!"#$ !

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A showcase of research and scho|arsh|p
|n se|ected art|c|es from 2013
2013/2014
Ed|tor|a| Board
Mark Johnston,
Editor-in-Chief
University of Colorado
School of Medicine
Tracey DePellegrin
Executive Editor
Cristy Gelling
Journals Assistant
Editor
Ruth lsaacson
Assistant Managing
Editor
BOARD OF SENIOR
EDITORS
Karen M. Arndt
University of Pittsburgh
Gary A. Churchill
The Jackson
Laboratory
Stanley Fields
University of
Washington
Mark Johnston
University of Colorado
School of Medicine
Charles H. Langley
University of California,
Davis
Terry R. Magnuson
University of North
Carolina at Chapel Hill
Michael W. Nachman
University of California,
Berkeley
Krista M. Nichols
NOAA Fisheries
Mark D. Rose
Princeton University
John C. Schimenti
Cornell University
John Wakeley
Harvard University
Lauren M. Mclntyre
University of Florida
Rasmus Nielsen
University of California,
Berkeley & University
of Copenhagen
Fred Winston
Harvard Medical School
CELLULAR GENETICS
Bruce Beutler
The University of Texas
Southwestern Medical
Center
Orna Cohen-Fix
NlDDK, National
lnstitutes of Health
Susan K. Dutcher
Washington University
School of Medicine
JoAnne Engebrecht
University of California,
Davis
David l. Greenstein
University of
Minnesota
Bob Goldstein
University of North
Carolina at Chapel Hill
Joseph Heitman
Duke University
Medical Center
Daniel J. Lew
Duke University
Medical Center
Piali Sengupta
Brandeis University
Linda D. Siracusa
Jefferson Medical
College of Thomas
Jefferson University
COMPLEX TRAITS
Joshua M. Akey
University of
Washington
Justin O. Borevitz
Australian National
University
Alain Charcosset
lnstitut National
de la Recherche
Agronomique
Stephen Chenoweth
The University of
Queensland
lna Hoeschele
virginia Polytechnic
lnstitute and State
University
Corbin D. Jones
University of North
Carolina at Chapel Hill
Loeske E. B. Kruuk
University of Edinburgh
Fernando F. Pardo
Manuel de villena
University of North
Carolina at Chapel Hill
Andrew H. Paterson
University of Georgia
Saunak Sen
University of California,
San Francisco
David W. Threadgill
Texas A&M University
Fred van Eeuwijk
Wageningen University
Jason B. Wolf
University of Bath
Naomi R. Wray
The University of
Queensland
Fei Zou
University of North
Carolina at Chapel Hill
DEVELOPMENTAL
AND BEHAVIORAL
GENETICS
Robert R. H. Anholt
North Carolina State
University
Hugo J. Bellen
Baylor College of
Medicine
Lynn Cooley
Yale University
Robert J. Duronio
University of North
Carolina at Chapel Hill
David l. Greenstein
University of
Minnesota
Marnie E. Halpern
Carnegie lnstitution for
Science
lswar K. Hariharan
University of California,
Berkeley
Kenneth J. Kemphues
Cornell University
Barbara J. Meyer
University of California,
Berkeley
David M. Parichy
University of
Washington
R. Scott Poethig
University of
Pennsylvania
Trudi Schpbach
Princeton University
William T. Sullivan
University of California,
Santa Cruz
Meera v. Sundaram
University of
Pennsylvania
Mariana F. Wolfner
Cornell University
GENE EXPRESSION
James A. Birchler
University of
Missouri
Michael Freitag
Oregon State
University
Audrey Gasch
University of
Wisconsin-Madison
Pamela Geyer
University of lowa
Michael Hampsey
Rutgers Robert Wood
Johnson Medical
School
Alan G. Hinnebusch
NlCHD, National
lnstitutes of Health
Ann Hochschild
Harvard Medical School
Aaron P. Mitchell
Carnegie Mellon
University
Craig S. Pikaard
lndiana University
R. Scott Poethig
University of
Pennsylvania
Eric U. Selker
University of
Oregon
Meera v. Sundaram
University of
Pennsylvania
GENOME INTEGRITY
AND TRANSMISSION
Sharon E. Bickel
Dartmouth College
Monica P. Colaicovo
Harvard Medical School
Gregory P. Copenhaver
University of North
Carolina at Chapel Hill
Nancy M.
Hollingsworth
Stony Brook University
Andreas Houben
Leibniz lnstitute of
Plant Genetics and
Crop Plant Research
Neil Hunter
University of California,
Davis
Jac A. Nickoloff
Colorado State
University
Steven J. Sandler
University of
Massachusetts
Jeff Sekelsky
University of North
Carolina at Chapel Hill
Shyam K. Sharan
NCl, National lnstitutes
of Health
Ting (C-tingj Wu
Harvard Medical School
GENOME AND
SYSTEMS BIOLOGY
Jef D. Boeke
New York University
Charles Boone
University of Toronto
Stanley Fields
University of
Washington
David A. Largaespada
University of
Minnesota
Brian P. Lazzaro
Cornell University
Jeffery F. Miller
University of California,
Los Angeles
Andrew W. Murray
Harvard University
Norbert Perrimon
Harvard Medical School
Enrico G. Petretto
lmperial College
London
Piali Sengupta
Brandeis University
Lars M. Steinmetz
European Molecular
Biology Laboratory &
Stanford University
Gary D. Stormo
Washington University
School of Medicine
Daniel F. voytas
University of
Minnesota
STATISTICAL
GENETICS AND
GENOMICS
lna Hoeschele
virginia Tech
Christina Kendziorski
University of
Wisconsin-Madison
Chiara Sabatti
Stanford University
Saunak Sen
University of California,
San Francisco
Eric A. Stone
North Carolina State
University
Nengjun Yi
University of Alabama
at Birmingham
METHODS,
TECHNOLOGY, AND
RESOURCES
Charles Boone
University of Toronto
Justin O. Borevitz
Australian National
University
George M. Church
Harvard Medical School
Oliver Hobert
Columbia University
Ann Hochschild
Harvard Medical School
Norbert Perrimon
Harvard Medical School
Jeff Sekelsky
University of North
Carolina at Chapel Hill
Jay Shendure
University of
Washington
Gary D. Stormo
Washington University
School of Medicine
David W. Threadgill
Texas A&M University
Daniel F. voytas
University of
Minnesota
EMPIRICAL
POPULATION
GENETICS
Daniel A. Barbash
Cornell University
David J. Begun
University of California,
Davis
James J. Bull
University of Texas at
Austin
Deborah Charlesworth
University of Edinburgh
Anna Di Rienzo
University of Chicago
Santiago C. Gonzlez-
Martinez
Forest Research
Centre (ClFOR-lNlAj
Matthew W. Hahn
lndiana University
Lynn B. Jorde
University of Utah
Jeffrey G. Lawrence
University of Pittsburgh
Brian P. Lazzaro
Cornell University
Leonie C. Moyle
lndiana University
Michael W. Nachman
University of California,
Berkeley
Bret A. Payseur
University of
Wisconsin-Madison
Outi Savolainen
University of Oulu
Stephen l. Wright
University of Toronto
THEORETICAL
POPULATION
GENETICS
Nick H. Barton
lnstitute of Science and
Technology Austria
Mark A. Beaumont
University of Bristol
Joachim Hermisson
University of vienna
Rasmus Nielsen
University of California,
Berkeley & University
of Copenhagen
Noah A. Rosenberg
Stanford University
Yun S. Song
University of California,
Berkeley
Wolfgang Stephan
University of Munich
Marcy K. Uyenoyama
Duke University
Lindi M. Wahl
Western University
Jeff D. Wall
University of California,
San Francisco
PRIMERS
Elizabeth A. De Stasio
Lawrence University
GENETICS
EDUCATION
Patricia J. Pukkila
University of North
Carolina at Chapel Hill
PERSPECTIVES
H. Allen Orr
University of Rochester
Adam S. Wilkins
Humboldt University
of Berlin
REVIEWS
Oliver Hobert
Columbia University
Jasper Rine
University of California,
Berkeley
Michael Turelli
University of California,
Davis
2
!"#"$%& (%))"&$%*# *+ , -,.*/ 0#$1*&2,#%# 345 6*#$/%78$%#9 $* :*;;%#,$*/<
-"=%,$"= >"?/*=8&$%@" A)*;,$%*# B"$C""# D%)$"/ D?"&%") *+ !"#$%$&
Yao-Wu Yuan, Jane||e M. Sagawa, R|ane O. Young, Br|an J. Ohr|stensen,
and Harvey D. Bradshaw Jr.
