syslons: lho aclivaloi-inhiLiloi syslon lhal was usoo foi liaining oala
gonoialion, ano lwo concoplually oiffoionl ioaclion oiffusion syslons: an
aclivaloi suLslialo syslon ano lho Liussolaloi.
Allhough lhis appioach is nol suiloo lo oullino lho Lounoaiios sopaial-
ing paianoloi spaco iogions showing qualilalivoly oiffoionl syslon Lohavioi
foi high-oinonsional paianoloi spacos ouo lo an oxpononlial incioaso of
sollings lhal woulo Lo nocossaiy lo oullino such Lounoaiios, lho nolhoo
ioliaLly ioonlifioo paianoloi sollings iosioing on such Lounoaiios. Il lhoio-
foio can Lo usoo lo guioo lho soaich piocoss lowaios a iogion showing a
coilain oosiioo qualilalivo syslon Lohavioi. 1hoioLy, plaloaus conlaining
paianoloi sollings lhal aio inoislinguishaLlo in loins of iosulling qualila-
livo Lohavioi can Lo avoiooo ano lho ovoiall caliLialion piocoss gols noio
officionl.
1ho socono appioach showoo on lho oxanplo of a noool foi SAM oovolop-
nonl ano nainlonanco in A. thaliana lo aio lho piocoss of noool caliLialion
oi paianoloi oslinalion oxploiling lho facl lhal oovolopnonlal liajocloiios
of such syslons aio hioiaichically sliucluioo ano iun lhiough a iango of
known liansionl slalos Lofoio lhoy ioach lhoii sloaoy slalo. Using lhoso
infoinalion il was possiLlo lo ooconposo lho iospoclivo noool inlo a sol
of noools foi lho oiffoionl liansionl slalos. 1ho pioposoo schono pioviooo
aooilional infoinalion foi lho ovoiall oplinizalion piocoss. Al lho sano
lino il iosulloo in a ioouclion of conpulalion lino nocossaiy foi noool
caliLialion—il allowoo lo sinulaloo loss lino consuning noools foi suL
syslons insloao of lho full syslon foi nany ovalualoo paianoloi sollings
ano lhoioLy savoo conpulalion lino. Sinco oovolopnonlal syslons shaio
lho hioiaichical sliucluio oxploiloo hoio, lhis appioach is consiooioo lo Lo
liansfoiaLlo lo fuilhoi syslons.
In conclusion, lho pioposoo appioachos oocunonloo lhal lho piocoss of
noool caliLialion can consiooiaLly Lonofil fion lho inclusion of oonain
knowloogo in lho caliLialion piocoss. In aooilion, il pioviooo schonos foi
92 Chupter : |ethoo: íor |ooe| Cu||orut|on. lncorporut|ng 0omu|n Know|eoge
such inclusions foi Lolh, nochanisn spocific oi lochnical knowloogo as woll
as Liological knowloogo.

Mode|Ing 5tem Ce|| HomeostasIs
and PatternIng In the 5hoot ApIca|
MerIstem of Arabidopsis thaliana
Arabidopsis thaliana Lolongs lo lho noool oiganisns consiooioo in oovolop-
nonlal Liology. Il is usoo lo sluoy vaiious aspocls of iogulalivo piocossos
lhal oflon havo aicholypo chaiacloi foi olhoi planls. In aooilion, sono io-
sulls can ovon Lo liansfoiioo lo olhoi lypos of oiganisns liko nannals. In
lhis iogaio, ospocially aspocls of planl oovolopnonl iolaloo lo slon colls aio
of inloiosl sinco foi nannals such sluoios aio nuch noio conplicaloo fion
an olhical poispoclivo.
1his chaploi is concoinoo wilh sluoying lho gono iogulalivo nolwoik (GIN)
unooilying shool apical noiislon (SAM) oovolopnonl ano nainlonanco in
Arabidopsis thaliana (A. thaliana), a lissuo lhal is iosponsiLlo foi aoiial
giowlh of lho planl ano foi lhis puiposo haiLois a pool of slon colls. As
nonlionoo aLovo, sluoying lho honooslasis of lhis slon coll oonain is of
inloiosl ouo lo ils possiLlo noool chaiacloi foi, o.g., nannalian oiganisns,
94 Chupter c |ooe||ng |uttern|ng |n the S/| oí / rho!|ono
as woll as noio lhoiough unooislanoing of nighl onaLlo iosoaichois lo lako
influonco on planl giowlh iolaloo aspocls liko ciop sizos.
Wilh iospocl lo noooling SAM iogulalion, Jonsson ol al. [_/[ hao pioviously
oosciiLoo a noool capluiing pail of lho inloiaclions Lolwoon lho lwo oo-
nains nainly iosponsiLlo foi shool apical noiislon iogulalion ano funclion,
lho WUSCHEL oxpiossing oiganizing conloi ano lho CLAVATA oxpiossing
slon coll oonain. 1hal noool conconlialoo on lho gonoialion of lho slon
coll oonain Ly a signal ooiivoo fion fion lho iogulaling oiganizing conloi
[_6[. Il oio nol yol incluoo lho nogalivo foooLack iogulalion of CLAVATA
signaling upon WUSCHEL oxpiossion, ano lho cioalion ano nainlonanco
of lho WUSCHEL oonain was nol sinulaloo. 1o confino lho CLAVATA
oonain lo lho noiislon lip, lho aulhois pioposoo lhal an (unioonlifioo)
facloi oiffusing fion lho ouloinosl noiislon layoi, lho L¡, logolhoi wilh
lho WUSCHEL-ooponoonl signal, inoucoo CLAVATA oxpiossion. 1hoy
laloi usoo a ioaclion-oiffusion (ID) noool conLinoo wilh lwo iopiossivo
signals, ooiivoo fion lho L¡ ano slon lissuo, lo aclivalo WUSCHEL ox-
piossion in a ooopoi noiislon iogion [_/[. Lolh noools woio succossful al
iopiooucing oilhoi lho oiganizing conloi oi lho slon coll oonain, Lul oio
nol incoipoialo lho nulual inloiooponoonco Lolwoon lho faclois lhal shapo
lho lwo oonains, ano woio loss paisinonious wilh syslon conpononls lhan
lho noool oosciiLoo hoio.
Anolhoi ioconlly puLlishoo noool Ly Goioi ol al. [._[ oio nol oosciiLo lho
spalial aiiangononl of lho SAM iogulaling oonains, Lul aooiossoo lho oL-
soivalion lhal slon coll oonain ano oiganizing conloi sizos vaiy sliongly
unooi changing onviionnonlal conoilions. 1ho noool oosciiLos lho slon
coll oonain ano oiganizing conloi as coll pools lhal aio connocloo via oif-
foionlialion ialos ano oxpano ouo lo coll piolifoialion, which is iogaiooo as
an oxloinally conliolloo paianoloi. Vaiialion in lho iolalivo sizos of slon
coll oonain ano oiganizing conloi can Lo oxplainoo Ly assuning lhal a oif-
foionlialion signal X is piooucoo Ly oiganizing conloi oi slon coll oonain,
which can Luffoi lho iosponso of lho coll pools againsl changos in piolifoia-
lion ialos. Allhough lhis noool oio nol allow iopiooucing all nulanl ano
ovoioxpiossion oxpoiinonls lhal aio sinulaloo hoio, il conLinoo noooling
c+ 3|o|og|cu| 3uc|grouno on S/| |egu|ut|on 95
appioachos wilh quanlilalivo oala, ano highlighloo lho onoinous oovolop-
nonlal plaslicily of lho noiislon.
1ho noool pioposoo hoio is concoinoo wilh sinulaling lho oiigin ano nain-
lonanco of a oofinoo slon coll oonain al lho lip of A. thaliana SAMs, Lasoo
on lho assunplion lhal noiislons aio solf-oiganizing syslons. 1his noool
conpiisos lwo couploo foooLack iogulaloo gonolic syslons lhal conliol slon
coll Lohavioi. Lasoo on a nininal sol of spalial paianolois, il allows lo pio-
oicl aulononous gonoialion, shapo ano sizo of lho slon coll oonain, ano
lho unooilying oiganizing conloi. Il lhoioLy oxlonos lho pioviously puL-
lishoo SAM noools ano is usoo lo oxploio lho paianoloi spaco lhal allows
slon coll nainlonanco, ano lo sinulalo lho consoquoncos of nulalions, gono
nis-oxpiossion ano coll aLlalions. hoio, lho oxploialion of lho noool pa-
ianoloi spaco has Loon oono using lochniquos lhal woio oovolopoo in lho
concuiionlly puisuoo woik on noool caliLialion. In luin lho nanual, hi-
oiaichical noool caliLialion piocoss usoo foi lhis noool ano oosciiLoo in
Soclion 6.·.· inspiioo lho appioach foi aulonaloo hioiaichical noool cali-
Lialion piosonloo in lho piovious chaploi.
6.1 · ßIo|ogIca| ßackground on 5AM Regu|atIon
Giowlh of lho aoiial pails of highoi planls iolios on a lifo-long supply
wilh colls Ly lho SAM. 1ho SAM conlains a snall populalion of non-
oiffoionlialing slon colls in lho conlial zono al lho noiislon lip [_3[. Afloi
coll oivisions in lho slon coll oonain (SCD), oaughloi colls aio shifloo lo-
waios lho suiiounoing poiiphoial zono, whoio oigan piinoioia aio inilialoo
ano colls can onloi a oiffoionlialion palhway. 1ho aichilocluial nakoup
of flowoi piinoioia, which givos iiso lo lho planlYs iopioouclivo oigans,
iosonLlos lhal of lho SAM wilh lho nain oiffoionco lhal slon coll acliv-
ily is swilchoo off in flowois afloi gonoialion of a spocios-spocific nunLoi
of oigans. Il is ovioonl lhal lano planls such as lioos, which can giow in
sizo ano pioouco now oigans foi hunoioos of yoais, nusl havo oovolopoo
ioLusl iogulaloiy syslons lhal onaLlo lhon lo nainlain aclivo slon coll
96 Chupter c |ooe||ng |uttern|ng |n the S/| oí / rho!|ono
populalions also unooi changing oi aovoiso onviionnonlal conoilions. Dis-
luiLing slon coll iogulalion can aiiosl lho giowlh of a planlYs shool lip, oi
nay iosull in gioss lissuo ovoi-piolifoialion ano failuio lo iopioouco. Moio
suLllo alloialions in slon coll piolifoialion can affocl ovoiall sizo of a sooo-
piooucing infloiosconco sliucluios, such as a naizo coL, lho sizo of a fiuil,
oi lho nunLoi of polals in a hoiliculluial flowoi. Wo aio only jusl Loginning
lo unooislano how lho falo of lho slon coll populalion is iogulaloo in highoi
planls.
Mainlonanco of lho unoiffoionlialing slon coll populalion ooponos on sig-
nals fion colls of lho oiganizing conloi (OC), which iosioo unooinoalh lho
SCD in a ooopoi iogion of lho noiislon. Sovoial gono piooucls havo Loon
ioonlifioo lhal onaLlo lhoso aojaconl coll gioups lo connunicalo wilh oach
olhoi. 1ho slon colls of A. thaliana sociolo lho CLAVA1A¸ (CLV¸) pop-
lioo, consisling of ¡· anino acios [_, .(, 6_[. CLAVATA (CLV) was shown
lo inloiacl wilh lho LII-iocoploi kinaso CLAVATA (CLV) lhal is ox-
piossoo in ano suiiounoing lho OC [1/, 3([. A socono iocoploi syslon
conposoo of lho LII-pioloin CLAVATA (CLV) ano lho nonLiano as-
socialoo kinaso CORYNE (CRN) is noio wiooly oxpiossoo in lho noiislon
ano vasculaluio, ano also conliiLulos lo signal poicoplion [_(, /_[. CLV
ooponoonl aclivalion of lho lwo iocoploi syslons iopiossos lho oxpiossion of
WUSCHEL (WUS), a honoooonain liansciiplion facloi lhal is noinally
piooucoo fion OC colls, ano which is ioquiioo foi lho nainlonanco of slon
colls [66, 63[. WUS ilsolf acls non-collaulononously lo pionolo slon coll
falo al lho noiislon lip. 1ho WUS pioloin ooos nol soon lo novo, ano il
coulo conliol lho oxpiossion of olhoi gonos lhal gonoialo a oiffusiLlo signal
which ullinaloly pionolos slon coll ioonlily [_/[. Soaichos foi laigol gonos
showoo lhal sovoial ARABIDOPSIS RESPONSE REGULATOR (ARR)
gonos, which aio nogalivo iogulalois of cylokinin signaling, aio iopiossoo
Ly WUS, lhus involving cylokinin in noiislon nainlonanco [6/[. Howovoi,
WUS inoucos slon coll falo only al lho noiislon lip, ano nol in lho (WUS
oxpiossing) OC colls oi olhoi suiiounoing colls, inoicaling lhal a spalially
iosliicloo cofacloi, oi a conpolonl collulai slalo is ioquiioo lo iospono lo
WUS aclivily [1c([.
c+ 3|o|og|cu| 3uc|grouno on S/| |egu|ut|on 97
Locauso slon colls signal Lack lo lho OC via CLV ano ils iocoplois lo
iosliicl WUS oxpiossion, a foooLack ciicuiliy is oslaLlishoo lhal nainlains
a slaLlo slon coll populalion. Suppoil foi lhis noool of slon coll honoosla-
sis conos fion a nunLoi of oxpoiinonlal oLsoivalions: (i) loss-of-funclion
nulanls of WUS cannol nainlain slon colls [66[; (ii) loss-of-funclion nu-
lanls of CLV (oi CLV, CLV oi CRN) allow foi loss iosliicloo WUS
oxpiossion ano pioouclion of oxcossivo slon colls [_, .(, /3, /_[; (iii) consli-
lulivo high lovol oxpiossion of CLV iopiossos WUS, causing slon coll loss
[_[; (iv) whon WUS oxpiossion is uncouploo fion iopiossion Ly CLV, o.g.,
whon conliolloo fion a holoiologous pionoloi, lho slon coll oonain ox-
panos [1c, _([; (v) lho CLV,WUS ciicuiliy is capaLlo of solf-oiganizalion.
1his was iovoaloo Ly lasoi aLlalion oxpoiinonls in lonalo, showing lhal af-
loi olininalion of Lolh SCD ano OC, now oonains of WUS oxpiossion aio
gonoialoo al poiiphoial silos lhal lhon inilialo now SCDs, which suppoil
fuilhoi giowlh of lho SAM [_c[.
Howovoi, all piovious sluoios poifoinoo on vaiious nulanls oi conslilulivo
nis-oxpiossion linos oio nol allow sluoying lho innooialo consoquoncos of
syslon poiluiLalions. Coll aLlalion oxpoiinonls aio fuilhoi conplicaloo Ly
wounoing offocls, ano oclopic coll oivisions in lho SAM which aio ioquiioo
foi iogonoialion. Analyzing lho oynanics of lho CLV,WUS ciicuiliy al
a shoiloi linoscalo ioquiioo iapio ano liansionl poiluiLalions of gono ox-
piossion. In a fiisl sluoy of lhis lypo, CLV oxpiossion was siloncoo Ly
Doxanolhason-inoucoo oxpiossion of a foloLack CLV INA [3_[. Livo inag-
ing of lho SAM Lofoio ano afloi CLV siloncing showoo lhal oxpiossion of a
CLV:GFI liansgono, acling as a iopoiloi foi slon coll ioonlily, oxlonooo
inlo colls aojaconl lo lho conlial zono wilhin ·¸ houis afloi inouclion. In-
poilanlly, lhis io-spocificalion of poiiphoial colls lo slon coll ioonlily was
nol piocoooo Ly coll oivisions. In a sinilaily oosignoo oxpoiinonl, inouclion
of high lovol CLV oxpiossion oown-iogulaloo Lolh WUS oxpiossion, ano lho
slon coll naikoi CLV, wilhin ¸ houis [/3[. 1ogolhoi, lhoso oxpoiinonls
showoo lhal lho CLV,WUS ciicuiliy is acling lhioughoul oovolopnonl,
ano lhal lho oulpul, slon coll nunLoi, can Lo conlinuously ioaojusloo in
iosponso lo changing anounls of lho signaling conpononls. In lino wilh
98 Chupter c |ooe||ng |uttern|ng |n the S/| oí / rho!|ono
lhis, fluclualions of conlial zono sizo woio oLsoivoo, inoicaling conlinuous
aclivily of lho ciicuiliy [3_[.
Howovoi, lho CLV,WUS ciicuiliy was also founo lo Lo suipiisingly io-
Lusl ano lo loloialo changos in CLV oxpiossion lovols ovoi a lonfolo iango
[/3[, inoicaling lhal slon colls oo nol oiioclly connunicalo lhoii nun-
Loi via lho anounl of ioloasoo CLV signal. Fuilhoinoio, whilo sliong
CLV signaling iapioly iopiossoo WUS oxpiossion, a slowly acling con-
ponsalion nochanisn appoaioo lo upiogulalo WUS wilh lino. 1ho conpo-
nonls of lhis conponsaloiy ciicuiliy aio unknown, Lul nay Lo founo anong
lho gono sol lhal conliols WUS oxpiossion. SPLAYED (SYD) oncooos a
SNF-lypo chionalin-ionoooling A1Iaso lhal is ioquiioo foi WUS lian-
sciiplion [6_[. LAID¡, caiiying LIC1 ano IING oonains, inloiacls wilh
ano anlagonizos SYD lo iosliicl WUS oxpiossion lo lho OC [(c[. HANABA
TARANU (HAN), cooing foi a GA1A-liansciiplion facloi, iopiossos WUS
posl-onLiyonically fion lho oovoloping vasculaluio [1c_[. 1ho inloiplay
Lolwoon lhoso conpononls is nol unooislooo, ano lhoy nay acl oxclusivoly
lo oslaLlish a oisciolo WUS oxpiossion oonain whon noiislons aio gonoi-
aloo. Duiing oovolopnonl, a socono foooLack nochanisn coulo opoialo via
lho cylokinin signaling palhway. WUS iopiossos lho oxpiossion of sovoial
ARRs in lho noiislon, which iosliicl cylokinin signaling [6/[. In luin, con-
linuous aclivalion of ARRs aiiosls noiislon aclivily ano WUS oxpiossion,
suggosling lhal WUS ano ARRs nulually iopioss oach olhoi.
Hoio, a conpulalional noool of slon coll falo iogulalion Ly lho CLV,WUS
ciicuiliy in lho SAM is pioposoo. 1ho noool incoipoialos lwo foooLack
iogulaloiy syslons lhal noigo upon WUS iogulalion. 1ho oiiving foico
foi noooling was lo Lolloi unooislano lho foicos lhal shapo lho CLV ano
WUS oxpiossion oonains, whilo naking lho nininal nunLoi of nocossaiy
assunplions aLoul lho faclois lo Lo involvoo. lho noool is usoo lo sluoy
lho offocls of laigoloo syslon poiluiLalions, ano lo oxploio lho paianoloi
spaco lhal allows foi slon coll honooslasis unooi fluclualing conoilions.
c2 S/| |ooe| 99
6.2· 5AM Mode|
In lhis soclion lho pioposoo noool is piosonloo. 1his piosonlalion oncon-
passos lho ooiivalion of lho noool oqualions ano oosciiplions of lho lho
occuiiing noool paianolois, oolails on noool caliLialion, ano infoinalion
concoining lho nunoiical sinulalion piocoss usoo lo gonoialo noool piooic-
lions.
6.2.1 · Mode|Ing 0etaI|s
Lasoo on lho gono inloiaclion oiagian shown in Fig. 6.¡, a syslon of couploo
oiffoionlial oqualions (DLs) is sol up lhal oosciiLos lho lonpoial ovolulion
of conconlialions of lho faclois [WUS], [FacX], [WUS
sig
], [sl], ano [CLV¸]
insioo lho colls of lho SAM. 1ho inloiplay Lolwoon [WUS] ano [FacX]
is inplononloo Ly a vaiianl of lho aclivaloi suLslialo ID syslon lhal is
known lo pioouco ciiculai oonains lhal ionain noLilo [61[. 1hoioLy, an OC
can foin in lho noiislon lip ano novo oown afloi inilialion of lho SCD. 1ho
kinolics foi lho ionaining spocios [WUS
sig
], [sl], ano [CLV¸] aio inspiioo Ly
lho law of nass aclion. 1ho lhioo-oinonsional oono of colls consliluling lho
SAM is iopiosonloo in lho noool Ly a lwo-oinonsional ailificial longiluoinal
soclion (soo Fig. 6.¡). 1his soclion was gonoialoo Ly posilioning coll conlois
ano using a Voionoi ooconposilion in oiooi lo gonoialo possiLlo coll walls
ano lhoioLy oofining lho colls. Foi lho sinulalions zoio flux Lounoaiios
confining lho sinulaloo oonain aio assunoo. 1ho noool oqualions aio
givon in lho following:
∂ [WUS]
∂t
=D
WUS
∆[WUS] +w
ko
ξρ
anc
[WUS]
2
[FacX]
1 + ([CLV¸] + [CLV¸
oxl
])
3
−µ
WUS
[WUS] +σ
WUS
, (6.¡)
∂ [FacX]
∂t
=D
FacX
∆[FacX] +w
ko
ξρ
anc
[WUS]
2
[FacX]
1 + ([CLV¸] + [CLV¸
oxl
])
3
+
σ
FacX
1 +
[FacX]
K
FacX
, (6.·)
100 Chupter c |ooe||ng |uttern|ng |n the S/| oí / rho!|ono
∂ [WUS
sig
]
∂t
=D
WUS
sig
∆[WUS
sig
] +ρ
WUS
sig
[WUS]
−µ
WUS
sig
[WUS
sig
] , (6.¸)
∂ [sl]
∂t
=D
sl
∆[sl] + 
id
(i) ρ
sl
(
[WUS
sig
]
K
sl
)
5
1 +
(
[WUS
sig
]
K
sl
)
5
−µ
sl
[sl] , (6.¸)
∂ [CLV¸]
∂t
=D
CLV¸
∆[CLV¸] +c
ko
ρ
CLV¸
[sl] −µ
CLV¸
[CLV¸] . (6.¸)
1ho noool ooponos on lho following paianolois: ioaclion ialos ρ, Lasal ox-
piossion ialos σ, oogiaoalion ialos µ, ano kinolic conslanls K. Whilo nosl
paianolois sollings aio sinilai foi all colls of lho consiooioo sinulaloo oo-
nain, lhoio aio lwo oxcoplions: (i) lho ioaclion ialo ρ
anc
(Lqs. 6.¡ ano 6.·) is
givon Ly a oisliiLulion wilh ils naxinun in lho noiislon lip (soo Fig. 6.¡),
an ailificial spalial conpononl nocossaiy foi coiiocl localion of oovoloping
SCD ano OC wilhin lho noiislon. In aooilion ρ
anc
is poiluiLoo Ly a snall
unifoinly ianoon valuo ξ ∈ [-u.u·¸, u.u·¸] which is a ianoon influonco
nocossaiy foi lhis suLsyslon lo pioouco palloins. (ii) 1ho ioaclion loin
guioing [sl] ooponos on lho inoicaloi funclion 
id
. Sinco only colls in lho
ouloi coll layois aio assunoo lo Lo conpolonl lo acquiio slon coll ioon-
lily, foi conpolonl colls i lho inoicaloi funclion ioluins a valuo 
id
=¡ ano