!"#"$%&' May 2013 194:255-263
LANDING SIGNALS Te bumblebee-pollinated monkeyfower Mimulus
lewisii and hummingbird-pollinated M. cardinalis are classic examples of
pollinator-mediated prezygotic reproductive isolation. Tese investigators
identifed an anthocyanin pigment regulatory gene causing a fower color
diference that contributes to pollinator preference for each species. Tis gene
likely plays a role in fower color variation in many other plants.
Tese images show a wild-type fower (upper left corner) and various stable
transgenic lines in which the expression of ROSE INTENSITY1, a repressor of
anthocyanin biosynthesis, was knocked down. Image courtesy of Yao-Wu Yuan.
3
A |ot can happen |n our fe|d |n a year, and 2013 prov|des
a good examp|e. Just |ast summer, GENETlOS pub||shed
the frst app||cat|on of ORlSPR-based genome ed|t|ng
to ()*'*+,%-. (p. 13}. That was qu|ck|y fo||owed by a
furry of papers on ORlSPR methods, |nc|ud|ng severa|
descr|b|ng |ts app||cat|on to /."#*),.01%$%' "-"3.#' and
other nematodes. Art|c|es that d|scuss the ways |n wh|ch
these methods are be|ng refned, extended, and app||ed
to other organ|sms cont|nue to appear |n GENETlOS.
Thanks to the t|re|ess efforts of our peer ed|tors,
rev|ewers and authors, |ast year we pub||shed |mportant
advances and |ns|ghts across the w|de breadth of
genet|cs and genom|cs research. l`m proud of the
except|ona| qua||ty of the work pub||shed |n GENETlOS,
and l`m exc|ted to share and ce|ebrate |t w|th you.
Of course, w|th so many exce||ent art|c|es to choose
from, we can`t hope to h|gh||ght more than a fract|on
|n th|s book|et. We`ve chosen a samp||ng of art|c|es to
showcase the d|vers|ty of research and scho|arsh|p
pub||shed |n GENETlOS |n 2013.
And l`m p|eased to say that 2014 |s shap|ng up to be
an even b|gger year for our journa|. On the hor|zon
are new procedures and po||c|es that w||| enhance
authors` exper|ences-and new themat|c sect|ons and
ed|tors that refect the chang|ng |andscape of our fe|d.
So keep an eye on GENETlOS, and subm|t your best
work for pub||cat|on |n one of the peer-ed|ted journa|s
of the Genet|cs Soc|ety of Amer|ca.
Mark Johnston
Ed|tor-|n-Oh|ef,
GENETlOS
GENETICS: A look back, a vision forward
ON THE COVER A variety of spheres illustrate one of the central concepts in biology
variability. Hulse and Cai (see p. 8) systematically explored genome-wide association between
genetic variants and gene expression variability in humans. Image courtesy of Evan Campbell.
4
CELLULAR GENETl CS
Nutritional Control of Epigenetic Processes
in Yeast and Human Cells
-"/8 EF D,=18G 3%,*#%#9 !8,#G H"% 5%G E,=" D,;")<5""G 0#$1*#2 4F A,@,/*#"G
-%#9 6F I,JJ*#=G KF L,&1"8) 6,#="G ,#= E,)?"/ >%#"
!"#"$%&' November 2013 195:831-844
EDITORS NOTE Nutr|t|ona| defc|ency |n humans can cause pers|stent
hea|th effects even |n the next generat|on. One way nutr|t|ona| status may
y|e|d ep|genet|c effects |s by affect|ng chromat|n mod|fcat|on. Th|s art|c|e
showed that fo|ate defc|ency d|srupts h|stone methy|at|on |n both yeast and
human ce||s. The authors suggest as an exp|anat|on metabo||c tr|age, where
nutr|ent scarc|ty prompts pr|or|t|zat|on of b|o|og|ca| processes.
ABSTRACT The v|tam|n fo|ate |s requ|red for meth|on|ne homeostas|s |n
a|| organ|sms. ln add|t|on to |ts ro|e |n prote|n synthes|s, meth|on|ne |s the
precursor to S-adenosy|-meth|on|ne (SAM}, wh|ch |s used |n myr|ad ce||u|ar
methy|at|on react|ons, |nc|ud|ng a|| h|stone methy|at|on react|ons. Here, we
demonstrate that fo|ate and meth|on|ne defc|ency |ed to reduced methy|at|on
of |ys|ne 4 of h|stone H3 (H3K4} |n 4.&&,.)*56&"' &")"7%'%.". The effect of
nutr|t|ona| defc|ency on H3K79 methy|at|on was |ess pronounced, but was
exacerbated |n 48 &")"7%'%." carry|ng a hypomorph|c a||e|e of Dot1, the enzyme
respons|b|e for H3K79 methy|at|on. Th|s resu|t suggested a h|erarchy of
ep|genet|c mod|fcat|ons |n terms of the|r suscept|b|||ty to nutr|t|ona| ||m|tat|ons.
Fo|ate defc|ency caused changes |n gene transcr|pt|on that m|rrored the effect
of comp|ete |oss of H3K4 methy|at|on. H|stone methy|at|on was a|so found to
respond to nutr|t|ona| defc|ency |n the fss|on yeast 4&,%9*'.&&,.)*56&"'
+*50" and |n human ce||s |n cu|ture.
5
COMPLEX TRAl TS
Te Protein Chaperone HSP90 Can Facilitate
the Divergence of Gene Duplicates
E"##%+"/ 5,&1*C%"&G 4M%$M%N% 5"J8)G E,J") IF 41*J,)G :,$/%&N EF -F -8/?12G
E"##%+"/ 5F O"J1,8)"/G ,#= 61/%)$%#" 38"%$)&1
!"#"$%&' Apr|| 2013 193:1269-1277
EDITORS NOTE A |ongstand|ng debate cont|nues on the |mportance of the
prote|n chaperone HSP90 |n evo|ut|onary processes and the magn|tude of |ts
effect. Th|s study bo|sters the hypothes|s that HSP90 fac|||tates evo|ut|on by
stab|||z|ng |ts c||ent prote|ns and a||ow|ng them to accumu|ate mutat|ons wh||e
at the same t|me rema|n|ng funct|ona|.
ABSTRACT The heat-shock prote|n 90 (HSP90} acts as a chaperone by
ensur|ng proper maturat|on and fo|d|ng of |ts c||ent prote|ns. The HSP90
capac|tor hypothes|s ho|ds that |nteract|ons w|th HSP90 a||ow prote|ns
to accumu|ate mutat|ons wh||e ma|nta|n|ng funct|on. Fo||ow|ng th|s |og|c,
HSP90 c||ents wou|d be pred|cted to show re|axed se|ect|on compared w|th
nonc||ents. ln th|s study, we |dent|fy a new HSP90 c||ent |n the p|ant stero|d
hormone pathway: the transcr|pt|on factor BES1. lts c|osest para|og, BZR1,
|s not an HSP90 c||ent. Th|s d|fference |n HSP90 c||ent status |n two h|gh|y
s|m||ar prote|ns enab|ed a d|rect test of the capac|tor hypothes|s. We fnd that
:;4< shows re|axed se|ect|on compared to :=><, ha||marks of neo- and
subfunct|ona||zat|on, and dynam|c HSP90 c||ent status across |ndependent
evo|ut|onary paths. These resu|ts suggested that HSP90`s |nfuence on
gene evo|ut|on may be detectab|e |f we compare gene dup||cates because
dup||cates share most other propert|es |nfuenc|ng evo|ut|onary rate that
m|ght otherw|se concea| the chaperone`s effect. We test th|s hypothes|s us|ng
systemat|ca||y |dent|fed HSP90 c||ents |n yeast and observe a s|gn|fcant
trend of HSP90 c||ents evo|v|ng faster than the|r nonc||ent para|ogs. Th|s trend
was not detected when yeast c||ents and nonc||ents were compared w|thout
cons|der|ng para|og status. Our data prov|de ev|dence that HSP90 |nfuences
se|ect|on on genes encod|ng |ts c||ents and fac|||tates d|vergence between
gene dup||cates.
6
DEvELOPMENTAL AND BEHAvl ORAL GENETl CS
Probing the Boundaries of Orthology:
Te Unanticipated Rapid Evolution of
Drosophila Centrosomin
>*7"/$ 6F P%)J,# ,#= 41*J,) 6F Q,8+J,#
!"#"$%&' August 2013 194:903-926
EDITORS NOTE We expect prote|ns that carry out |mportant funct|ons
to be conserved |n evo|ut|on. Th|s art|c|e, however, showed otherw|se
for an essent|a| prote|n requ|red |n ear|y c|eavage d|v|s|ons of ()*'*+,%-..
The authors found that the &"#$)*'*5%# gene evo|ves rap|d|y and |dent|fed
changes |n gene structure and prote|n sequences that suggest a nove|
mechan|sm for fast evo|ut|on of some genes.
ABSTRACT The rap|d evo|ut|on of essent|a| deve|opmenta| genes and the|r
prote|n products |s both |ntr|gu|ng and prob|emat|c. The rap|d evo|ut|on of
gene products w|th s|mp|e prote|n fo|ds and a |ack of we||-character|zed
funct|ona| doma|ns typ|ca||y resu|t |n a |ow d|scovery rate of ortho|ogous
genes. Add|t|ona||y, |n the absence of ortho|ogs |t |s d|ffcu|t to study the
processes and mechan|sms under|y|ng rap|d evo|ut|on. ln th|s study, we
have |nvest|gated the rap|d evo|ut|on of &"#$)*'*5%# ?&##@, an essent|a| gene
encod|ng centrosoma| prote|n |soforms requ|red dur|ng syncyt|a| deve|opment
|n ()*'*+,%-. 5"-.#*3.'$"). nt|| recent|y the rap|d d|vergence of &## made
|dent|fcat|on of ortho|ogs d|ffcu|t and quest|onab|e because Onn v|o|ates
many of the assumpt|ons under|y|ng mode|s for prote|n evo|ut|on. To overcome
these ||m|tat|ons, we have |dent|fed a group of |nsect ortho|ogs and present
conserved features ||ke|y to be requ|red for the funct|ons attr|buted to &## |n
(8 5"-.#*3.'$"). We a|so show that the rap|d d|vergence of Onn |soforms |s
apparent|y due to frequent cod|ng sequence |nde|s and an acce|erated rate of
|ntron|c add|t|ons and e||m|nat|ons. These changes appear to be buffered by
mu|t|-exon and mu|t|-read|ng frame max|mum potent|a| ORFs, s|mp|e prote|n
fo|ds, and the sp||c|ng mach|nery. These buffer|ng features a|so occur |n other
genes |n ()*'*+,%-. and may he|p prevent potent|a||y de|eter|ous mutat|ons due
to |nde|s |n genes w|th |arge cod|ng exons and exon-dense reg|ons separated
by sma|| |ntrons. Th|s work prom|ses to be usefu| for future |nvest|gat|ons of &##
and potent|a||y other rap|d|y evo|v|ng genes and prote|ns.
7
DEvELOPMENTAL AND BEHAvl ORAL GENETl CS
Unexpected Role for Dosage Compensation
in the Control of Dauer Arrest, Insulin-Like
Signaling, and FoxO Transcription Factor
Activity in Caenorhabditis elegans
Q,$1;""# EF (8J,)G 6*;%# PF (";,#"2G D$"?1,#" H;%7*$$"G (*#,;= !F -*"/J,#G
!2*/92% 6),#N*@)MN%G ,#= :,$/%&N EF I8
!"#"$%&' Ju|y 2013 194:619-629
EDITORS NOTE The /8 "-"3.#' dosage compensat|on mach|nery reduces
express|on of -||nked genes |n hermaphrod|tes to ba|ance transcr|pt |eve|s
between the sexes. Th|s report uncovered an unexpected ro|e of dosage
compensat|on |n the contro| of dauer arrest |n /8 "-"3.#' through regu|at|ng
-||nked components of a conserved |nsu||n-||ke s|gna||ng pathway that
|nh|b|ts FoxO transcr|pt|on factor act|v|ty.