id
=u olhoiwiso. Whilo lho foinoi paianolois iofoi lo piocossos laking
placo wilhin lho colls, lho noool incluoos inloiaclions Lolwoon noighLoiing
colls as woll. 1his inloiaclion is noooloo Ly oiffusion loins D∆, whoio ∆
is lho Laplaco opoialoi in lwo oinonsions ano D is a oiffusion ialo. Nolo
lhal allhough [WUS] ano [sl] aio consiooioo lo Lo only locally aclivo, lhoii
noool oqualions (Lqs. 6.¡ ano 6.¸) conlain oiffusion loins sinco foi lhoso
lwo faclois a woak loakago oiffusion is assunoo.
On lop of lho paianolois lhal aio alioaoy oosciiLoo, lho noool conlains a
sol of paianolois lhal is usoo lo acconnooalo lho oiffoionl noooloo nu-
lanls ano oxpoiinonls. In lhis conloxl, c
ko
is usoo lo sinulalo iogulalion
of onoogonous CLV¸; c
ko
nooifios lho ioaclion loin guioing CLV oxpios-
sion whoio c
ko
=¡ sinulalos a wilolypo silualion whilo c
ko
=u iopiosonls a
c2 S/| |ooe| 101
knockoul ano valuos c
ko
>¡ iopiosonl ovoioxpiossion of onoogonous CLV¸.
Choosing c
ko
valuos c
ko
∈ [u, ∞), giaooo sconaiios can Lo sinulaloo. Using
a conpaiaLlo paianoloi w
ko
∈ [u, ¡], il is possiLlo lo sinulalo giaooo WUS
knockouls (soo Apponoix A). Again a valuo of w
ko
=¡ iopiosonls a wilolypo
sconaiio whilo w
ko
=u iopiosonls a knockoul. 1ho paianoloi [CLV¸
oxl
] is
usoo lo sinulalo a CLAVA1A Lackgiouno in all colls. In a wilolypo sco-
naiio, [CLV¸
oxl
] is sol lo u ano wilh [CLV¸
oxl
] ∈ [u, ∞) a iango of giaooo
CLV¸ Lackgiouno slionglhs can Lo sinulaloo. In aooilion, foi sinulalions
losling conoilions wilh iospocl lo factor X (FacX) unooi which OC ano
SCD aio gonoialoo lho alioaoy inliooucoo paianoloi K
FacX
is vaiioo.
6.2.2· Mode| Ca|IbratIon
1ho noool paianoloi solling foi lho wilolypo sinulalions as woll as foi
lho sinulalions of nulanls aio givon in 1aLs. 6.¡ ano 6.·. As nonlionoo
alioaoy in lho inlioouclion, al lho lino whoio lho noool was gonoialoo
only piololypos of lho laloi oovolopoo paianoloi caliLialion nolhoo havo
Loon availaLlo. 1hoiofoio, al lhis slago noool paianolois havo Loon lunoo
Ly hano using a lypo of hioiaichical ooconposilion of lho syslon: fion
a oovolopnonlal poispoclivo fiislly lho OC is foinoo which lhon inoucos
lho foinalion of a SCD. Foi lho paianoloi luning piocoss lhoiofoio lho
syslon has Loon oiviooo inlo lwo pails. (i) Lqualions 6.¡ ano 6.· which
aio iosponsiLlo foi lho foinalion of lho OC. (ii) Lqualions 6.¸, 6.¸, ano
6.¸ lhal conslilulo lho SCD gonoialing pail of lho syslon. Duiing a lhioo-
slago luning piocoss fiisl only lho OC gonoialing syslon is consiooioo in
oiooi lo ioonlify paianolois iosulling in a singlo ano spalially confinoo
OC oonain. Foi lhis suLsyslon, inilial paianoloi sollings as oocunonloo
pioviously [61[ woio usoo, ano il was possiLlo lo ioonlify filling paianolois
ioasonaLly closo lo lho inilial sollings. Using lho iosulling OC as inpul,
lho paianolois foi lho SCD gonoialing pail of lho syslon havo Loon lunoo.
Hoio, lho foooLack of CLV¸ on WUS was noglocloo ano insloao lho goal
was lo ioonlify paianoloi sollings which iosulloo in an SCD of appiopiialo
sizo ano an aioa unooi CLV¸ influonco lhal oxlonos lho SCD Lul ionains
spalially confinoo as woll. In lho lasl slop, lho full syslon was consiooioo,
102 Chupter c |ooe||ng |uttern|ng |n the S/| oí / rho!|ono
Tab|e 6.±. Summury oí con:tunt mooe| purumeter: ρ
onc
ío||ow: u con:tunt o|:tr|out|on
:hown |n ||g 61
|urumeter 0
wUS
0
|uc`
0
wUS
:|g
0
:t
0
CLv_
ρ
onc
ρ
wUS
:|g
ρ
:t
ρ
CLv_
vu|ue ccc. cc. cc. ccc. cc. o|:t c_ c6 cc_
|urumeter µ
wUS
µ
wUS
:|g
µ
:t
µ
CLv_
σ
wUS
σ
|uc`
r
|uc`
r
:t
vu|ue ccc( cc_ cc_ cc1 cccc. ccc( c. 1
Tab|e 6.z Scenur|o oepenoent mooe| purumeter:
w|th the|r re:pect|ve vu|ue: w¯ oe:cr|oe: the w||o
type :ett|ng CLv_↑. over-e·pre::|on oí CLv_ |n u||
ce||: (:tem ce||: uno non-:tem ce||:) CLv_↓. CLv_
|o:: oí íunct|on mutunt C|v_≫wUS. L·pre::|on oí
wUS |n the :tem ce|| oomu|n, contro||eo oy the C|v_
promoter
[C|v_
c.r
] c
ko
w¯ c 1
Lu:er /o|ut|on c 1
CLv_↑, meo|um 1 1
CLv_↑, :trong 1_ 1
CLv_↓ c c
CLv_↓, gruouu| c c.
C|v_ ≫wUS c 1
aojusling lho paianolois iosponsiLlo foi lho foooLack piocoss Lolwoon lho
lwo suLsyslons. 1his hioiaichical appioach lo noool caliLialion gavo iiso
lo lho aulonaloo hioiaichical caliLialion nolhoo oosciiLoo in Soclion ¸.·.
6.2.3· 5Imu|atIon 0etaI|s
Foi lho nunoiical sinulalion of lho noool pailial oiffoionlial oqualions
(IDLs), zoio flux conoilions on lho Lounoaiios of lho coll plano aio as-
sunoo. In oiooi lo sinulalo lho lino ovolulion of lho noool, lho noool
oqualions aio nunoiically inlogialoo. 1ho oqualions havo lo Lo oisciolizoo
wilh iospocl lo lino ano spaco, hoio using a conslanl lino slop δ
t
=u.·¸
ano applying a finilo oiffoionco schono in collulai iosolulion lo lho spaco-
ooponoonl oiffusion loins. Lach coll is lhoioLy iopiosonloo Ly ils conloi
ano foi lho sako of sinplicily, coll volunos aio consiooioo lo show lho gia-
oionls lhal woulo Lo assunoo Lolwoon lho conconlialions sinulaloo foi lho
coll conlois. In aooilion, fioo oiffusion is assunoo as lho only noans of con-
nunicalion Lolwoon colls. Locauso lho piociso connunicalion unooilying
WUS ooponoonl signaling is slill unknown, fioo oiffusion iopiosonls a soil
c2 S/| |ooe| 103
of ’naxinun onliopy choico’. In loins of noooling conploxily wo Lono-
fil fion lhis facl: wilh fioo oiffusion, oxliacollulai spacos, coll walls ano
nonLianos can Lo noglocloo ouiing lho sinulalion piocoss. In aooilion,
ouo lo lho Voionoi ooconposilion usoo lo gonoialo lho consiooioo soclion
lhiough lho noiislons, coll volunos ano suifacos lono lo ovon oul. Sinco
lho noool is nol supposoo lo gonoialo quanlilalivo oala, Lul ialhoi lo in-
vosligalo qualilalivo Lohavioi, lho influonco of coll suifacos ano volunos
ouiing sinulalions is noglocloo.
1ho oiffusion loins in lho consiooioo syslon lono lo Lo sliff, ano lhoiofoio
a vaiianl of lho socono oiooi inplicil Ciank-Nicolson inlogialoi is applioo
lo lhoso loins, whilo lo lho only-lino-ooponoonl loins a fasloi oxplicil
Aoans-Lashfoio schono is applioo. 1his inplicil-oxplicil (IMLX) schono
(soo Soclion ¸.·.¸ in Chaploi ¸) is choson in oiooi lo ioach an appiopiialo
liaoo-off Lolwoon nocossaiy conpulalional offoil ano sinulalion accuiacy:
ouo lo lhoii sliffnoss, lho oiffusion loins aio oifficull lo sinulalo. 1hoiofoio,
lho conpulalionally oonanoing Lul noio accuialo Ciank-Nicolson nolhoo
is usoo. 1ho ioaclion loins in conliasl aio nuch loss oonanoing ano can
lhoiofoio Lo sinulaloo using a nuch fasloi Lul loss accuialo oxplicil schono.
1ho nunoiical sinulalions foi lho consiooioo sconaiios aio oono in a lwo-
slago piocoss. 1ho fiisl slago is usoo lo oquiliLialo lho syslon slailing
fion lho inilial conoilions. Hoio, unooi ’oquiliLiiun slalo’ a syslon slalo
in which all ooiivalivos aio ioasonaLly closo lo zoio is unooislooo. Duiing
lho socono slago lho paianolois aio aoaploo in oiooi lo acconnooalo lho
consiooioo sconaiios. As inilial conoilion foi lho fiisl slago, lho WUS lovol
of all colls is honogonoously inilializoo wilh a slailing conconlialion of
[WUS]=u.u¡. All olhoi spocios aio inilializoo wilh a valuo of u. In lho fiisl
slago, lho syslon is sinulaloo foi ¸uuuu lino unils. Foi lho socono slago
lho oquiliLiiun conconlialions oLlainoo in lho fiisl slago aio usoo as inilial
conoilions, lho paianolois aio aoaploo ano in caso of lho lasoi aLlalion
sconaiio lho lissuo lopology is aoaploo. Afloiwaios lho syslon is sinulaloo
foi fuilhoi ¡¸uuu lino slops.
104 Chupter c |ooe||ng |uttern|ng |n the S/| oí / rho!|ono
FIgure 6.± |ooe||ng compo-
nent: uno ce||u|ur írumewor|
/. Component: uno the|r
|nteruct|on: regu|ut|ng :tem
ce|| homeo:tu:|: |n / rho!|ono
3. ¯wo o|men:|onu| mer|:tem
írume w|th u::umeo unchor-
|ng o|:tr|out|on |no|cuteo oy
co|or|ng
B A
low
high
stem cell
identity
WUS dependent
signal (diffusive)
WUS
factor X
(diffusive)
CLV3
(diffusive)
6.3· 5Imu|atIon Resu|ts
A IDL noool following lho oynanics of gono iogulalion acioss lho SAM
(soo Fig. 6.¡) is pioposoo. Concoplually, al lho conloi of lho noool lios
lho iogulalion of WUS via lwo sopaiaLlo foooLack opoialoo ID syslons, a
connonly usoo lypo of DL noools foi oovolopnonlal piocossos in Liology
[1c_[. Insloao of iopiosonling lho onliio noiislon sliucluio, lho spalial
conpononl is iosliicloo lo lwo oinonsions using an ailificial longiluoinal
soclion lhiough lho SAM (soo Fig. 6.¡). Colls wilhin lhis noiislon soclion
aio noooloo as oisciolo onlilios. Giowlh ano coll oivisions aio noglocloo
foi lwo ioasons: fiislly, lhis sluoy focusos on noiislon honooslasis, i.o.,
noiislon sizo ionains unalloioo, ano soconoly, lho gono iogulalion lhal is
consiooioo in lhis sluoy is fasloi lhan lho coll cyclo. 1ho collulai oi lissuo
fianowoik lhus ionains slalic. 1ho iogulalivo piocossos wilhin colls aio
nappoo lo a sol of IDLs consliluling a gono iogulalivo piogian, which is
oxoculoo in oach coll. 1ho conpononls ano unooilying assunplions of lho
noool aio sunnaiizoo as follows (soo Fig. 6.¡):
5temness: Colls of lho noiislon can acquiio slon coll ioonlily, ioflocloo in
lhoii lovol of slonnoss, which is conliolloo Ly a WUS-ooponoonl signal
(WUS-signal, soo Lolow). An ailificial ano slalic cul-off conconlialion
foi WUS-signal is avoiooo, aLovo which colls swilch lo lho slon coll
slalus, ano insloao a oynanic, Lul signoioal iosponso lo WUS-signal is
oslaLlishoo, iosulling in vaiiaLlo lovols of slonnoss lo iopiosonl a collYs
slalo.
c: S|mu|ut|on |e:u|t: 105
Lxpoiinonlal ovioonco fion WUS nisoxpiossion shows lhal only ouloi
coll layois acquiio slon coll ioonlily. 1ho unooilying faclois iosponsiLlo
foi lhis aio nol known. Low nol anolhoi signal is poslulaloo, Lul lhis
oLsoivalion is lakon inlo accounl Ly allowing only colls in ouloi coll layois
lo acquiio slon coll ioonlily. 1hoiofoio, only colls in lho ouloi layois of
lho noiislon aio conpolonl lo ioacl lo WUS-signal ano slonnoss is
iosliicloo lo lho ouloi layois. Slon colls oxpioss lho signaling noloculo
CLV¸, piopoilional lo lhoii slonnoss lovol. 1ho slonnoss lovols aio
oxpiossoo Ly lho noool vaiiaLlo [sl].
CLv_: CLV¸ fiooly oiffusos lo noighLoiing colls. 1o avoio floooing lho on-
liio noool wilh CLV¸, lho CLV¸ poplioo is iogaiooo lo oocay wilh lino.
1ho nooo foi iocoploi pioloins oi olhoi signaling conpononls is olini-
naloo Locauso insufficionl quanlilalivo oala aio availaLlo lo assoss lhoii
conliiLulion. Fuilhoinoio, CLV-signaling appoais lo Lo laigoly con-
liolloo Ly lho anounl of availaLlo CLV¸ poplioo [/3[. 1hus, lho local
CLV¸ conconlialion is conpuloo lo oiioclly iosliicl WUS oxpiossion.
1ho CLV¸ lovols aio oxpiossoo Ly lho noool vaiiaLlo [CLV¸].
WU5: Il is assunoo lhal WUS pioloin is nol noLilo ano lhoiofoio ionains
noslly in lho colls whoio lho WUS gono is oxpiossoo [_/[, oxcopl foi woak
loakago oiffusion. Whilo all colls of lho noool noiislon aio in piincipal
aLlo lo oxpioss WUS, a spalial paianoloi is aoooo which nakos colls
lhal iosioo closoi lo lho noiislon lip noio conpolonl lo aclivalo WUS
oxpiossion (Fig. 6.¡). 1his anchoiing was founo lo Lo nocossaiy in lho
piosonloo noool lo onsuio coiiocl posilioning of lho lwo funclional oo-
nains (SCD ano OC) wilhin lho oono. Wilhoul lho spalial conpononl,
innooialoly noighLoiing SCD ano OC aio slill foinoo, Lul al noio ian-
oon localions (soo Fig. 6.·). 1ho ioquiiononl foi a spalial conpononl
ioflocls lho facl lhal lhis viilual noiislon is nol sliucluioo, i.o., all
colls aio inliinsically oqual ano caiiy no posilional infoinalion. In planl
noiislons, such spalial infoinalion will Lo pioviooo Ly signals wilhin
ano Lolwoon coll layois, oi fion lho vasculaluio. A posilivo foooLack loop
foi WUS via aulo-aclivalion is inliooucoo. Allhough nol oxpoiinonlally
piovon, il is suppoiloo Ly lho oLsoivalion of a iapio upiogulalion of WUS
oxpiossion in iogonoialing callus [__[. WUS pionolos lho oxpiossion of
106 Chupter c |ooe||ng |uttern|ng |n the S/| oí / rho!|ono
FIgure 6.z Sy:temw|thout unchor-
|ng o|:tr|out|on Lqu|||or|um :tute
oí u :|mu|ut|on where the unchor|ng
o|:tr|out|on gu|o|ng wUS e·pre::|on
|: e·chungeo oy u con:tunt wJS
reuct|on rute /: u re:u|t oí the
m|::|ng po:|t|onu| |níormut|on, SC0
uno 0C |eep the|r po:|t|on: re|ut|ve
to euch other, out the SC0 |: now
íormeo ut u runoom |ocut|on |n the
outer mer|:tem |uyer:
[ ] WUS [ ] facX [ ] 3 CLV
max min
WUS-signal, which is noLilo ano can oiffuso lo noighLoiing colls. 1ho
WUS lovols aio oxpiossoo Ly lho noool vaiiaLlo [WUS].
WU5-sIgna|: WUS-signal is gonoialoo Ly all WUS oxpiossing colls, ano lho
anounl piooucoo ooponos on lho lovols of WUS oxpiossion. Sinilai lo
CLV¸, WUS-signal is noLilo ano oogiaooo al a conslanl ialo. Colls ioacl
lo lho anounl of WUS-signal lhoy iocoivo wilh slonnoss. Only ouloi coll
layois of lho noiislon aio conpolonl lo iospono lo lho WUS-signal. 1ho
WUS-signal lovols aio oxpiossoo Ly lho noool vaiiaLlo [WUS
sig
].
factor X: 1o accounl foi CLAVATA (CLV) inooponoonl iogulalion of WUS
oxpiossion, FacX is incoipoialoo. Al lho slail of lho sinulalion, FacX is
oxpiossoo honogonoously in all colls ano is fiooly oiffusing. FacX inoucos
WUS oxpiossion, Lul is ilsolf unooi nogalivo foooLack iogulalion Ly WUS
[/3[. 1his is inplononloo lhiough aclivo oogiaoalion oi consunplion of
FacX Ly WUS. 1ho inloiaclions Lolwoon WUS ano FacX aio lhus Lasoo
on an aclivaloi-suLslialo-liko nochanisn lhal will gonoialo a oisciolo
WUS oonain. FacX lovols aio oxpiossoo Ly lho noool vaiiaLlo [FacX].
1ho oosciiLoo onlilios aio conpiloo inlo a IDL iopiosonlalion of lho inlia-
collulai gono iogulalivo piogian givon Ly Lqs. 6.¡-6.¸ (soo Soclion 6.·). An
ovoiviow of lho inloiaclions is givon in Fig. 6.¡.
1ho iosulling noool ooponos on a sol of paianolois liko kinolic conslanls;
valioalion of lho noool lhoiofoio ioquiioo fiisl lo ioonlify a paianoloi sol-
ling lhal allow iopiooucing lho lwo funclional noiislon oonains, i.o., lho
CLV-oxpiossing SCD ano lho WUS-oxpiossing OC, al appioxinaloly lhoso
c: S|mu|ut|on |e:u|t: 107
localions which aio oxpoiinonlally oLsoivoo in wilolypo noiislons (soo
Fig. 6.¸).
6.3.1 · 5Imu|atIon of WI|dtype
Slailing fion alnosl zoio conconlialions of all consiooioo conpononls, lho
syslon was sinulaloo unlil an oquiliLiiun slalo was ioachoo (soo Fig. 6.¸);
sinco syslon Lohavioi is invosligaloo Ly noans of nunoiical inlogialion of
lho noool oqualions, unooi ’oquiliLiiun slalo’ a slalo is unooislooo whoio
all ooiivalos aio zoio oi ioasonaLly closo lo zoio. In lho wilo-lypo sconaiio, a
givon noiislon showoo WUS oxpiossion fiisl al lho noiislon lip, liiggoioo
Ly a sufficionlly high lovol of FacX. WUS lhon incioasoo, lhoioLy iopioss-
ing FacX al lho sano localion. 1ho conloi of lho OC is shifloo oownwaios.
1ho oisliiLulion of WUS-signal ovoilaps wilh lhal of WUS, Lul sinco WUS-
signal is oiffusiLlo, il is localoo in a wiooi oonain ano oxlonooo always lo
lho noiislon lip. 1ogolhoi wilh an incioaso of slonnoss al lho noiislon lip,
CLV¸ Loconos oxpiossoo, pushing lho OC oownwaios fion ils inilial posi-
lion. 1his lino couiso iopiooucos lho oynanic changos in gono oxpiossion
palloins lhal aio oLsoivoo ouiing onLiyonic oovolopnonl of lho SAM.
6.3.2· 5Imu|atIons of mutants and system perturbatIons
In lho following, fuilhoi sinulalions foi known nulanl oxpoiinonls aio
shown ano conpaioo lo lho iospoclivo oxpoiinonlal oala.
ReducIng CLV expressIon
Fiisl lho consoquoncos of iooucing CLV oxpiossion is losloo. Whon CLV is
oowniogulaloo ouiing planl oovolopnonl, Lolh lho SCD ano lho OC oxpano
laloially ouo lo uniosliicloo WUS oxpiossion [_, 3_, _([. Fuilhoinoio, WUS
oxpiossion is lhon no longoi oxcluooo fion lho noiislon lip.
1ho in silico analysis slailoo fion an oquiliLialoo wilolypo noiislon, lhus
sinulaling a conoilional knock-oul of CLV. Whon CLV oxpiossion was
sloppoo, lho SCD iapioly onlaigoo ouo lo iociuilnonl of laloial colls. Al
lho sano lino, lho OC oxpanooo ano shifloo lowaios lho noiislon lip (soo
108 Chupter c |ooe||ng |uttern|ng |n the S/| oí / rho!|ono
min
max
s
i
g
W
U
S