ABSTRACT Dur|ng embryogenes|s, an essent|a| process known as
dosage compensat|on |s |n|t|ated to equa||ze gene express|on from sex
chromosomes. A|though much |s known about how dosage compensat|on
|s estab||shed, the consequences of modu|at|ng the stab|||ty of dosage
compensat|on postembryon|ca||y are not known. Here we defne a ro|e for
the /."#*),.01%$%' "-"3.#' dosage compensat|on comp|ex (DOO} |n the
regu|at|on of DAF-2 |nsu||n-||ke s|gna||ng. ln a screen for dauer regu|atory
genes that contro| the act|v|ty of the FoxO transcr|pt|on factor DAF-16, we
|so|ated three mutant a||e|es of 1+6AB<, wh|ch encodes a conserved DOO
component. Knockdown of mu|t|p|e DOO components |n hermaphrod|te
and ma|e an|ma|s |nd|cates that the dauer suppress|on phenotype of 1+6AB<
mutants |s due to a defect |n dosage compensat|on +") '". ln 1+6AB<
mutants, express|on of severa| -||nked genes that promote dauer bypass |s
e|evated, |nc|ud|ng four genes encod|ng components of the DAF-2 |nsu||n-||ke
pathway that antagon|ze DAF-16/FoxO act|v|ty. Accord|ng|y, 1+6AB< mutat|on
reduced the express|on of DAF-16/FoxO target genes by promot|ng the
exc|us|on of DAF-16/FoxO from nuc|e|. Thus, dosage compensat|on enhances
dauer arrest by repress|ng -||nked genes that promote reproduct|ve
deve|opment through the |nh|b|t|on of DAF-16/FoxO nuc|ear trans|ocat|on.
Th|s work |s the frst to estab||sh a spec|fc postembryon|c funct|on for dosage
compensat|on |n any organ|sm. The |nfuence of dosage compensat|on
on dauer arrest, a |arva| deve|opmenta| fate governed by the |ntegrat|on of
mu|t|p|e env|ronmenta| |nputs and s|gna||ng outputs, suggests that the dosage
compensat|on mach|nery may respond to externa| cues by modu|at|ng
s|gna||ng pathways through chromosome-w|de regu|at|on of gene express|on.
8
GENE EXPRESSl ON
Genetic Variants Contribute to Gene Expression
Variability in Humans
0J,#=, -F I8;)" ,#= E,J") EF 6,%
!"#"$%&' January 2013 193:95-108
EDITORS NOTE lncreas|ng ev|dence suggests that the var|ance (as
opposed to the mean} of phenotypes |s genet|ca||y contro||ed and ||ke|y to be
se|ectab|e. ln th|s study, the authors |dent|fed human express|on var|ab|||ty OT|
(evOT|}, |oc| assoc|ated w|th the gene express|on var|ances among genotypes
of a b|a||e||c SNP. Because the phenotyp|c var|ance |s ||ke|y to d|ffer under the
|nfuence of genet|c |nteract|ons, detect|ng evOT| may prov|de a new method
for |nteract|on screen|ng.
ABSTRACT Express|on quant|tat|ve tra|t |oc| (eOT|} stud|es have estab||shed
conv|nc|ng re|at|onsh|ps between genet|c var|ants and gene express|on.
Most of these stud|es focused on the mean of gene express|on |eve|, but not
the var|ance of gene express|on |eve| (%8"8C gene express|on var|ab|||ty}. ln the
present study, we systemat|ca||y exp|ore genome-w|de assoc|at|on between
genet|c var|ants and gene express|on var|ab|||ty |n humans. We adapt the
doub|e genera||zed ||near mode| (dg|m} to s|mu|taneous|y ft the means and the
var|ances of gene express|on among the three poss|b|e genotypes of a b|a||e||c
SNP. The genom|c |oc| show|ng s|gn|fcant assoc|at|on between the var|ances
of gene express|on and the genotypes are termed "D+)"''%*# 7.)%.0%-%$6 OT|
(evOT|}. s|ng a data set of gene express|on |n |ymphob|asto|d ce|| ||nes
(|O|s} der|ved from 210 HapMap |nd|v|dua|s, we |dent|fy &%'-act|ng evOT|
|nvo|v|ng 218 d|st|nct genes, among wh|ch 8 genes, E(/F<, /GHHEB, (EEIB,
J;>IGB, KLM, NLO(B, 4HPQ, and GHJ>4J<<:, are cross-va||dated us|ng an
extra express|on data set of the same |O|s. We a|so |dent|fy ~300 $).#'-
act|ng evOT| between >13,000 common SNPs and 500 random|y se|ected
representat|ve genes. We emp|oy two d|st|nct scenar|os, emphas|z|ng s|ng|e-
SNP and mu|t|p|e-SNP effects on express|on var|ab|||ty, to exp|a|n the format|on
of evOT|. We argue that detect|ng evOT| may represent a nove| method for
effect|ve|y screen|ng for genet|c |nteract|ons, espec|a||y when the mu|t|p|e-SNP
|nfuence on express|on var|ab|||ty |s |mp||ed. The |mp||cat|on of our resu|ts for
revea||ng genet|c mechan|sms of gene express|on var|ab|||ty |s d|scussed.
9
GENOME AND SYSTEMS Bl OLOGY
Genome Reduction Promotes Increase in
Protein Functional Complexity in Bacteria
R*9")1C,/ (F Q";N,/ ,#= I*C,/= S&1J,#
!"#"$%&' January 2013 193:303-307
EDITORS NOTE Many prote|ns 'mu|t|task" or 'moon||ght" by perform|ng
new or a|ternate funct|ons. Th|s art|c|e prov|ded ev|dence that bacter|a show
a broad, genome-w|de trend toward |ncreas|ng prote|n funct|ona| d|vers|ty |n
sma||er genomes. The authors argued that as benefc|a| genes are |ost dur|ng the
course of genome reduct|on, the rema|n|ng genes are se|ected for d|vers|fcat|on.
ABSTRACT Ob||gate pathogen|c and endosymb|ot|c bacter|a typ|ca||y
exper|ence gene |oss due to funct|ona| redundancy, asexua||ty, and genet|c
dr|ft. We hypothes|ze that reduced genomes |ncrease the|r funct|ona|
comp|ex|ty through prote|n mu|t|task|ng, |n wh|ch many genes adopt new
ro|es to counteract gene |oss. Oompar|sons of |nteract|on networks among s|x
bacter|a that have var|ed genome s|zes (I6&*+-.'5. +#"R5*#%.", G)"+*#"5.
+.--%1R5, S"-%&*0.&$") +6-*)%, /.5+6-*0.&$") T"TR#%, 46#"&,*&6'$%' '+8, and
I6&*0.&$")%R5 $R0")&R-*'%'} revea| that prote|ns |n sma|| genomes |nteract
w|th prote|ns from a w|der range of funct|ons than do the|r ortho|ogs |n |arger
genomes. Th|s suggests that surv|v|ng prote|ns form |ncreas|ng|y comp|ex
funct|ona| re|at|onsh|ps to compensate for genes that are |ost.
10
GENOME AND SYSTEMS Bl OLOGY
How Biochemical Constraints of Cellular
Growth Shape Evolutionary Adaptations
in Metabolism
E,# B"/N1*8$G P@"/$ B*)=/%")MG PJ/,1 O%N"/";G (*8C" -*;"#,,/G (%&N =" >%=="/G
B,) 4"8)%#NG ,#= H/,#N EF B/899"J,#
!"#"$%&' June 2013 194:505-512
EDITORS NOTE Metabo||c evo|ut|on |s constra|ned by the b|osynthet|c
capac|ty of organ|sms. As such, there |s a tradeoff between the cost of
synthes|z|ng an enzyme and the benefts of |ts cata|yt|c act|v|ty. For opt|ma|
regu|at|on of metabo||c pathways, each enzyme must be ma|nta|ned at
|eve|s where these costs and benefts add up to a max|mum net return. By
ca|cu|at|ng enzyme costs and benefts from k|net|c and b|ochem|ca| data, the
authors presented a theoret|ca| framework for pred|ct|ng the ways |n wh|ch
enzyme |eve|s shou|d change to atta|n max|ma| metabo||c fux.