[
]
3
C
L
V
[
]
s
t
[
]
f
a
c
X
[
]
W
U
S
0 1500 3000 6000
FIgure 6._. ¯|me cour:e :|mu|ut|on oí u w||o-type mer|:tem Cruo|ng írom our| (m|n|mum)
to ||ght (mu·|mum) |||u:trute: the re|ut|ve concentrut|on oí the |no|cuteo component: |rom
|eſt to r|ght, the :|mu|ut|on: were oeve|opeo írom c|o:e to zero concentrut|on: íor numoer oí
:tep: :hown oe|ow, unt|| the (:tuo|e) equ|||or|um :tute wu: reucheo
c: S|mu|ut|on |e:u|t: 109
max
min
[
]
W
U
S
[
]
f
a
c
X
0 250 650 1500
[
]
3
C
L
V
FIgure 6.µ. ¯|me cour:e :|mu|ut|on íor u c!._ |o::-oí-íunct|on mutunt 0n|y the concen-
trut|on: oí wUS, |uc` uno CLv_ ure :hown, :turt|ng írom un equ|||oruteo w||otype /t the
oeg|nn|ng oí the :|mu|ut|on, CLv_ concentrut|on |: :et to c, uno :|mu|ut|on: proceeo unt||
equ|||or|um Note thut the wUS oomu|n e·puno: uno :h|ſt: upwuro:
Fig. 6.¸). A sinilai, Lul loss pionouncoo offocl was soon whon CLV was
slill oxpiossoo, Lul al iooucoo lovols (soo Fig. A.¡ in Apponoix A).
IncreasIng CLV LxpressIon
Ilanls lhal conlinuously oxpioss CLV fail lo nainlain a shool noiislon
ouo lo an oaily aiiosl of WUS oxpiossion ano slon coll oiffoionlialion [_[.
Howovoi, inouciLlo ovoioxpiossion ouiing oovolopnonl was founo lo Lo con-
ponsaloo in sono flowoi noiislons, iosulling in a iocovoiy of WUS oxpios-
sion al laloi slagos [/3[. In sinulalions, high lovol oxpiossion of CLV in
all colls causoo a iapio shiinkago of lho OC, oowniogulalion of WUS, ano
a ioouclion in slonnoss, conconilanl wilh a ioouclion in CLV oxpiossion
110 Chupter c |ooe||ng |uttern|ng |n the S/| oí / rho!|ono
lovols fion lho SCD (soo Fig. 6.¸). Ovoioxpiossion of CLV sol al an inloi-
nooialo lovol iosulloo in WUS iopiossion ano a iapio loss of slonnoss, which
iocovoioo wilh lino (soo Fig. 6.¸). A sinilai Lohavioi was oLsoivoo in planl
floial noiislons, in iosponso lo inoucoo ovoioxpiossion of CLV [/3[. Low
lovol ovoioxpiossion of CLV allowoo lho syslon lo ioach a now slaLlo oqui-
liLiiun slalo, wilh a snalloi OC ano SCD (soo Fig. A.¸ in Apponoix A).
Fuilhoi, lho ioLuslnoss of lho syslon againsl poiluiLalions was losloo Ly
analyzing lho iosponso lo alloioo onoogonous CLV oxpiossion in snall,
oisciolo slops: lho offoclivonoss of slonnoss-ooponoonl CLV oxpiossion is
losloo in a iango fion ¡u/ lo 6·u/ in ¡u/ slops. Vaiying CLV lovols fion
¸u/ lo 6·u/ conpaioo lo wilolypo affocloo lho sizo of lho SCD, whilo OC
coll nunLoi ionainoo conslanl (soo Fig. A.¸ in Apponoix A). 1his inoicalos
lhal OC ano SCD sizos aio nol sliiclly couploo, which has Loon also noloo
oxpoiinonlally whon analyzing lho sizos of OC ano SCD in planls giown
unooi oivoiso onviionnonlal conoilions [._[.
A|terIng WUS expressIon
Lowoiing WUS oxpiossion lovols iooucos lho sizos of Lolh SCD ano OC lo
a sinilai oxlonl, ano will causo a loss of Lolh oonains whon WUS is fully
iopiossoo (soo Fig. A.¸ in Apponoix A). Lclopic WUS oxpiossion was losloo
Ly changing lho offocl of CLV signaling on WUS aclivily fion iopiossivo
lo aclivaling. In planls, lhis has Loon achiovoo Ly oxpiossing WUS fion
lho CLV pionoloi [1c[, which causoo lho coalosconco of OC ano SCD al
lho noiislon lip, logolhoi wilh laloial oxpansion of lhis joinl oonain. 1his
coll Lohavioi is also oLsoivoo in lho piosonloo sinulalions (Fig. 6.6).
RegeneratIon and 0e-Novo CeneratIon of DC and 5C0
Afloi aLlaling SCD ano OC fion lho noiislon Ly poinling a lasoi Loan al
lho noiislon lip, WUS Loconos oxpiossoo al lho poiiphoiy, ano lho OC ano
SCD aio iogonoialoo wilh lino [_c[, highlighling lhal colls al lho poiiphoiy
aio capaLlo of, Lul noinally inhiLiloo fion lho acquisilion of OC ioonlily.
1ho lasoi aLlalion oxpoiinonl was sinulaloo slailing fion an oquiliLialoo
wilolypo noiislon, whoio all WUS oi CLV oxpiossing colls aio olininaloo
c: S|mu|ut|on |e:u|t: 111
max
min
[
]
W
U
S
[
]
f
a
c
X
0 500 6500 15000
max
min
[
]
W
U
S
[
]
f
a
c
X
0 500 4000 60000
A
B
[
]
.
3
e
n
d
o
C
L
V
[
]
.
3
e
n
d
o
C
L
V
FIgure 6._. |e:pon:e to C|v_ overe·pre::|on |n the ent|re mer|:tem ¯|me-evo|ut|on oí wJS,
¯oc\ uno C|v_ concentrut|on: upon :trong (/) or |ntermeo|ute (3) |eve| overe·pre::|on oí C|v_
|: :hown, :turt|ng írom equ|||oruteo w||o-type mer|:tem unt|| the :|mu|ut|on: reuch u new
equ|||or|um :tute |ere, [cnJo C|v_] corre:pono: to C|v_ e·pre::|on írom the enoogenou:
promoter, tu|en u: reporter íor :tem ce|| |oent|ty Note thut ooth, u wJS e·pre::|on oomu|n
uno :tem ce||: ure re-|n|t|uteo |n (3), out not |n (/)
112 Chupter c |ooe||ng |uttern|ng |n the S/| oí / rho!|ono
max
min
[
]
W
U
S
[
]
f
a
c
X
0 150 250 750
[
]
3
C
L
V
FIgure 6.6. S|mu|ut|on íor wJS m|:e·pre::|on |n the :tem ce|| oomu|n Sturt|ng írom un
equ|||oruteo w||otype mer|:tem, m|:e·pre::|on oí wJS írom the C|v_ promoter (C|v_≫wJS)
|: :|mu|uteo unt|| u new equ|||or|um :tute |: reucheo Ce||: |n the mer|:tem now ucqu|re m|·eo
|oent|t|e: uno e·pre:: ooth the 0C uno SC0 mur|er gene:
fion lho noiislon. Il luinoo oul lhal now OC was gonoialoo which inoucoo
a SCD noaiLy (soo Fig. 6.¸). 1his shows lho solf-gonoialivo capacily of lho
noiislon noool. Duiing noinal planl oovolopnonl, now noiislons aio
gonoialoo ouiing onLiyogonosis, flowoiing, ano whon axillaiy noiislons
aio inilialoo. Ly sinply alloiing FacX oxpiossion lovols in a givon collulai
fianowoik, il was possiLlo lo sinulalo lho gonoialion of a now OC ano SCD,
which cooioinaloo incioaso in sizo whon FacX is fuilhoi upiogulaloo (soo
Fig. A.¸ in Apponoix A).
Ro|e of FacX and WUS Feedback Regu|atIon
In aooilion lo lho alioaoy oosciiLoo sconaiios lhal aio all inspiioo Ly piovi-
c: S|mu|ut|on |e:u|t: 113
max
min
[
]
W
U
S
[
]
f
a
c
X
0 1500 10000 15000
[
]
3
C
L
V
FIgure 6.). S|mu|ut|on íor u ce|| uo|ut|on :cenur|o ¯he centru| reg|on oí the mer|:tem wu:
e||m|nuteo oy v|rtuu| ce|| uo|ut|on Note thut even |n the uo:ence oí un SC0 uno unoer|y|ng
0C, ooth oomu|n: cun oe purt|u||y re:toreo
ously conoucloo oxpoiinonls, lho iolo of FacX ano lho inloiaclion of WUS
wilh FacX is analyzoo. Wilhoul foooLack of WUS lo FacX, FacX coulo
Lo oxchangoo foi a conslanl oxpiossion of WUS. 1his iooa was losloo Ly
olininaling lho foooLack loin of WUS on FacX (soo Lq. 6.·). Howovoi,
using an ovolulion slialogy lo soaich lho paianoloi spaco of lho iosulling
noool (soo Chaploi ¸), no paianoloi sollings iosulling in lho oosiioo syslon
Lohavioi coulo Lo founo, showing sopaialo Lul aojaconl SCD ano OC. In
conclusion, FacX ano lho foooLack Lolwoon WUS ano FacX aio vilal foi lho
noool lo inilialo slaLlo 1uiing palloining. Canoioalos lo ioalizo lho iolo of
FacX aio gonos ano funclions lhal conliol WUS oxpiossion. Locauso olini-
naling FacX ooslaLilizos lho OC, nulalions in gonos conliiLuling lo FacX
114 Chupter c |ooe||ng |uttern|ng |n the S/| oí / rho!|ono
FIgure 6.8 Sy:tem neg|ect-
|ng íeeoouc| oí wJS on ¯oc\
/rchetype :y:tem oehuv|or íor
:|mu|ut|on: w|thout íeeoouc|
oí wJS on ¯oc\. the mer|:tem
overpro||íerute:, wJS |: e·pre::eo
|n u|| mer|:tem ce||: uno u|| ce||:
|n the outer |uyer: ucqu|re :tem
ce|| |oent|ty |no|cuteo oy the|r
e·pre::|on oí the :tem ce|| mur|er
C|v_
[ ] WUS [ ] facX [ ] 3 CLV
max min
funclion shoulo iosull in oilhoi uniosliicloo WUS oxpiossion ano noiislon
ovoipiolifoialion (soo Fig. 6.S), oi noiislon aiiosl.
Influence of AnchorIng Factor 0IstrIbutIon on 5ystem ßehavIor
Ailificial posilional infoinalion in foin of an anchoiing oisliiLulion (soo
Fig. 6.¡) was inliooucoo lo slinulalo SCD ano OC posilioning al lho noiis-
lon lip. 1o losl lho possiLlo influonco of lhis anchoiing oisliiLulion on lho
palloin foinalion capaLililios of lho noool, lho oisliiLulion is oxchangoo
foi a conslanl valuo. Allhough posilioning of SCD ano OC Locano noio
vaiiaLlo now, slill paianoloi sollings lhal iosull in spalially confinoo ano
aojaconl SCD ano OC (soo Fig. 6.·) havo Loon ioonlify. 1his inoicalos lhal
lho anchoiing oisliiLulion has no significanl influonco on lho qualilalivo
Lohavioi of lho pioposoo noool.
6.4· 0IscussIon
1ho inilial allonpl in noooling lho inloiplay Lolwoon lho funclional oo-
nains SCDano OC was sololy Lasoo on lho inloiaclion Lolwoon lwo aclivaloi-
inhiLiloi lypo syslons (WUS,CLV, ano WUS,FacX) which woio linkoo via
WUS as lho connon nooo. Concoplually, lho unooilying assunplion was
lhal SCD ano OC coulo oiiginalo inooponoonlly of oach olhoi, Lul lhal
lhoii nainlonanco ano iolalivo posilion aio conliolloo Ly nulual foooLack
c4 0|:cu::|on 115
iogulalion. Howovoi, such a noool failoo lo iopioouco lho oonain aiiango-
nonl oLsoivoo in aclual noiislons foi lho noool’s paianoloi spaco which
was oxploioo using noool caliLialion lochniquos piosonloo in lho piovi-
ous lwo chaplois. 1his inoicalos lhal an ossonlial conpononl was nissing
fion lhis noool. 1ho nosl connon oulcono was nol juxlaposilion, Lul
an ovoilap of lho SCD wilh lho OC. 1o inpiovo lho spalial sopaialion of
lho lwo oonains, il was aooilionally consiooioo lhal colls wilhin an aclual
noiislon oiffoi fion oach olhoi Ly lhoii posilion. Sovoial nisoxpiossion
oxpoiinonls using WUS hao pioviously shown lhal lho collulai iosponso
lo WUS-ooiivoo signals ooponos on a collsY iolalivo posilion wilhin lho
noiislon, coiiosponoing lo ils oovolopnonlal liajocloiy. Only Ly aooing
spalial conpononls lo lho noool il was possiLlo lo achiovo a ioalislic sizing
ano aiiangononl of lho lwo oonains wilhin lho noiislon; ionoval of lhis
spalial conpononl causos oxlonsivo spalial ovoilapping of lho SCD ano OC.
1ho noool was challongoo Ly alloiing conlial syslon paianolois lo sinu-
lalo nulanl phonolypos ano puLlishoo liansgonic oxpoiinonls. In all ox-
poiinonls, lho piosonloo noool piovoo lo Lo ioLusl againsl snall-scalo poi-
luiLalions (soo Soclion A.6 in Apponoix A). 1his slaLilily pioLaLly iosulls
fion lho conLinalion of lwo foooLack opoialoo syslon, whoioLy ono of
lhon, lho WUS,FacX syslon, acls as a Luffoi lhal oanpons fluclualions
in WUS lovols. Fuilhoinoio, lho ioaclion ialos lhal influonco WUS ox-
piossion in lho piosonloo sinulalions aio ono oiooi of nagniluoo snalloi
lhan lhoso conliolling CLV lovols. Incioasoo slaLilily againsl signaling
noiso was uncovoioo in lho analysis of couploo posilivo foooLack syslons if
lho lwo linkoo iogulaloiy loops opoialoo al oiffoionl spooos [11, 1.[. 1ho
noool has iovoaloo lhal conLinoo foooLack syslons aio sufficionl lo allow
lho gonoialion ano ioLusl nainlonanco of lwo oislincl collulai oonains in
a noiislon, ioquiiing only nininal assunplions aLoul spalial iosliiclions
of lho syslon. 1ho challongos ahoao aio now lo oxlono lho coll noool inlo
lho lhiio oinonsion, ano incoipoialo coll oivisions, Lul also lo aoo olhoi
iogulaloiy nolwoiks lhal conliol oigan inilialion ano coll oiffoionlialion,
appioaching lho goal of a viilual noiislon.