ABSTRACT Evo|ut|onary adaptat|ons |n metabo||c networks are fundamenta| to
evo|ut|on of m|crob|a| growth. Stud|es on unneeded-prote|n synthes|s |nd|cate
reduct|ons |n ftness upon nonfunct|ona| prote|n synthes|s, show|ng that ce||
growth |s ||m|ted by constra|nts act|ng on ce||u|ar prote|n content. Here, we
present a theory for opt|ma| metabo||c enzyme act|v|ty when ce||s are se|ected
for max|ma| growth rate g|ven such growth-||m|t|ng b|ochem|ca| constra|nts. We
show how opt|ma| enzyme |eve|s can be understood to resu|t from an enzyme
beneft m|nus cost opt|m|zat|on. The constra|nts we cons|der or|g|nate from
d|fferent b|ochem|ca| aspects of m|crob|a| growth, such as compet|t|on for
||m|t|ng amounts of r|bosomes or RNA po|ymerases, or ||m|tat|ons |n ava||ab|e
energy. Enzyme beneft |s re|ated to |ts k|net|cs and |ts |mportance for ftness,
wh||e enzyme cost expresses to what extent resource consumpt|on reduces
ftness through constra|nt-|nduced reduct|ons of other enzyme |eve|s. A
metabo||c ftness |andscape |s |ntroduced to defne the ftness potent|a| of an
enzyme. Th|s concept |s re|ated to the se|ect|on coeffc|ent of the enzyme and
can be expressed |n terms of |ts ftness beneft and cost.
11
GENOME l NTEGRl TY AND TRANSMl SSl ON
EDITORS NOTE Two compan|on art|c|es reported nove| p|ayers |n me|ot|c
s||enc|ng by unpa|red DNA (MSD} |n H"R)*'+*)., |nc|ud|ng sma|| RNAs and
the frst known prote|n requ|red for MSD that |s |oca||zed to the nuc|eus, where
recogn|t|on of unpa|red DNA occurs. The new|y |dent|fed MSD prote|ns are
un|que |n that they are not requ|red for me|os|s, prov|d|ng the frst |nd|cat|on that
MSD |s not necessar||y coup|ed to sexua| deve|opment.
Novel Proteins Required for Meiotic Silencing by Unpaired
DNA and siRNA Generation in Neurospora crassa
41*J,) -F I,JJ*#=G I8, T%,*G P/%# 6F B**#"G 5*9,# -F ("&N"/G D"8#9 0F 5""G
4*#2 (F :"/=8"G :,$/%&%, EF :8NN%;,G ,#= :,$/%&N QF 4F D1%8
!"#"$%&' May 2013 194:91-100
ABSTRACT Dur|ng me|os|s |n the f|amentous fungus H"R)*'+*). &).''., unpa|red
genes are |dent|fed and s||enced by a process known as me|ot|c s||enc|ng by unpa|red
DNA (MSD}. Prev|ous work has uncovered s|x prote|ns requ|red for MSD, a|| of
wh|ch are a|so essent|a| for me|ot|c progress|on. Add|t|ona||y, they a|| |oca||ze |n the
per|nuc|ear reg|on, suggest|ng that |t |s a center of MSD act|v|ty. Neverthe|ess, at
|east a subset of MSD prote|ns must be present |ns|de the nuc|eus, as unpa|red DNA
recogn|t|on undoubted|y takes p|ace there. ln th|s study, we |dent|fed and character|zed
two new prote|ns requ|red for MSD, name|y SAD-4 and SAD-5. Both are prev|ous|y
uncharacter|zed prote|ns spec|fc to Ascomycetes, w|th SAD-4 hav|ng a range that
spans severa| funga| c|asses and SAD-5 seem|ng|y restr|cted to a s|ng|e order. Both
genes appear to be predom|nant|y expressed |n the sexua| phase, as mo|ecu|ar study
comb|ned w|th ana|ys|s of pub||c|y ava||ab|e mRNA-seq datasets fa||ed to detect
s|gn|fcant express|on of them |n the vegetat|ve t|ssue. SAD-4, ||ke a|| known MSD
prote|ns, |oca||zes |n the per|nuc|ear reg|on of the me|ot|c ce||. SAD-5, on the other
hand, |s found |n the nuc|eus (as the frst of |ts k|nd}. Both prote|ns are un|que compared
to prev|ous|y |dent|fed MSD prote|ns |n that ne|ther |s requ|red for sexua| sporu|at|on.
Th|s homozygous-fert||e phenotype uncoup|es MSD from sexua| deve|opment and
a||ows us to demonstrate that both SAD-4 and SAD-5 are |mportant for the product|on
of mas|RNAs, wh|ch are the sma|| RNA mo|ecu|es assoc|ated w|th me|ot|c s||enc|ng.
Identifcation of Small RNAs Associated with Meiotic
Silencing by Unpaired DNA
41*J,) -F I,JJ*#=G K%;;%,J !F D?*;;"#G 5*9,# -F ("&N"/G D",# -F B;,N"G
!*/=*# QF D?/%#9"/G ,#= :,$/%&N QF 4F D1%8
!"#"$%&' May 2013 194:279-284
ABSTRACT ln H"R)*'+*). &).''., unpa|red genes are s||enced by a mechan|sm
ca||ed me|ot|c s||enc|ng by unpa|red DNA (MSD}. A|though some RNA |nterference
prote|ns are necessary for th|s process, |ts requ|rement of sma|| RNAs has yet to be
forma||y estab||shed. Here we report the character|zat|on of sma|| RNAs target|ng an
unpa|red reg|on, us|ng l||um|na sequenc|ng.
12
METHODS, TECHNOLOGY, AND RESOURCES - CRl SPR
Genome Engineering of Drosophila with the
CRISPR RNA-guided Cas9 Nuclease
D&*$$F EF !/,$MG 0;"U,#="/ -F 68JJ%#9)G E"##%+"/ OF O982"#G (,#%";;" 6F I,JJG
5,8/, QF (*#*18"G -";%)), -F I,//%)*#G E%;; K%;=*#9"/G ,#= Q,$" -F SV6*##*/<!%;")
!"#"$%&' August 2013 194:1029-1035
EDITORS NOTE Th|ngs move fast |n th|s fe|d. On|y two years after |t was
proposed, qu|ck and effc|ent genome eng|neer|ng w|th the ORlSPR/Oas9
system |s a|ready a rea||ty. |ast summer, Gratz "$ .-8 reported the frst use of
the ORlSPR/Oas9 system for targeted mutagenes|s |n ()*'*+,%-., show|ng that
stab|e mutant ||nes cou|d be generated w|th|n a month. Short|y after, GENETlOS
pub||shed two commentar|es and severa| more descr|pt|ons of ORlSPR
eng|neer|ng |n mode| organ|sms, |nc|ud|ng fve methods for gene ed|t|ng |n
/8 "-"3.#' and other nematodes. A|ready |n 2014, GENETlOS |s pub||sh|ng
|mprovements and e|aborat|ons on the method for workhorse mode|
organ|sms, p|us one of the frst reports of |ts app||cat|on |n a non-mode| an|ma|.