Conc|usIons
1his lhosis is concoinoo wilh lho noooling of GINs lhal unooily palloin
foinalion piocoss wilh iospocl lo gono oxpiossion lhal conliol oovolopnon-
lal piocossos. Il aooiossoo lwo oiffoionl aioas: (i) Luiloing a noool foi lho
GIN unooilying oovolopnonl ano nainlonanco of lho SAM in A. thaliana,
ano (ii) lho oovolopnonl of nolhoos foi caliLialion of such noools foi which
noslly qualilalivo oala is availaLlo. Wilh iospocl lo lhoso lwo lopics il pio-
vioos lho following koy conliiLulions:
• A IDL noool foi lho GIN iosponsiLlo foi SAM oovolopnonl ano nain-
lonanco is sol up. 1ho noool Luilos on ID syslons as nochanisn foi
palloin gonoialion. Il covois inloiaclions Lolwoon lho lwo involvoo func-
lional oonains, SCD ano OC, ano noooling lhoso signaling loops is ca-
paLlo of iopiooucing iopoiloo oxpoiinonls wilh iospocl lo poiluiLalions
of inloiaclions Lolwoon lhoso lwo oonains. 1ho noool is usoo lo oxploio
lho paianoloi spaco unooilying lhis iogulalivo piocossos.
118 Chupter ´ Conc|u:|on:
• A fianowoik foi paianoloi caliLialion of spalial DL noools using only
qualilalivo oala is sol up. Il conslilulos lho noool iopiosonlalion, choico
of a suilaLlo nolhoo foi noool sinulalion using nunoiical inlogialion,
choico of a houiislic foi noool caliLialion, ano nocossaiy inloifacos Lo-
lwoon lhoso conpononls. In lhis iogaio, lho najoi iosull is an invosliga-
lion on nocossaiy chaiacloiislics foi a ciiloiion lo guioo lho caliLialion
piocoss using only qualilalivo oala. Alongsioo wilh lhis sluoy, nolhoos
foi quanlificalion of sinilaiilios Lolwoon sinulaloo ano oxpoiinonlally
ooloininoo palloins aio pioposoo.
• A nolhoo lo incoipoialo analylical iosulls concoining lho palloin foina-
lion nochanisn ’ID syslons’ is pioposoo lhal is capaLlo of avoioing lho
pioLlon of iogions conlaining paianoloi sollings lhal aio inoislinguish-
aLlo in loins of qualilalivo noool fil—plaloaus which aio iosulling fion
lypically non-linoai inloiaclions ano olhoiwiso conplicalo a oiiocloo cali-
Lialion piocoss ano iosull in unoosiiaLlo, ialhoi ianoon soaich Lohavioi.
• A slialogy is pioposoo lo nako uso of liansionl slalos ouiing oovolopnon-
lal liajocloiios insloao of only consiooiing lho final oquiliLiiun syslon
slalo. Il is Lasoo on a hioiaichical ooconposilion of iospoclivo piocossos
wilh iospocl lo lho involvoo nooulos in lho consiooioo GINs. 1his
nolhoo is oononslialoo on lho oxanplo of lho pioposoo SAM noool.
ConLinoo wilh lho oovolopoo schono of whon lo consiooi coilain slagos
ouiing lho caliLialion piocoss, il is capaLlo of consiooiaLly inpioving lho
convoigonco chaiacloiislics of lho iospoclivo noool caliLialion piocossos.
1hoioLy, lhis lhosis pioviooo a noool foi lho iogulalivo foooLack loops lhal
aio conlial foi oovolopnonl ano nainlonanco of SAMs in A. thaliana. 1o-
golhoi wilh lho piosonloo lools foi noool caliLialion, il foins a Lasis lhal
can Lo oxlonooo lo incluoo suLsyslons iosponsiLlo foi fuilhoi aspocls of
planl oovolopnonl. In consoquonco, il can Lo soon as a fiisl slop lowaios lho
ullinalo goal of Luiloing a viilual noiislon oi ovon planl—a sliucluio lhal
woulo Lo a conpiohonsivo knowloogo-Laso foi planls. Al lho sano lino, il
inplicilly piovioos insighls inlo conpaiaLlo syslons foi olhoi spocios, o.g.,
slon coll iogulalion in insocls liko Drosophila oi ovon nannalians. In ao-
oilion, lho pioposoo fianowoik ano caliLialion lochniquos lhonsolvos can
Lo usoo foi noooling olhoi oovolopnonlal syslons.
´+ |uture |er:pect|ve: 119
7.1 · Future PerspectIves
1ho iosulls piosonloo hoio foin a souno Lasis foi fuluio iosoaich:
• 1ho SAM noool is Lasoo on a lwo-oinonsional spalial oonain iopio-
sonling an ailificial longiluoinal soclion lhiough lho lhioo-oinonsional
oono foining lho noiislon. Allhough lhis lwo-oinonsional oonain is
sufficionl lo piovioo insighls concoining lho palloin foinalion capaLili-
lios of a pulalivo GIN, lho noool gains in aulhonlicily whon ioplacing
lho ailificial lwo-oinonsional oonain wilh oxpoiinonlally ooloininoo
lhioo-oinonsional sliucluios.
• 1ho iogulalivo piocossos consiooioo in lho pioposoo SAM noool all hap-
pon in lino-scalos snalloi lhan lho coll cyclo. 1hoiofoio il was sufficionl
lo consiooi slalic lissuo iopiosonlalions foi noooling puiposos. Following
lho ain of cioaling full viilual noiislons, on lho olhoi hano il is noc-
ossaiy lo incluoo giowlh nochanics as woll. 1hoiofoio, conLining lho
pioposoo GIN noool wilh a fiano woik sinulaling giowlh conslilulos
a pionising iosoaich oiioclion.
• 1ho noooloo WUS,CLV foooLack loop is conlial foi honooslasis of lho
slon coll pool in lho SAM. Novoilholoss, olhoi iogulalivo syslons havo
sono influonco on lhis piocoss as woll as lho oxislonco of lho slon colls
inpacls a iango of sliucluios iolaloo lo il. Il lhoiofoio is pionising lo
aoo such aooilional iogulalivo syslons liko lhoso foining lho Lounoaiy
iogion of lho noiislon oi AUXIN iolaloo syslons. Hoio, lho lalloi nighl
havo an influonco on posilioning of lho SCD whilo lho foinoi pioLaLly
ooponos on lho oxislonco of lho SCD oi al loasl oopono on a connon
signal. Inclusion of such inloiaclions woulo ooopon lho unooislanoing
of noiislon iogulalion ano woulo Lo a fuilhoi slop lowaio a viilual
noiislon.
• 1ho iopoiloo sluoios concoining lho oovolopnonl of nolhoos foi noool
caliLialion up lo now focus on inoivioual aspocls of lho ovoiall lask.
A Lasolino caliLialion slialogy has Loon oosignoo ano oxlonsions liko
nolhoos lo incoipoialo oiffoionl souicos of oonain knowloogo oi lo foi
palloin iocognilion havo Loon pioposoo. Allhough all singlo aspocls
havo lhoii iospoclivo uso, conLining lho oiffoionl iooas ano lochniquos
120 Chupter ´ Conc|u:|on:
inlo ono inlogialoo appioach woulo piovioo a valuaLlo aooilion foi lho
giowing fiolo of noooling of oovolopnonlal syslon.
• In aooilion, lho pioposoo fianowoik ano usoo noooling lochniquos aio
suilaLlo foi olhoi lypos of oiganisns. Wilh a conpaiaLlo long-loin
goal of cioaling viilual oiganisns, liansfoiiing lho oovolopoo concopls
piovioos lho possiLilily lo cioalo conpiohonsivo knowloogo Lasos lhal
can assisl Liologisls in visualizing cuiionl knowloogo ano lo oosign now
oxpoiinonls lo ooopon lho unooislanoing of lhoso oiganisns.
A
Comp|ementary 5Imu|atIons on
5hoot ApIca| MerIstem
MaIntenance In
Arabidopsis thaliana
In aooilion lo lho sinulalion iosulls piosonloo in Chaploi 6: Modeling Pat-
terning in the SAM of A. lhaliana, hoio a sol of conplononlaiy sinulalions
aio shown lhal fuilhoi oxploio lho iospoclivo noool Lohavioi.
122 /ppeno|· / Comp|ementury S|mu|ut|on: on S/| |u|ntenunce |n / rho!|ono
max
min
[
]
W
U
S
[
]
f
a
c
X
0 150 350 1500
[
]
3
C
L
V
endogenous CLV3 levels
n
u
m
b
e
r