ABSTRACT We have adapted a bacter|a| ORlSPR RNA/Oas9 system to
prec|se|y eng|neer the ()*'*+,%-. genome and report that Oas9-med|ated
genom|c mod|fcat|ons are effc|ent|y transm|tted through the germ||ne. Th|s
RNA-gu|ded Oas9 system can be rap|d|y programmed to generate targeted
a||e|es for prob|ng gene funct|on |n ()*'*+,%-..
13
CRl SPR
S$1"/ 6>AD:> ,/$%&;")W
High|y Efcient Genome Modications Mediated by CRISPR/Cas9 in '()&)*+"%,
Zhongsheng Yu, Mengda Ren, Zhanx|ang Wang, Bo Zhang, Y|kang S. Rong,
Renj|e J|ao, and Guanjun Gao
!"#"$%&' September 2013 195:289-291
>O0<!8%="= O8&;",)")W 0 O"C P/, +*/ P#9%#""/%#9 $1" !"#*J") *+ -*="; ,#=
O*#J*="; S/9,#%)J)
Kent G. Go||c
!"#"$%&' October 2013 195:303-308
:/"&%)" ,#= I"/%$,7;" !"#*J" P=%$%#9 %# P@*;8$%*#,/%;2 (%@"/)" O"J,$*=") X)%#9
TALENs and CRISPR/Cas9 to Engineer Insertions and De|etions
Te-Wen |o, Oather|ne S. P|ck|e, Steven ||n, Edward J. Ra|ston, Mark Gur||ng,
Oa|t||n M. Schartner, O|an B|an, Jenn|fer A. Doudna, and Barbara J. Meyer
!"#"$%&' October 2013 195:331-348
PU&%$%#9 :/*)?"&$) +*/ :/"&%)" P#9%#""/%#9 *+ -,./)(+,01"2"& .%.4,/& !"#*J")
with CRISPR/Cas9
Ohr|st|an Frokjr-Jensen
!"#"$%&' November 2013 195:635-642
High|y Improved Gene Targeting by Germ|ine-Specic Cas9 Expression in
'()&)*+"%,
Shu Kondo and Ryu eda
!"#"$%&' November 2013 195:715-721
4/,#)9"#"<H/"" !"#*J" P=%$%#9 %# -,./)(+,01"2"& .%.4,/& X)%#9 6>AD:><6,)
Hu| Oh|u, H|||e| T. Schwartz, lgor Antoshechk|n, and Pau| W. Sternberg
!"#"$%&' November 2013 195:1167-1171
Targeted Heritab|e Mutation and Gene Conversion by Cas9-CRISPR in
-,./)(+,01"2"& .%.4,/&
lskra Kat|c and He|ge Gro3hans
!"#"$%&' November 2013 195:1173-1176
I"/%$,7;" !"#" Q#*&N*8$ %# -,./)(+,01"2"& .%.4,/& 72 (%/"&$ A#."&$%*# *+
Cas9-sgRNA Ribonuc|eoproteins
Seung Woo Oho, J|hyun |ee, Dana Oarro||, J|n-Soo K|m, and Junho |ee
!"#"$%&' November 2013 195:1177-1180
Heritab|e Custom Genomic Modications in -,./)(+,01"2"& .%.4,/& @%, ,
CRISPR-Cas9 System
Yonatan B. Tzur, Ar| E. Fr|ed|and, Saravanapr|ah Nadarajan, George M. Ohurch,
John A. Oa|arco, and Mon|ca P. Oo|a|covo
!"#"$%&' November 2013 195:1181-1185
CRISPR/Cas9-Targeted Mutagenesis in -,./)(+,01"2"& .%.4,/&
Se|ma Waa|jers, v|ncent Porteg|js, Jana Kerver, Benn|e B. |. G. |emmens,
Marce| T|jsterman, Sander van den Heuve|, and M|ke Boxem
!"#"$%&' November 2013 195:1187-1191
14
METHODS, TECHNOLOGY, AND RESOURCES
A Novel Strategy for Cell Autonomous Gene
Knockdown in Caenorhabditis elegans Defnes
a Cell-specifc Function for the G-protein
Subunit GOA-1
Q,$1/2# OF -,1"/G 0%)1C,/2, DC,J%#,$1,#G :,/$1 :,$";G ,#= (,#%"; 5F 61,)"
!"#"$%&' June 2013 194:363-373
EDITORS NOTE A major drawback of doub|e-stranded RNA |nterference
(dsRNA|} |n /8 "-"3.#' |s that dsRNAs or the|r |ntermed|ates can be
transported between ce||s to cause system|c knockdown effects. Th|s
art|c|e descr|bed a nove| method for ce|| type-spec|fc knockdown that does
not re|y on RNA |nterference, but |nstead uses the host ce||`s nonsense-
med|ated decay mechan|sms to contro| gene express|on. Because th|s new
knockdown method |s both genet|ca||y stab|e and str|ct|y ce|| autonomous, |t
can be used to |nvest|gate prote|n funct|on w|th s|ng|e ce|| reso|ut|on.
ABSTRACT We deve|oped a nove| knockdown strategy to exam|ne ce||-
spec|fc gene funct|on |n /."#*),.01%$%' "-"3.#'. ln th|s strategy a nu||
mutat|on |n any gene |s rep|aced w|th a genet|ca||y stab|e transgene that
conta|ns a w||d-type copy of the gene fused to a 3' tag that targets the mRNA
transcr|pt for degradat|on by the host nonsense-med|ated decay (NMD}
mach|nery. ln NMD-defect|ve an|ma|s, tagged transgene mRNA |s expressed
at |eve|s s|m||ar to the endogenous gene |t rep|aced and |s trans|ated |nto w||d-
type prote|n that fu||y rescues gene funct|on. Oe||-spec|fc act|vat|on of NMD
ce|| autonomous|y knocks down transgene express|on |n spec|fc ce|| types
w|thout affect|ng |ts express|on or funct|on |n other ce||s of the organ|sm. To
demonstrate the ut|||ty of th|s system, we rep|aced the 3*.A< gene, encod|ng
the pan-neurona||y expressed G-prote|n subun|t GOA-1, w|th a degradat|on-
tagged transgene. We then knocked down express|on of the transgene from
on|y two neurons, the hermaphrod|te-spec|fc neurons (HSNs}, and showed
that GOA-1 acts ce|| autonomous|y |n the HSNs to |nh|b|t egg-|ay|ng behav|or.
15
PRl MERS
SMG-ly Knocking Out Gene Expression in
Specifc Cells: An Educational Primer for Use
with A Novel Strategy for Cell-Autonomous
Gene Knockdown in Caenorhabditis elegans
Defnes a Cell-Specifc Function for the
G-Protein Subunit GOA-1
:1%;%? -F -"#"";2 ,#= E*/=,#, 6F B;**J
!"#"$%&' December 2013 195:1201-1207
EDITORS NOTE Pr|mers are des|gned to he|p both educators and students
|n the c|assroom. Each Pr|mer re|ates to a current art|c|e |n GENETlOS and
|ays out the necessary background (%8"8, what was the quest|on and why d|d
that quest|on matter?}, exp|a|ns the hypothes|s or approach, descr|bes the
methodo|ogy, gu|des the reader through the resu|ts, and prov|des a prec|se
summary of the d|scuss|on. The goa| |s not to rep|ace the art|c|e, but rather to
make the art|c|e |tse|f access|b|e by offer|ng a road map. Hav|ng a Pr|mer |n
hand makes |t easy for educators to choose an art|c|e and teach |t effect|ve|y.