o
f

c
e
l
l
s

i
n

f
u
n
c
t
i
o
n
a
l

d
o
m
a
i
nOC size
SCD size
0 1 2 3 4 5 6
0
2
4
6
8
10
12
14
16
18

A B
FIgure A.±. Lffect: oí reouceo CLv_ |eve|: on 0C uno SC0 /. ¯|me cour:e :|mu|ut|on íor
u cono|t|onu||y reouceo C|v_ e·pre::|on 3. lmpuct oí C|v_ e·pre::|on |eve|: on the :|ze: oí
0C uno SC0 ¯o u::e:: the numoer oí ce||: |n the re:pect|ve oomu|n:, the concentrut|on:
were o|:cret|zeo u:|ng thre:ho|o: re|ut|ve to the w||o type concentrut|on:. |or [:t]. δ
sr
·c.1,
íor [wUS]. δ
wJS
·c_1
A.1 · ReducIng CLV LxpressIon
Conoilional loss-of-funclion of CLV iosulls in an oxpansion of lho OC ano
lho SCD. In aooilion, lho OC is shifloo lowaios lho lip ouo lo a loss of
nogalivo foooLack Ly CLV. Whon CLV oxpiossion lovols aio only niloly
iooucoo, a giaooo iosponso was oLsoivoo: SCD ano OC onlaigo, Lul lho
localion of lho OC is nol affocloo ouo lo aclivo CLV¸ signaling. A lypical
lino couiso of a sinulalion foi a conoilional ioouclion in CLV oxpiossion
is shown in Fig. A.¡. Inloioslingly, OC sizo ionainoo unaffocloo foi a wioo
iango of onoogonous CLV oxpiossion lovols (soo Fig. A.¡), inoicaling a
pailial uncoupling of OC ano SCD sizos.
A.2· 5Imu|atIng Loss-Df-FunctIon Mutants In CLV
1ho phonolypo of clv loss-of-funclion nulanls is conpaiaLlo lo a oowniog-
ulalion of CLV oxpiossion. Malhonalically, a clv loss-of-funclion nulanl
/: Cruouu| lncreu:e oí L·ogenou: C|v3 L·pre::|on Leve|: 123
can Lo incoipoialoo Ly oxlonoing Lqs. 6.¡ ano 6.· wilh a facloi c1
ko
lhal
nooulalos lho iosponso of WUS lo CLV oxpiossion. 1ho coiiosponoing
oqualions aio givon hoio:
∂ [WUS]
∂t
=D
WUS
∆[WUS]
+ξρ
anc
[WUS]
2
[FacX]
1 + (c1
ko
[CLV¸] + [CLV¸
oxl
])
−µ
WUS

WUS
,
∂ [FacX]
∂t
=D
FacX
∆[FacX]
+ξρ
anc
[WUS]
2
[FacX]
1 + (c1
ko
[CLV¸] + [CLV¸
oxl
])
+
σ
FacX
1 +
[FacX]
K
FacX
.
Ly solling c1
ko
lo valuos c1
ko
∈ [u, ¡], oiffoionl iosioual aclivily lovols of
CLV can Lo sinulaloo, whoio c1
ko
=u iopiosonls a loss-of-funclion, ano
c1
ko
=¡ iopiosonls lho wilolypo sconaiio. 1ypical sinulaloo lino couisos foi
giaooo clv loss-of-funclion nulanls aio shown in Fig. A.·.
A.3· Cradua| Increase of Lxogenous CLV LxpressIon Leve|s
In Soclion 6.¸.· sinulalions foi noiislons wilh sliongly incioasoo CLV ox-
piossion lovols havo Loon shown. Incioasoo lovols of CLV iosulloo in noiis-
lon aiiosl, ano inloinooialo ovoioxpiossion lovols causoo an only liansionl
loss of lho SCD, which iocovoioo wilh lino. Ly sluoying a iango of CLV
ovoioxpiossion lovols, il was uncovoioo lhal Lolh oonains aio giaoually
iooucoo in sizo (soo Fig. A.¸). Howovoi, lho SCD (solio lino in Fig. A.¸)
iosponos noio ioaoily, inoicaling no sliicl inloiooponoonco of oonain sizos.
A.4· A|terIng WUS LxpressIon
1ho consoquoncos of iooucing WUS oxpiossion lo oiffoionl lovols havo Loon
oxploioo: ninoi ioouclions of WUS lovols causo a coiiosponoing snall io-
124 /ppeno|· / Comp|ementury S|mu|ut|on: on S/| |u|ntenunce |n / rho!|ono
FIgure A.z ¯|me cour:e: íor
gruoeo c!.1 |o::-oí-íunct|on
mutunt :|mu|ut|on:, /. C|v1
|o::-oí-íunct|on :cenur|o
(c1
ko
·c), 3. :|mu|ut|on where
C|v1 retu|n: :ome uct|v|ty
(c1
ko
·c.)
max
min
[
]
W
U
S
[
]
f
a
c
X
0 250 650 1500
[
]
3
C
L
V
max
min
[
]
W
U
S
[
]
f
a
c
X
0 150 350 1500
[
]
3
C
L
V
A
B
ouclion in OC ano SCD sizo (soo Fig. A.¸). A nooiun ioouclion causos
a liansionl loss of SCD ano OC unlil FacX ioachos a lovol lhal allows lo
io-inilialo a now noiislon (soo Fig. A.¸). In caso of a WUS knockoul, lho
noiislon is aiiosloo wilhoul iocovoiy (soo Fig. A.¸).
A.5· RegeneratIon and 0e Novo CeneratIon of DC and 5C0
Now noiislons can Lo foinoo ouiing oniyogonosis oi flowoiing. 1ho pio-
posoo noool allows sinulaling lho oo novo gonoialion of noiislons Ly vaiy-
/c Sen:|t|v|ty /nu|y:|: 125
max
min
[
]
W
U
S
[
]
f
a
c
X
0 150 350 1500
A B
[
]
.
3
e
n
d
o
C
L
V
0 0.4 0.8 1.2 1.6 2
0
2
4
6
8
10
12
exogenous CLV3 levels
n
u
m
b
e
r

o
f

c
e
l
l
s

i
n

f
u
n
c
t
i
o
n
a
l

d
o
m
a
i
n

OC size
SCD size
FIgure A._. Cruouu| re:pon:e to e·ogenou: C|v_ e·pre::|on /. ¯|me cour:e :|mu|ut|on íor u
|ow |eve| C|v_ overe·pre::|on ([CLv_
e·t
]·c.) 3. Cruoeo :y:tem re:pon:e to o|fferent e·oge-
nou: C|v_ e·pre::|on |eve|: ¯he [CLv_
e·t
] |eve| |: vur|eo |n [CLv_
e·t
] ∈ [c, .] ¯o u::e:: the
numoer oí ce||: |n the re:pect|ve oomu|n:, the concentrut|on: oí :temne:: uno wJS were o|:-
cret|zeo u:|ng thre:ho|o: re|ut|ve to the w||otype concentrut|on: |or [:t]. δ
:t
·c.1, íor [wUS].
δ
wUS
·c_1
ing FacX iogulalion. Figuio A.¸ shows lho syslon iosponso lo oiffoionl lov-
ols of lho kinolic conslanl K
FacX
ano lho iosulling sizos of OC ano SCD.
K
FacX
is vaiioo ovoi a iango K
FacX
∈ [u.¡, ¡], whilo K
FacX
=u.¸ is usoo
foi wilo lypo sinulalions.
A.6· 5ensItIvIty Ana|ysIs
1ho sonsilivily of lho pioposoo noool was invosligaloo wilh iospocl lo poi-
luiLalions of singlo paianolois of lho wilolypo paianoloi solling. 1ho pa-
ianolois havo Loon poiluiLoo using lho following changos in aLsolulo valuos:
{-¸u/, -·¸/, -¡u/, ·¸/, ¸u/, ¡uu/, ¡¸u/, ·uu/}. 1ho coiiosponoing sin-
ulalions oocunonl a consiooiaLlo ioLuslnoss wilh iospocl lo lhoso poilui-
Lalions: apail fion vaiying lho fivo paianolois (ρ
WUS
, µ
WUS
, ρ
WUS
sig
,
µ
WUS
sig
, K
sl
), lho sinulaloo syslon iosponso was qualilalivoly unchangoo;
126 /ppeno|· / Comp|ementury S|mu|ut|on: on S/| |u|ntenunce |n / rho!|ono
FIgure A.µ ¯|me cour:e: íor
gruoeo wJS |noc|out mutunt
:|mu|ut|on: /. S|mu|ut|on íor
:||ght|y reouceo wJS e·pre:-
:|on |eve| (.
ko
·c6), 3. :|mu|u-
t|on íor |ntermeo|ute wJS e·-
pre::|on (.
ko
·c¸), C. :|mu|u-
t|on íor u wJS |o::-oí-íunct|on
:cenur|o (.
ko
·c)
max
min
[
]
W
U
S
[
]
f
a
c
X
0 500 4000 60000
[
]
3
C
L
V
max
min
[
]
W
U
S
[
]
f
a
c
X
0 150 250 2500
[
]
3
C
L
V
max
min
[
]
W
U
S
[
]
f
a
c
X
0 6000 15000 25000
[
]
3
C
L
V
A
B
C
/c Sen:|t|v|ty /nu|y:|: 127
FIgure A._ Con:equence: oí ¯oc\ e·pre::|on |eve|:
íor the :|ze: oí 0C uno SC0 ¯o u::e:: the num-
oer oí ce||: |n the re:pect|ve oomu|n:, concentrut|on:
were o|:cret|zeo u:|ng thre:ho|o: re|ut|ve to the w||o-
type concentrut|on: |or :temne::. δ
sr
·c.1, íor wUS.
δ
wUS
·c_1
10¹ 10⁰
0
5
10
15
20
25
30