Our rea| hope, however, |s that a Pr|mer w||| serve as the 'jump|ng off" po|nt that
encourages students to d|ve confdent|y |nto an art|c|e. ln 2014, GENETlOS has
a|so begun to pub||sh mode| organ|sm Pr|mers.
ABSTRACT A recent art|c|e by Maher "$ .-8 |n GENETlOS |ntroduces an
a|ternat|ve approach to ce||-type-spec|fc gene knockdown |n /."#*),.01%$%'
"-"3.#', us|ng nonsense-med|ated decay. Th|s strategy has the potent|a|
to be app||cab|e to other organ|sms (th|s strategy requ|res that an|ma|s can
surv|ve w|thout nonsense-med|ated decay-not a|| can}. Th|s Pr|mer art|c|e
prov|des a gu|de and resource for educators and students by descr|b|ng
d|fferent gene knockdown methodo|og|es, by ass|st|ng w|th the techn|ca||y
d|ffcu|t port|ons of the Maher "$ .-8 art|c|e, and by prov|d|ng conceptua|
quest|ons re|at|ng to the art|c|e.
16
POPULATl ON AND EvOLUTl ONARY GENETl CS
Rare Variants in Hypermutable Genes Underlie
Common Morphology and Growth Traits in
Wild Saccharomyces paradoxus
E"/"J2 AF >**? ,#= >,&1"; BF B/"J
!"#"$%&' October 2013 195:513-525
EDITORS NOTE What are the re|at|ve contr|but|ons of rare and common
var|ants to tra|t d|fferences? Roop and Brem d|scovered that unre|ated,
recent|y ar|sen a||e|es of human neurofbromatos|s gene HJ< homo|ogs
|nfuence hundreds of common tra|ts |n w||d yeasts. The|r resu|ts |mp||cate
rare var|ants |n yeast morpho|ogy, stress res|stance, and metabo||sm-
m|rror|ng the hundreds of rare mutat|ons |n HJ< known to under||e d|sease
|n humans. Thus, the propens|ty for 1" #*7* mutat|ons w|th dramat|c
phenotypes at th|s human d|sease |ocus may have or|g|nated m||||ons of years
ago |n a un|ce||u|ar ancestor.
ABSTRACT nderstand|ng the mo|ecu|ar bas|s of common tra|ts |s a pr|mary
cha||enge of modern genet|cs. One mode| ho|ds that rare mutat|ons |n many
genet|c backgrounds may often phenocopy one another, together exp|a|n|ng
the preva|ence of the resu|t|ng tra|t |n the popu|at|on. For the vast major|ty of
phenotypes, the ro|e of rare var|ants and the evo|ut|onary forces that under||e
them are unknown. ln th|s work, we use a popu|at|on of 4.&&,.)*56&"'
+.).1*DR' yeast as a mode| system for the study of common tra|t var|at|on.
We observed an unusua|, foccu|at|on and |nvas|ve-growth phenotype |n
one-th|rd of 48 +.).1*DR' stra|ns, wh|ch were otherw|se unre|ated. ln crosses
w|th each stra|n |n turn, these morpho|og|es segregated as a recess|ve
Mende||an phenotype, mapp|ng e|ther to K>E< or to K>E<, yeast homo|ogs of
the hypermutab|e human neurofbromatos|s gene HJ<. The causa| K>E< and
K>E< hap|otypes were of d|st|nct evo|ut|onary or|g|n and, |n add|t|on to the|r
morpho|og|ca| effects, assoc|ated w|th hundreds of stress-res|stance and
growth tra|ts, both benefc|a| and d|sadvantageous, across 48 +.).1*DR'.
S|ng|e-gene mo|ecu|ar genet|c ana|yses confrmed var|ant K>E< and K>E<
hap|otypes as causa| for these growth character|st|cs, many of wh|ch were
|ndependent of morpho|ogy. Our data make c|ear that common growth and
morpho|ogy tra|ts |n yeast resu|t from a su|te of var|ants |n master regu|ators,
wh|ch funct|on as a mutat|on-dr|ven sw|tch between phenotyp|c states.
17
POPULATl ON AND EvOLUTl ONARY GENETl CS
Inferring Admixture Histories of Human
Populations using Linkage Disequilibrium
:*<>8 5*1G -,/N 5%?)*#G O%&N :,$$"/)*#G :/%2, -**/.,#%G E*)"?1 QF :%&N/";;G
(,@%= >"%&1G ,#= B*##%" B"/9"/
!"#"$%&' Apr|| 2013 193:1233-1254
EDITORS NOTE ln humans, ||nkage d|sequ|||br|um between |oc| |s typ|ca||y
neg||g|b|e after a few hundred k||obases. But |onger-range adm|xture ||nkage
d|sequ|||br|um (A|D} can resu|t from h|stor|ca| m|x|ng events between
prev|ous|y separated popu|at|ons. The authors showed how stat|st|cs based
on ||nkage d|sequ|||br|um can be used to construct a robust test for adm|xture
and to |nfer adm|xture-re|ated parameters such as dates, m|xture proport|ons,
and phy|ogenet|c re|at|onsh|ps.
ABSTRACT |ong-range m|grat|ons and the resu|t|ng adm|xtures between
popu|at|ons have been |mportant forces shap|ng human genet|c d|vers|ty. Most
ex|st|ng methods for detect|ng and reconstruct|ng h|stor|ca| adm|xture events
are based on a||e|e frequency d|vergences or patterns of ancestry segments |n
chromosomes of adm|xed |nd|v|dua|s. An emerg|ng new approach harnesses
the exponent|a| decay of adm|xture-|nduced ||nkage d|sequ|||br|um (|D} as a
funct|on of genet|c d|stance. Here, we comprehens|ve|y deve|op |D-based
|nference |nto a versat||e too| for |nvest|gat|ng adm|xture. We present a new
we|ghted |D stat|st|c that can be used to |nfer m|xture proport|ons as we|| as
dates w|th fewer constra|nts on reference popu|at|ons than prev|ous methods.
We defne an |D-based three-popu|at|on test for adm|xture and |dent|fy
scenar|os |n wh|ch |t can detect adm|xture events that prev|ous forma| tests
cannot. We further show that we can uncover phy|ogenet|c re|at|onsh|ps
among popu|at|ons by compar|ng we|ghted |D curves obta|ned us|ng a su|te
of references. F|na||y, we descr|be severa| |mprovements to the computat|on
and ftt|ng of we|ghted |D curves that great|y |ncrease the robustness and
speed of the ca|cu|at|ons. We |mp|ement a|| of these advances |n a software
package, A|DER, wh|ch we va||date |n s|mu|at|ons and app|y to test for
adm|xture among a|| popu|at|ons from the Human Genome D|vers|ty Project
(HGDP}, h|gh||ght|ng |ns|ghts |nto the adm|xture h|story of Oentra| Afr|can
Pygm|es, Sard|n|ans, and Japanese.