n
u
m
b
e
r

o
f

c
e
l
l
s

i
n

f
u
n
c
t
i
o
n
a
l

d
o
m
a
i
n
constant factor X regulation
OC size
SCD size
only slighl vaiialions in oonain sizo ano oogioo of sopaialion Lolwoon OC
ano SCD occuiioo.
ρ
WUS
varIatIon
Foi a poiluiLalion in ρ
WUS
of -¸u/, OC ano SCD aio no longoi spalially
sopaialoo Lul Lolh aio localoo in lho lip. Foi vaiialions of ÷¡¸u/ oi
÷·uu/, lho funclional oonains aio onlaigoo Lul sopaialoo, slill ouiing
sinulalions snall nunoiical inslaLililios occuiioo inoicaling lhal ρ
WUS
is
ioaching lovol lhal Loconos inliaclaLlo Ly lho cuiionl sinulalion solup. Foi
lho ionaining poiluiLalions lho syslon ionainoo qualilalivoly slaLlo.
µ
WUS
varIatIon
Foi a poiluiLalions of ÷¡¸u/ ano ÷·uu/ lho foinoo oonains aio no longoi
spalially sopaialoo ano localoo in lho noiislon lip. Foi lho ionaining
poiluiLalions lho syslon ionainoo qualilalivoly slaLlo.
ρ
WUS
sig
varIatIon
Wilh giowing ρ
WUS
sig
lovols, oonain sizos slail lo shiink ano foi poilui-
Lalions of ÷¡uu/ lo ÷·uu/ sinulalions show snall nunoiical inslaLililios.
Foi lho ionaining poiluiLalions lho syslon ionainoo qualilalivoly slaLlo.
µ
WUS
sig
varIatIon
Foi a poiluiLalion of -¸u/ oonains aio no longoi spalially sopaialoo ano
128 /ppeno|· / Comp|ementury S|mu|ut|on: on S/| |u|ntenunce |n / rho!|ono
Lolh aio localoo in lho lip. 1his sinulalion shows snall nunoiical inslaLili-
lios as woll. Foi poiluiLalion lovols of ÷¡¸u/ ano ÷·uu/ sinulalions again
no longoi show spalial sopaialion Lolwoon funclional oonains, lhis lino lho
sinulalions havo Loon nunoiically slaLlo. Foi lho ionaining poiluiLalions
lho syslon ionainoo qualilalivoly slaLlo.
K
st
varIatIon
Only foi a poiluiLalion of -¸u/, lho syslon shows snall nunoiical inslaLil-
ily, Lul foi all losloo poiluiLalion lovols lho syslon ionains qualilalivoly
slaLlo.
B
Mode|s for 0Ifferent 5tages of
0ecomposed 5hoot ApIca|
MerIstem 0eve|opment
Foi lho appioach lo noool caliLialion Lasoo incluoing infoinalion on lho
oovolopnonlal liajocloiy of lho iospoclivo syslon, lho noool foi lho losl
syslon slon coll honooslasis in lho SAM of A. thaliana piosonloo in Chap-
loi 6 is ooconposoo inlo noools foi oiffoionl slagos of ils oovolopnonl.
130 /ppeno|· 3 |ooe|: íor 0|fferent Stuge: oí 0ecompo:eo S/| 0eve|opment
Lofoio lho nowly inliooucoo noools foi oailioi oovolopnonlal slagos aio
piosonloo, fiisl lho full noool is iopoaloo:
∂ [WUS]
∂t
=D
s
∆[WUS] +w
ko
ξρ
anc
[WUS]
2
[FacX]
1 + [CLV¸]
3
−µ
WUS
[WUS] +σ
WUS
, ]
∂ [FacX]
∂t
=D
q
∆[FacX] +w
ko
ξρ
anc
[WUS]
2
[FacX]
1 + [CLV¸]
3
+
σ
FacX
1 +
[FacX]
K
FacX
,
∂ [WUS
sig
]
∂t
=D
q
∆[WUS
sig
] +ρ
WUS
sig
[WUS] −µ
WUS
sig
[WUS
sig
] ,
∂ [sl]
∂t
=D
s
∆[sl] + 
id
(i) ρ
sl
(
[WUS
sig
]
K
sl
)
5
1 +
(
[WUS
sig
]
K
sl
)
5
−µ
sl
[sl] ,
∂ [CLV¸]
∂t
=D
q
∆[CLV¸] +c
ko
ρ
CLV¸
[sl] −µ
CLV¸
[CLV¸] .
Hoio, lho D
q
ano D
s
aio oiffusion conslanls which aio assunoo lo Lo sinilai
foi lho quickly oiffusing conpononls ([FacX], [WUS
sig
], ano [CLV¸]) ano foi
lho local conpononls ([WUS] ano [sl]) lhal slill unooily sono woak loakago
oiffusion. 1ho ρ
i
wilh i ∈ {anc, WUS, FacX, WUS
sig
, sl, CLV¸} aio ioaclion
ialos lhal aio oqual in all colls wilh ono oxcoplion Loing ρ
anc
, lho so calloo
anchoiing oisliiLulion lhal is nocossaiy in lho noool lo conponsalo foi
nissing sliucluial infoinalion guioing oxacl posilioning of lho funclional
oonains aclivo in lho noiislon. µ
i
wilh i ∈ {anc, WUS, FacX, WUS
sig
,
sl,CLV¸} aio oogiaoalion ialos, σ
WUS
ano σ
FacX
aio loins iopiosonling
Lasal oxpiossion, a chaiacloiislic funclion 
id
ooloinining slon coll con-
polonl layois, ano a ianoon poiluiLalion ξ ∈ [-u.u·¸, u.u·¸] nocossaiy lo
inilialo palloin foinalion. An ovoiviow on foasiLilily inloivals usoo foi lho
oiffoionl lypos of paianolois is givon in 1aL. L.¡.

id
(i) =



1, if coll i ∈ {L, L}
0, olso
131
Tab|e ß.±. |eu:|o|||ty runge: u:eo íor o|fferent mooe| purumeter: our|ng opt|m|zut|on
|urumeter 0 ρ µ σ r
|unge [cccc1, c_] [cc1, 1_] [cccc1, c1] [cccc1, cc1] [ccc1, 1]
Duiing lho fiisl slago of SAM oovolopnonl, only lho so calloo OC is foinoo.
1o inilialo lhis oonain of WUS oxpiossing colls only lho noool onlilios
[WUS] ano [FacX] nooo lo Lo consiooioo iosulling in a iooucoo noool con-
siooioo in lhis slago givon Ly lho following oqualions:
∂ [WUS]
∂t
=D
s
∆[WUS] +ξρ
anc
ρ
WUS
[WUS]
2
[FacX]
−µ
WUS
[WUS] +σ
WUS
,
∂ [FacX]
∂t
=D
q
∆[FacX] −ξρ
anc
ρ
FacX
[WUS]
2
[FacX] +
σ
FacX
1 +
[FacX]
K
FacX
.
Moving on lo lho socono oovolopnonlal slago, lho noool of slago ono is
oxlonooo conpononls ioalizing lho foinalion of a SCD, yol loaving oul lho
foooLack fion SCD lo lho OC. 1ho noool foi slago lwo is givon Lo lho
following oqualions:
∂ [WUS]
∂t
=D
s
∆[WUS] +w
ko
ξρ
anc
[WUS]
2
[FacX]
−µ
WUS
[WUS] +σ
WUS
,
∂ [FacX]
∂t
=D
q
∆[FacX] +w
ko
ξρ
anc
[WUS]
2
[FacX] +
σ
FacX
1 +
[FacX]
K
FacX
,
∂ [WUS
sig
]
∂t
=D
q
∆[WUS
sig
] +ρ
WUS
sig
[WUS] −µ
WUS
sig
[WUS
sig
] ,
∂ [sl]
∂t
=D
s
∆[sl] + 
id
(i) ρ
sl
(
[WUS
sig
]
K
sl
)
5
1 +
(
[WUS
sig
]
K
sl
)
5
−µ
sl
[sl] .
1ho SAM sinulalions aio oono using nunoiical inlogialion of lho iospoclivo
syslons. Foi lho inlogialion lho IMLX schono Lasoo on a nooifioo Ciank-
132 /ppeno|· 3 |ooe|: íor 0|fferent Stuge: oí 0ecompo:eo S/| 0eve|opment
Nicolson inlogialoi conLinoo wilh an Aoans-Lashfoio schono [_1[ is usoo.
As spalial oisciolizalion foi lho Ciank-Nicolson schono a giio of collulai
iosolulion is usoo ano lino is oisciolizoo using a conslanl lino slops δ
t
=u.¸
of oinonsionloss lino. Lach sinulalion lasls foi ¡·uuuu lino slops.
ßIb|Iography
¦1¦ 3 /|oert:, 0 3ruy, ¦ Lew|:, | |uff, K |ooert:, uno ¦ 0 wut:on |o!ccu!or f|o!o¸, Dj
¯hc Cc!! Cur|uno, New Yor|, NY, US/, _ro eo|t|on, 1__(
¦.¦ K /mon||rov|mun, N / Khure, 0 | ¯ree, w S Chen, ¦ 0 /·e|roo, uno C ¦ ¯om||n
|uthemut|cu| |ooe||ng oí ||unur Ce|| |o|ur|ty to Unoer:tuno 0om|neer|ng Nonuuton-
omy Sc|cncc, _c/(_/c3).(._–(.6, .cc_
¦_¦ / /uger uno N |un:en |eríormunce evu|uut|on oí un uovunceo |ocu| :eurch evo|u-
t|onury u|gor|thm ln Con¸rcss on f.o!ur|onor, Comµuror|on (CfC .cc_;, vo|ume ., puge:
1///–1/3(, ||:cutuwuy, N¦, US/, .cc_ lLLL |re::
¦(¦ ¦ 3uoer uno L Z|tz|er |ypL. /n /|gor|thm íor |u:t |ypervo|ume-3u:eo |uny-0o¦ect|ve
0pt|m|zut|on ¯lK |eport .36, Computer Lng|neer|ng uno Networ|: Luoorutory (¯lK),
L¯| Zur|ch, Novemoer .cc3
¦_¦ N 3eume uno C |uoo|ph |u:ter S-|etr|c Cu|cu|ut|on oy Con:|oer|ng 0om|nuteo |y-
pervo|ume u: K|ee’: |eu:ure |roo|em ¯echn|cu| |eport Cl-.16/c6, Sonoeríor:chung:-
oere|ch __1 Computut|onu| lnte|||gence, Un|ver:|tut 0ortmuno, .cc6 :horter ver:|on
puo||:heo ut l/S¯L0 lnternut|onu| Coníerence on Computut|onu| lnte|||gence (Cl .cc6)
¦6¦ C | 3|:hop |curo! |cr.orks jor |orrcrn ¯cco¸n|r|on 0·íoro Un|ver:|ty |re::, 0·íoro,
UK, 1___
¦/¦ S 3ornho|ot 3oo|eun networ| mooe|: oí ce||u|ur regu|ut|on. pro:pect: uno ||m|tut|on:
; ¯ Soc |nrcrjocc, _(Supp| 1).S3_–S_(, .cc3
¦3¦ 0 3ouyer, | Ce|er, | Krug|er, / Schn|ttger, | |e:ch, K we:ter, | 3u||unoe, ¦ ¯|mmer,
C ||ec|, uno | |u|:|ump ¯wo-0|men:|onu| |uttern|ng oy u ¯rupp|ng/0ep|et|on |ech-
un|:m. ¯he |o|e oí ¯¯C1 uno CL_ |n /ruo|oop:|: ¯r|chome |ormut|on ||oS f|o!, 6(6).
e1(1, .cc3
¦_¦ U 3runo, ¦ C |e|t:cher, | |ooe, L | |eyerow|tz, uno | S|mon 0epenoenoence oí
Stem Ce|| |ute |n /ruo|oop:|: on u |eeoouc| Loop |egu|uteo oy CLv_ /ct|v|ty Sc|cncc,
.3_(_(/_).61/–61_, .ccc
¦1c¦ U 3runo, | Crunewu|o, | |ooe, uno | S|mon |egu|ut|on oí CLv_ L·pre::|on oy ¯wo
|omeooo· Cene: |n /ruo|oop:|: |!onr |h,s|o!, 1._(.)._6_–_/_, .cc.
134 3|o||ogruphy
¦11¦ 0 3runomun uno ¯ |eyer |eeoouc| Loop: Shupe Ce||u|ur S|gnu|: |n Spuce uno ¯|me
Sc|cncc, _..(__cc).__c–___, .cc3
¦1.¦ 0 3runomun, ¦ L |erre||, ¦r, | L|, uno ¯ |eyer lnter||n|eo |u:t uno S|ow |o:|t|ve
|eeoouc| Loop: 0r|ve |e||uo|e Ce|| 0ec|:|on: Sc|cncc, _1c(_/(/).(_6–(_3, .cc_
¦1_¦ K 3r|ngmunn uno ¯ |r|eor|ch /ppro·|mut|ng the vo|ume oí Un|on: uno lnter:ect|on:
oí ||gh-0|men:|onu| Ceometr|c 0o¦ect: ln S | |ong, | Nugumoch|, uno ¯ |u|unugu,
eo|tor:, |nrcrnor|ono! S,mµos|um on /!¸or|rhms onJ Comµuror|on (|S//C .cc8;, vo|ume
__6_ oí ||CS, puge: (_6–((/, 3er||n, Cermuny, .cc3 Spr|nger
¦1(¦ 0 3roc|hoff, ¯ |r|eor|ch, N |eoo|nghuu:, C K|e|n, | Neumunn, uno L Z|tz|er 0o /o-
o|t|onu| 0o¦ect|ve: |u|e u |roo|em |uroer¯ ln 0 ¯h|eren: et u|, eo|tor:, Ccncr|c onJ
f.o!ur|onor, Comµuror|on Conjcrcncc (CfCCD .cc,;, puge: /6_–//., New Yor|, NY, US/,
.cc/ /C| |re::
¦1_¦ ¯ / 3rown Ccnomcs, chupter 6 w||ey-L|::, .no eo|t|on, .cc.
¦16¦ | ¦ 3uc| uno ¦ 0 L|eo Chl|-ch|p. con:|oerut|on: íor the oe:|gn, unu|y:|: uno upp||-
cut|on oí genome-w|oe chromut|n |mmunoprec|p|tut|on e·per|ment: Ccnom|cs, 3_(_).
_(_–_6c, .cc(
¦1/¦ S L C|ur|, | w w||||um:, uno L | |eyerow|tz ¯he CL/v/¯/1 Cene Lncooe: u |utut|ve
|eceptor K|nu:e ¯hut Contro|: Shoot uno ||oru| |er|:tem S|ze |n /ruo|oop:|: Cc!!, 3_
(()._/_–_3_, 1__/
¦13¦ w ¦ Conover |rocr|co! |onµoromcrr|c Sror|sr|cs ¦ohn w||ey, _ro eo|t|on, 1___
¦1_¦ | oe ¦ong |ooe||ng uno S|mu|ut|on oí Cenet|c |egu|utory Sy:tem:. / L|teruture |e-
v|ew ; Comµur f|o!, _(1).6/–1c_, .cc.
¦.c¦ K 0eo |u!r|-D!,ccr|.c Dµr|m|.or|on Js|n¸ f.o!ur|onor, /!¸or|rhms w||ey, Ch|che:ter, UK,
.cc1
¦.1¦ 3 0omon uno | /eoer:o|o |u:: Spectrometry uno |rote|n /nu|y:|: Sc|cncc, _1.
(__/1)..1.–.1/, .cc6
¦..¦ 0 Lnoy uno | 3rent |ooe|||ng ce||u|ur oehuv|our |orurc, (c_(6313).__1–___, .cc1
¦._¦ 0 ||ehn |etuoo|om|c: – the ||n| oetween genotype: uno phenotype: |!onr |o! f|o!,
(3(1–.).1__–1/1, .cc.
¦.(¦ ¦ C ||etcher, U 3runo, | | |unn|ng, | S|mon, uno L | |eyerow|tz S|gnu||ng oí
Ce|| |ute 0ec|:|on: oy CL/v/¯/_ |n /ruo|oop:|: Shoot |er|:tem: Sc|cncc, .3_(_(c_).
3|o||ogruphy 135
1_11–1_1(, 1___
¦._¦ ¦ / |o:ter Lvo|ut|onury Computut|on |or ¯c. Ccncr, .(6).(.3–(_6, .cc1
¦.6¦ N |r|eomun, | L|n|u|, l Nuchmun, uno 0 |e’er U:|ng 3uye:|un Networ|: to /nu|yze
L·pre::|on 0utu ; Comµur f|o!, /(_–().6c1–6.c, .ccc
¦./¦ / Curg, K |ohunrum, / 0| Curu, C 0e ||che||, uno l `enur|o: |ooe||ng :tochu:t|c|ty
uno roou:tne:: |n gene regu|utory networ|: f|o|njormor|cs, ._(1.).|1c1–1c_, .cc_
¦.3¦ | | Curv|e ||n|te-0|fference Scheme: íor |euct|on-0|ffu:|on Lquut|on: |ooe||ng
|reoutor-|rey lnteruct|on: |n |/¯L/3 f |orh f|o!, 6_(_).__1–__6, .cc/
¦._¦ | Ce|er, ¦ U Lohmunn, | Cer:tung, / ¯ |u|er, ¦ ¯|mmer, uno C ||ec| / (uunt|tut|ve
uno 0ynum|c |ooe| íor ||unt Ce|| |egu|ut|on ||oS D|f, _(1c).e____, .cc3
¦_c¦ / C|erer Cenerut|on oí 3|o|og|cu| |uttern: uno |orm. Some |hy:|cu|, |uthemut|cu|,
uno Log|cu| /:pect: |ro¸ f|oµh,s |o! f|o!, _/(1).1–(/, 1_3.
¦_1¦ / C|erer uno | |e|nhurot / theory oí o|o|og|cu| puttern íormut|on r,!crncr|k, 1.(1).
_c–__, 1_/.
¦_.¦ / C|erer, S 3er||ng, | 3ooe, C N 0uv|o, K |||c|, C |un:munn, | Schu||er, uno
L ¯re|ner |egenerut|on oí hyoru íromreuggreguteo ce||: |or |c.f|o, .__(_1)._3–1c1,
1_/.
¦__¦ 0 ¯ C|||e:p|e L·uct :tochu:t|c :|mu|ut|on oí coup|eo chem|cu| reuct|on: ; |h,s Chcm-
JS, 31(._).._(c–._61, 1_//
¦_(¦ 0 ¯ C|||e:p|e ¯he chem|cu| Lungev|n equut|on ; |h,s Chcm-JS, 11_(1).._/–_c6, .ccc
¦__¦ S | Coroon, | C |e|:|er, C v |eooy, C 0hno, uno L | |eyerow|tz |uttern íormut|on
our|ng oe novo u::emo|y oí the /ruo|oop:|: :hoot mer|:tem 0c.c!oµmcnr, 1_((1_).
____–__(3, .cc/
¦_6¦ | | Crun|tto, | | veroe:, uno | / Cecutto Neuru| networ| en:emo|e:. evu|uut|on oí
uggregut|on u|gor|thm: /rr|j |nrc!!, 16_(.).1__–16., .cc_
¦_/¦ | Cro¦-|urot, | Lenhuro, uno ¯ Luu· wUSC|LL :|gnu||ng íunct|on: |n |nterreg|onu|
commun|cut|on our|ng /ruo|oop:|: ovu|e oeve|opment Ccnc 0c., 16(.1).11._–11_3,
.cc.
¦_3¦ | |uoermun f!cmcnror, /µµ!|cJ 0|ffcrcnr|o! f¸uor|ons .|rh ¯our|cr Scr|cs onJ founJor,
vo!uc |ro!!cms |rent|ce |u||, Lng|ewooo C||ff:, N¦, US/, .no eo|t|on, 1_3/
136 3|o||ogruphy
¦__¦ | |uffter uno C Nu::|e|n-vo|huro Lurge :cu|e genet|c: |n u :mu|| verteorute, the ze-
orufi:h |nr ; 0c. f|o!, (c(1)...1–../, 1__6
¦(c¦ | |un, ( L|, uno Y-` Zhu |utut|on oí /ruo|oop:|: 3/|01 Cuu:e: |er|:tem 0eíect:
oy |u|||ng to Confine wUSC|LL L·pre::|on to the 0rgun|z|ng Center |!onr Cc!!, .c(6).
1(3.–1(__, .cc3
¦(1¦ ¦ |uno| uno ¦ Know|e: /n Lvo|ut|onury /pprouch to |u|t|oo¦ect|ve C|u:ter|ng |fff ¯
f.o!ur Comµur, 11(1)._6–/6, .cc/
¦(.¦ ¦ |uno|, S Love||, uno ¦ Know|e: |u|t|oo¦ect|v|zut|on oy 0ecompo:|t|on oí Scu|ur Co:t
|unct|on: ln C |uoo|ph et u|, eo|tor:, Conjcrcncc on |oro!!c! |ro!!cmSo!.|n¸ ¯rom|orurc
(||S| \;, vo|ume _1__ oí ||CS, puge: _1–(c Spr|nger, .cc3
¦(_¦ ¦ |uno|, S C Love||, uno ¦ Know|e: lnve:t|gut|on: |nto the Lffect oí |u|t|oo¦ect|v|zut|on
|n |rote|n Structure |reo|ct|on ln C |uoo|ph et u|, eo|tor:, Conjcrcncc on |oro!!c! |ro!!cm
So!.|n¸ ¯rom |orurc (||S| \;, vo|ume _1__ oí ||CS, puge: /c.–/11 Spr|nger, .cc3
¦((¦ N |un:en uno / 0:terme|er Comp|ete|y 0erunoom|zeo Se|í-/ouptut|on |n Lvo|ut|on
Struteg|e: f.o! Comµur, _(.).1__–1__, .cc1
¦(_¦ w |oeffo|ng |roouo|||ty lnequu||t|e: íor Sum: oí 3ounoeo |unoom vur|uo|e: ; /m Sror
/ssoc, _3(_c1).1_–_c, 1_6_
¦(6¦ ¯ |ohm uno L Z|tz|er |ooe||ng the Shoot /p|cu| |er|:tem |n / thu||unu. |urumeter
L:t|mut|on íor Sput|u| |uttern |ormut|on ln L|enu |urch|or|, ¦u:on | |oore, uno ¦u-
guth C |u¦upu|:e, eo|tor:, f.o!ur|onor, Comµuror|on |och|nc |corn|n¸ onJ 0oro ||n|n¸
|n f|o|njormor|cs (c.of|D .cc,;, vo|ume (((/ oí ||CS, puge: 1c.–11_ Spr|nger, .cc/
¦(/¦ ¯ |ohm uno L Z|tz|er |u|t|oo¦ect|v|zut|on íor purumeter e:t|mut|on. u cu:e-:tuoy on
the :egment po|ur|ty networ| oí oro:oph||u ln | |oth|uuí et u|, eo|tor:, CfCCD ’c_
Ccncr|c onJ f.o!ur|onor, Comµuror|on Conjcrcncc (CfCCD .cc_;, puge: .c_–.16, New
Yor|, NY, US/, .cc_ /C|
¦(3¦ ¯ |ohm uno L Z|tz|er / |u|t|oo¦ect|ve Lvo|ut|onury /|gor|thm íor Numer|cu| |urumeter
Spuce Churucter|zut|on oí |euct|on 0|ffu:|on Sy:tem: ln v Kuo|r|umunuthun et u|,
eo|tor:, |nrcrnor|ono! Conjcrcncc on |orrcrn ¯cco¸n|r|on |n f|o|njormor|cs (|¯|f .cc_;,
vo|ume _/3c oí ||f|, puge: 16.–1/(, |e|oe|oerg, Cermuny, .cc_ Spr|nger
¦(_¦ ¯ |ohm uno L Z|tz|er |u|t|ce||u|ur |uttern |ormut|on. |urumeter L:t|mut|on íor 00L-
ou:eo Cene |egu|utory Networ| |ooe|: |fff fn¸ |cJ f|o!, .3(()._.–_/, .cc_
¦_c¦ | |or:t, | | |urou|o:, uno N vun ¯hou| |nrroJucr|on ro C!o!o! Dµr|m|.or|on Spr|nger,
3er||n, Cermuny, 1:t eo|t|on, 1___
3|o||ogruphy 137
¦_1¦ / |uno|ng, S/ Kuuffmun, uno 3C Cooow|n 0ro:oph||u Segmentut|on. Supercomputer
S|mu|ut|on oí |reputtern ||erurchy ; ¯hcor f|o!, 1(_(_)._6_–_3(, 1__c
¦_.¦ C lge|, N |un:en, uno S |oth Covur|unce |utr|· /ouptut|on íor |u|t|-oo¦ect|ve 0pt|-
m|zut|on f.o! Comµur, 1_(1).1–.3, .cc/
¦__¦ | ¯ ¦en:en |e|per-0o¦ect|ve:. U:|ng |u|t|-0o¦ect|ve Lvo|ut|onury /|gor|thm: íor
S|ng|e-0o¦ect|ve 0pt|m|:ut|on ;ourno! oj |orhcmor|co! |oJc!!|n¸ onJ /!¸or|rhms, _(().
_._–_(/, .cc(
¦_(¦ S ¦eong, / L ¯rotochuuo, uno S L C|ur| ¯he /ruo|oop:|: CL/v/¯/. Cene Lncooe: u
|eceptor-|||e |rote|n |equ|reo íor the Stuo|||ty oí the CL/v/¯/1 |eceptor-|||e K|nu:e
|!onr Cc!!, 11(1c).1_._–1__(, 1___
¦__¦ | ¦ ¦|ung, | / / S Chouohury, uno S L Shuh 0etect|on uno o|ugno:|: oí p|unt-w|oe
o:c|||ut|on: írom |nou:tr|u| outu u:|ng the :pectru| enve|ope methoo ; |roccss Conrr, 1/
(.).1(_–1__, .cc/
¦_6¦ | ¦on::on, 3 L Shup|ro, L | |eyerow|tz, uno L |¦o|:ne:: S|gnu|||ng |n mu|t|ce||u|ur
mooe|: oí p|unt oeve|opment ln S Kumur uno ¦ 3ent|ey, eo|tor:, Dn ¸ro.rh ¯orm onJ
Comµurcrs, puge: 1_6–161 L|:ev|er, /m:teroum, NL, .cc_
¦_/¦ | ¦on::on, | |e|:|er, C v |eooy, v /gruwu|, v Cor, 3 L Shup|ro, L |¦o|:ne::, uno
L | |eyerow|tz |ooe||ng the orgun|zut|on oí the wUSC|LL e·pre::|on oomu|n |n
the :hoot up|cu| mer|:tem f|o|njormor|cs, .1(Supp| 1).|._.–|.(c, .cc_
¦_3¦ S / Kuuffmun |etuoo||c :tuo|||ty uno ep|gene:|: |n runoom|y con:tructeo genet|c net:
; ¯hcor f|o!, ..(_).(_/–(6/, 1_6_
¦__¦ ¦ Know|e:, | wut:on, uno 0 Corne |eouc|ng Locu| 0pt|mu |n S|ng|e-0o¦ect|ve |roo-
|em: oy |u|t|-oo¦ect|v|zut|on ln L Z|tz|er et u|, eo|tor:, Conjcrcncc on f.o!ur|onor, |u!r|-
Cr|rcr|on Dµr|m|.or|on (f|D .cc1;, vo|ume 1___ oí ||CS, puge: .6_–.3_, 3er||n, .cc1
Spr|nger
¦6c¦ L Knu:t 0ro:oph||u morphogene:|:. |ovement oeh|no the eoge Curr f|o!, /(_).
|__3–|_61, 1__/
¦61¦ / ¦ Koch uno | |e|nhurot 3|o|og|cu| puttern íormut|on. írom ou:|c mechun|:m: to
comp|e· :tructure: ¯c. |oJ |h,s, 66(().1(31–1_1c, 1__(
¦6.¦ l S Kohune, / ¯ Kho, uno / ¦ 3utte ||croorro,s jor on |nrc¸ror|.c Ccnom|cs |l¯ |re::,
.cc_
138 3|o||ogruphy
¦6_¦ ¯ Konoo, S Suwu, / K|no:h|tu, S ||zuno, ¯ Ku||moto, | |u|uou, uno Y Su|ugum| /
||unt |ept|oe Lncooeo oy CLv_ loent|fieo oy |n S|tu |/L0l-¯0| |S /nu|y:|: Sc|cncc,
_1_(_/33).3(_–3(3, .cc6
¦6(¦ 3 / Kr|ze| uno ¦ C ||etcher |o|ecu|ur mechun|:m: oí flower oeve|opment. un urmchu|r
gu|oe |or ¯c. Ccncr, 6(_).633–6_3, .cc_
¦6_¦ C S Kwon, C Chen, uno 0 wugner wUSC|LL |: u pr|mury turget íor trun:cr|pt|onu|
regu|ut|on oy S|L/YL0 |n oynum|c contro| oí :tem ce|| íute |n /ruo|oop:|: Ccncs 0c.,
1_(3).__.–1cc_, .cc_
¦66¦ ¯ Luu·, K | ` |uyer, ¦ 3erger, uno C ¦urgen: ¯he wUSC|LL gene |: requ|reo íor
:hoot uno floru| mer|:tem |ntegr|ty |n /ruo|oop:|: 0c.c!oµmcnr, 1..(1).3/–_6, 1__6
¦6/¦ / Le|oír|eo, ¦ | C ¯o, w 3u:ch, S Steh||ng, / Keh|e, | 0emur, ¦ ¦ K|eoer, uno ¦ U
Lohmunn wUSC|LL contro|: mer|:tem íunct|on oy o|rect regu|ut|on oí cyto||n|n-
|nouc|o|e re:pon:e regu|utor: |orurc, (_3(/c/1).11/.–11/_, .cc_
¦63¦ K | ` |uyer, | Schooí, / |uec|er, | Lenhuro, C ¦urgen:, uno ¯ Luu· |o|e oí
wUSC|LL |n |egu|ut|ng Stem Ce|| |ute |n the /ruo|oop:|: Shoot |er|:tem Cc!!, __(6).
3c_–31_, 1__3
¦6_¦ | |e|nhurot |oJc!s Dj f|o!o¸|co! |orrcrn ¯ormor|on /cuoem|c |re::, Lonoon, UK, 1_3.
¦/c¦ | |e|nhurot / mooe| íor puttern-íormut|on oí hypo:tome, tentuc|e: uno íoot |n |yoru.
how to íorm :tructure: c|o:e to euch other, how to íorm them ut o|:tunce 0c. f|o!, 1_/
(.)._.1–___, 1___
¦/1¦ | |e|nhurot ¯hc o!¸or|rhm|c !cour, oj sco shc!!s Spr|nger, New Yor|, NY, US/, 1___
¦/.¦ | |e|nhurot uno / C|erer Cenerut|on uno |egenerut|on oí Sequence uno Structure
0ur|ng |orphogene:|: ; ¯hcor f|o!, 3_(_).(._–(_c, 1_3c
¦/_¦ | |enoe: uno 0 3 Ke|| Non-||neur opt|m|zut|on oí o|ochem|cu| puthwuy:. upp||cut|on:
to metuoo||c eng|neer|ng uno purumeter e:t|mut|on f|o|njormor|cs, 1((1c).36_–33_,
1__3
¦/(¦ K ||ett|nen |on!|ncor |u!r|o!,ccr|.c Dµr|m|.or|on K|uwer, 3o:ton, |/, US/, 1___
¦/_¦ / ||gou|u:, | | |urou|o:, uno | vuroruno |u!r|!c.c! Dµr|m|.or|on /!¸or|rhms onJ
/µµ!|cor|ons Spr|nger, 3er||n, Cermuny, 1:t eo|t|on, 1__/
¦/6¦ L |¦o|:ne::, 0 | Shurp, uno ¦ |e|n|tz Connect|on|:t |ooe| oí 0eve|opment ; ¯hcor
f|o!, 1_.(().(._–(__, 1__1
3|o||ogruphy 139
¦//¦ C C |o|e:, | |enoe:, uno ¦ | 3ungu |urumeter L:t|mut|on |n 3|ochem|cu| |uthwuy:.
/ Compur|:on oí C|oou| 0pt|m|zut|on |ethoo: Ccnomc ¯cs, 1_(11)..(6/–.(/(, .cc_
¦/3¦ | |u||er, L 3orgh|, 0 Kw|ut|ow:|u, | Luuí:, uno | S|mon 0ynum|c uno Compen:utory
|e:pon:e: oí /ruo|oop:|: Shoot uno ||oru| |er|:tem: to CLv_ S|gnu||ng |!onr Cc!!, 13
(_).1133–11_3, .cc6
¦/_¦ | |u||er, / 3|ec|munn, uno | S|mon ¯he |eceptor K|nu:e C0|YNL oí /ruo|oop:|:
¯run:m|t: the Stem Ce||-L|m|t|ng S|gnu| CL/v/¯/_ lnoepenoent|y oí CL/v/¯/1 |!onr
Cc!!, .c(().__(–_(6, .cc3
¦3c¦ ¦ 0 |urruy |orhcmor|co! f|o!o¸, Spr|nger, New Yor|, NY, US/, .cc_
¦31¦ l ¯ Nuoney |f¯|/f /!¸or|rhms jor |orrcrn ¯cco¸n|r|on /ovunce: |n |uttern |ecogn|-
t|on Spr|nger, 0·íoro, UK, .no eo|t|on, .cc_
¦3.¦ / Nu|umu:u, C ¯u|uhu:h|, / Kunuoe, uno S Konoo lnteruct|on: oetween zeorufi:h
p|gment ce||: re:pon:|o|e íor the generut|on oí ¯ur|ng puttern: |roc |or! /coJ Sc| JS/,
1c6(.1).3(._–3(_(, .cc_
¦3_¦ | Neumunn uno l wegener ||n|mum Spunn|ng ¯ree: |uoe Lu:|er v|u |u|t|-0o¦ect|ve
0pt|m|zut|on |oruro! Comµur|n¸, _(_)._c_–_1_, .cc6
¦3(¦ | 0guwu, | Sh|nohuru, Y Su|ugum|, uno Y |ut:uouyu:h| /ruo|oop:|: CLv_ |ept|oe
0|rect|y 3|no: CLv1 Lctooomu|n Sc|cncc, _1_(_361).._(, .cc3
¦3_¦ w | |re::, S / ¯eu|o|:|y, w ¯ vetter||ng, uno 3 | ||unnery |umcr|co! ¯cc|µcs Cum-
or|oge Un|ver:|ty |re::, Cumor|oge, UK, _ro eo|t|on, .cc/
¦36¦ l |r|gog|ne uno | Leíever Symmetry 3reu||ng ln:tuo|||t|e: |n 0|::|put|ve Sy:tem: ;
Chcm |h,s, (3(().16__–1/cc, 1_63
¦3/¦ | (uu:t, | 3uuoe, uno 0 |e|mer: Lvo|ut|on Struteg|e: upp||eo to the proo|em oí ||ne
profi|e oecompo:|t|on |n (S0 :pectru /srron /srroµh,s, (_1(_).116/–11/_, .cc_
¦33¦ | |uffuro, K /mon||rov|mun, ¦ 0 /·e|roo, uno C ¦ ¯om||n /utomut|c purumeter |oent|-
ficut|on v|u the uo¦o|nt methoo, w|th upp||cut|on to unoer:tuno|ng p|unur ce|| po|ur|ty ln
|fff Conjcrcncc on 0cc|s|on onJ Conrro! (C0C .cc6;, puge: 1_–13, ||:cutuwuy, N¦, US/,
.cc6 lLLL |re::
¦3_¦ C v |eooy uno L | |eyerow|tz Stem-Ce|| |omeo:tu:|: uno Crowth 0ynum|c: Cun
3e Uncoup|eo |n the /ruo|oop:|: Shoot /pe· Sc|cncc, _1c(_/(3).66_–66/, .cc_
140 3|o||ogruphy
¦_c¦ 0 |e|nhurot, | |renz, ¯ |unoe|, uno C Kuh|eme|er ||cro:urg|cu| uno |u:er uo|u-
t|on unu|y:|: oí |nteruct|on: oetween the zone: uno |uyer: oí the tomuto :hoot up|cu|
mer|:tem 0c.c!oµmcnr, 1_c(1/).(c/_–(c3_, .cc_
¦_1¦ S ¦ |uuth lmp||c|t-e·p||c|t methoo: íor reuct|on-o|ffu:|on proo|em: |n puttern íormu-
t|on ; |orh f|o!, _((.).1(3–1/6, 1___
¦_.¦ U Suuer ||gh-throughput phenom|c:. e·per|mentu| methoo: íor mupp|ng flu·ome:
Curr Dµ|n f|orcchno!, 1_(1)._3–6_, .cc(
¦__¦ | / Suvugeuu /||ometr|c morphogene:|: oí comp|e· :y:tem:. 0er|vut|on oí the ou:|c
equut|on: írom fir:t pr|nc|p|e: |roc |or! /coJ Sc| JS/, /6(1.).6c._–6c._, 1_/_
¦_(¦ | Schooí, | Lenhuro, / |uec|er, K | ` |uyer, C ¦urgen:, uno ¯ Luu· ¯he Stem
Ce|| |opu|ut|on oí /ruo|oop:|: Shoot |er|:tem: |: |u|ntu|neo oy u |egu|utory Loop
oetween the CL/v/¯/ uno wUSC|LL Cene: Cc!!, 1cc(6).6__–6((, .ccc
¦__¦ L / Sege| uno ¦ L ¦uc|:on 0|::|put|ve :tructure. /n e·p|unut|on uno un eco|og|cu|
e·ump|e ; ¯hcor f|o!, _/(_)._(_–___, 1_/.
¦_6¦ / ¦ C Shur|ey, eo|tor Com!|n|n¸ /rr|fic|o! |curo! |crs fnscm!!c onJ |oJu!or |u!r|-|cr
S,srcms Spr|nger, Lonoon, UK, 1___
¦_/¦ 0 | Smyth ||ower oeve|opment Curr f|o!, 11(_).|3.–|3(, .cc1
¦_3¦ Y Stuh| uno | S|mon ||unt :tem ce|| n|che: |nr ; 0c. f|o!, (_(_–6).(/_–(3_, .cc_
¦__¦ 0 S Stoffer, 0 L ¯y|er, uno / ¦ |c0ougu|| Spectru| unu|y:|: íor cutegor|cu| t|me :er|e:.
Scu||ng uno the :pectru| enve|ope f|omcrr|ko, 3c(_).611–6.., 1___
¦1cc¦ 0 S Stoffer, 0 L ¯y|er, uno 0 / wenot ¯he Spectru| Lnve|ope uno lt: /pp||cut|on:
Sror Sc|, 1_(_)...(–.__, .ccc
¦1c1¦ S | Strogutz |on!|ncor 0,nom|cs onJ Choos Stuo|e |n Non||neur|ty we:tv|ew, Cum-
or|oge, |/, US/, .ccc
¦1c.¦ | ¯homu: |egu|utory networ|: :een u: u:ynchronou: uutomutu. / |og|cu| oe:cr|pt|on
; ¯hcor f|o!, 1__(1).1–._, 1__1
¦1c_¦ C ¦ ¯om||n uno 0 /·e|roo 3|o|ogy oy numoer:. muthemut|cu| mooe|||ng |n oeve|op-
mentu| o|o|ogy |or ¯c. Ccncr, 3(_).__1–_(c, .cc/
¦1c(¦ | | ¯uc|er, / ||nze, L ¦ ¯uc|er, S ¯u|uou, C ¦urgen:, uno ¯ Luu· vu:cu|ur :|gnu|||ng
meo|uteo oy ZwlLLL potent|ute: wUSC|LL íunct|on our|ng :hoot mer|:tem :tem ce||
oeve|opment |n the /ruo|oop:|: emoryo 0c.c!oµmcnr, 1__(1/)..3__–.3(_, .cc3
3|o||ogruphy 141
¦1c_¦ / ¯ur|ng ¯he chem|cu| ou:|: íor morphogene:|: |h|!os ¯rons ¯ Soc |onJ f, ._/(6(1).
_/–/., 1__.
¦1c6¦ L 0 vo|t Comµuror|ono! /no!,s|s oj f|ochcm|co! S,srcms Cumor|oge Un|ver:|ty |re::,
Cumor|oge, UK, .ccc
¦1c/¦ C von 0u::ow, L |e|r, L | |unro, uno C | 0oe|| ¯he :egment po|ur|ty networ| |: u
roou:t oeve|opmentu| moou|e |orurc, (c6(6/_.).133–1_., .ccc
¦1c3¦ | Yumuguch|, L Yo:h|moto, uno S Konoo |uttern regu|ut|on |n the :tr|pe oí zeorufi:h
:ugge:t: un unoer|y|ng oynum|c uno uutonomou: mechun|:m |roc |or! /coJ Sc| JS/,
1c((1.).(/_c–(/__, .cc/
¦1c_¦ Y Zhuo, L |eoruno, K 0hu:h|, ¦ C ||etcher, | Yu, | Su|u|, uno L | |eyerow|tz
|/N/3/ ¯/|/NU l: u C/¯/ ¯run:cr|pt|on |uctor ¯hut |egu|ute: Shoot /p|cu| |er|:tem
uno ||ower 0eve|opment |n /ruo|oop:|: |!onr Cc!!, 16(1c).._36–.6cc, .cc(
¦11c¦ L Z|tz|er uno L ¯h|e|e |u|t|oo¦ect|ve 0pt|m|zut|on U:|ng Lvo|ut|onury /|gor|thm: - /
Compurut|ve Cu:e Stuoy ln Conjcrcncc on |oro!!c! |ro!!cm So!.|n¸ jrom |orurc (||S| v;,
puge: ._.–_c1, /m:teroum, 1__3
¦111¦ L Z|tz|er, L ¯h|e|e, | Luumunn:, C | |on:ecu, uno v Crunert ou |on:ecu |eríormunce
/::e::ment oí |u|t|oo¦ect|ve 0pt|m|zer:. /n /nu|y:|: uno |ev|ew |fff ¯ronsocr|ons on
f.o!ur|onor, Comµuror|on, /(.).11/–1_., .cc_
¦11.¦ L Z|tz|er, L ¯h|e|e, uno ¦ 3uoer S|/|. Set |reíerence /|gor|thm íor |u|t|oo¦ect|ve
0pt|m|zut|on ln C |uoo|ph et u|, eo|tor:, Conjcrcncc on |oro!!c! |ro!!cm So!.|n¸ ¯rom
|orurc (||S| \;, vo|ume _1__ oí ||CS, puge: 3(/–3_3 Spr|nger, .cc3
Acronyms
5AM shool apical noiislon
A. thaliana Arabidopsis thaliana
CRN gono iogulalivo nolwoik
CMA-L5 Covaiianco Maliix Aoaplion Lvolulion Slialogy
MD-CMA-L5 MullioLjoclivo Covaiianco Maliix Aoaplion Lvolulion Slialogy
0NA oooxyiiLonucloic acio
RNA iiLonucloic acio
mRNA nossongoi INA
0L oiffoionlial oqualion
D0L oioinaiy oiffoionlial oqualion
P0L pailial oiffoionlial oqualion
R0 ioaclion-oiffusion
IMLX inplicil-oxplicil
5C0 slon coll oonain
DC oiganizing conloi
WUS WUSCHEL
WU5 WUSCHLL
CLV CLAVATA
CLv CLAVA1A
CLV CLAVATA
clv clavata
CLV CLAVATA
144 3|o||ogruphy
CLV CLAVATA
clv clavata
CLv_ CLAVA1A¸
FacX factor X
FacX facloi X
LRR loucino iich iopoal
CRN CORYNE
ARR ARABIDOPSIS RESPONSE REGULATOR
CFP gioon fluoiosconl pioloin
SYD SPLAYED
SNF sucioso non-foinonling ·
ATPase aoonosino liiphosphalaso
ßAR0± LICA¡ associaloo IING oonain ¡
HAN HANABA TARANU
WG wingless
HH hedgehog
EN engrailed
CC connocloo conpononl
ANN ailificial nouial nolwoik
CurrIcu|um vItae
Persona| InformatIon
1in Hohn
Loin Apiil S, ¡¸¸¸ in Hannovoi, Goinany
Cilizon of Goinany
LducatIon
·uu6–·uu¸ oocloial sluoonl al Conpuloi Lnginooiing ano Nolwoiks LaL-
oialoiy (1IK), L1H Zuiich, Swilzoilano
·uu¸–·uu6 iosoaich assislanl al conloi of aovancoo ouiopoan sluoios ano
iosoaich (caosai), Lonn, Goinany
¡¸¸¸–·uu¸ oiplona sluoios in conpuloi scionco (Dipl.-Infoin.) al lho Uni-
voisily of Doilnuno, Goinany
¡¸¸S–¡¸¸¸ alloinalivo civilian soivico (Ziviloionsl), AiLoiloi Sanaiiloi
Luno, Lsson, Goinany
¡¸¸S ALilui al Holnhollzschulo, Lsson, Goinany

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