18
POPULATl ON AND EvOLUTl ONARY GENETl CS
Rate of Adaptation in Sexuals and Asexuals:
A Solvable Model of the Fisher-Muller Efect
D8<61,# :,/N ,#= E*,&1%J Q/89
!"#"$%&' November 2013 195:941-955
EDITORS NOTE What use |s sex? ln the 1930s, F|sher and Mu||er argued
that sex speeds up adaptat|on of |arge popu|at|ons by a||ow|ng d|fferent
benefc|a| mutat|ons to comb|ne |nto a s|ng|e genome. These authors showed
that the F|sher-Mu||er mechan|sm can resu|t |n a two-fo|d |ncrease of the
adaptat|on rate |n |arge popu|at|ons.
ABSTRACT The adaptat|on of |arge asexua| popu|at|ons |s hampered by the
compet|t|on between |ndependent|y ar|s|ng benefc|a| mutat|ons |n d|fferent
|nd|v|dua|s, wh|ch |s known as c|ona| |nterference. ln c|ass|c work, F|sher and
Mu||er proposed that recomb|nat|on prov|des an evo|ut|onary advantage |n
|arge popu|at|ons by a||ev|at|ng th|s compet|t|on. Based on recent progress
|n quant|fy|ng the speed of adaptat|on |n asexua| popu|at|ons undergo|ng
c|ona| |nterference, we present a deta||ed ana|ys|s of the F|sher-Mu||er
mechan|sm for a mode| genome cons|st|ng of two |oc| w|th an |nfn|te number
of benefc|a| a||e|es each and mu|t|p||cat|ve (nonep|stat|c} ftness effects. We
so|ve the determ|n|st|c, |nfn|te popu|at|on dynam|cs exact|y and show that,
for a part|cu|ar, natura| mutat|on scheme, the speed of adaptat|on |n sexua|s
|s tw|ce as |arge as |n asexua|s. Th|s resu|t |s argued to ho|d for any nonzero
va|ue of the rate of recomb|nat|on. Gu|ded by the |nfn|te popu|at|on resu|t and
by prev|ous work on asexua| adaptat|on, we postu|ate an express|on for the
speed of adaptat|on |n fn|te sexua| popu|at|ons that agrees w|th numer|ca|
s|mu|at|ons over a w|de range of popu|at|on s|zes and recomb|nat|on rates.
The rat|o of the sexua| to asexua| adaptat|on speed |s a funct|on of popu|at|on
s|ze that |ncreases |n the c|ona| |nterference reg|me and approaches 2 for
extreme|y |arge popu|at|ons. The s|mu|at|ons a|so show that the |mba|ance
between the numbers of accumu|ated mutat|ons at the two |oc| |s strong|y
suppressed even by a sma|| amount of recomb|nat|on. The genera||zat|on
of the mode| to an arb|trary number L of |oc| |s br|efy d|scussed. lf each
offspr|ng samp|es the a||e|es at each |ocus from the gene poo| of the who|e
popu|at|on rather than from two parents, the rat|o of the sexua| to asexua|
adaptat|on speed |s approx|mate|y equa| to L |n |arge popu|at|ons. A poss|b|e
rea||zat|on of th|s scenar|o |s the reassortment of genet|c mater|a| |n RNA
v|ruses w|th L genom|c segments.
19
TRUE COLORS Male guppies, like the wild-type fsh (top), display exquisite
color patterns that evolved in response to a complex interplay between sexual
and natural selection. Although these selection pressures have been extensively
studied, little is known about the underlying genes. In 2013, Kottler et al.
provided the frst molecular insight into guppy pigment pattern formation by
identifying two receptor tyrosine kinases essential for guppy ornamentation
and corresponding to the loci blue (mutant second from top) and golden
(mutant third from top). Guppies with a double blue golden mutation present
with a ghostlike appearance (bottom). Image courtesy of Verena Kottler.
:%9J"#$ :,$$"/# H*/J,$%*# %# $1" !8??2G 5).6"%", (.2"6$%,2,G
A#@*;@") $1" Q%$, ,#= 6)+Y/, >"&"?$*/ 42/*)%#" Q%#,)")
verena A. Kott|er, Andrey Fadeev, Det|ef We|ge|, and Ohr|st|ne Dreyer
!"#"$%&' Ju|y 2013 194:631-646
20
PERSPECTl vES
Te Genetics of Canine Skull Shape Variation
E"++/"2 EF D&1*"#"7"&N ,#= P;,%#" 0F S)$/,#="/
!"#"$%&' February 2013 193:317-325
EDITORS NOTE Dogs are the most morpho|og|ca||y d|verse spec|es of a||
|and mamma|s. Thousands of years of domest|cat|on and the r|g|d standards
demanded by dog breeders have shaped the can|ne |nto a un|que mode| for
the genet|cs under|y|ng comp|ex tra|ts, |nc|ud|ng sku|| shape. Th|s Perspect|ve
d|scussed cran|ofac|a| deve|opment as a prom|nent examp|e of a comp|ex
tra|t and rev|ews recent progress us|ng genome-w|de assoc|at|on stud|es.
ABSTRACT A dog`s cran|ofac|a| d|vers|ty |s the resu|t of cont|nua| human
|ntervent|on |n natura| se|ect|on, a process that began tens of thousands
of years ago. To date, we know ||tt|e of the genet|c underp|nn|ngs and
deve|opmenta| mechan|sms that make dog sku||s so morpho|og|ca||y p|ast|c.
ln th|s Perspect|ves, we d|scuss the or|g|ns of dog sku|| shapes |n terms
of h|story and b|o|ogy and h|gh||ght recent advances |n understand|ng the
genet|cs of can|ne sku|| shapes. Of part|cu|ar |nterest are those mo|ecu|ar
genet|c changes that are assoc|ated w|th the deve|opment of d|st|nct breeds.
Te diminutive Chihuahua skull (left) is dwarfed by that of the Irish Wolfhound
(right), though both are members of the same species, Canis lupus familiaris.
Closer examination reveals that the morphological diferences between these
two breeds extends beyond size. Despite recent advances, the genetic variations
underlying this diversity remain a source of intrigue. Image courtesy of Lisa
Schublin/Naturhistorisches Museum der Burgergemeinde Bern.
21
REvl EWS AND YEASTBOOK
GENETlOS pub||shes scho|ar|y rev|ews wr|tten by |eaders |n the|r respect|ve
fe|ds. A|| 2013 regu|ar rev|ews are ||sted be|ow. GENETlOS |s a|so p|eased
to offer the YeastBook ser|es, a comprehens|ve and evo|v|ng compend|um
that presents the current state of know|edge of the mo|ecu|ar b|o|ogy, ce||u|ar
b|o|ogy, and genet|cs of the yeast 4.&&,.)*56&"' &")"7%'%.". The near|y
40 YeastBook art|c|es pub||shed so far |nc|ude contr|but|ons on the ce||
cyc|e, ce|| s|gna||ng and deve|opment, ce|| structure and traffck|ng, gene
express|on and metabo||sm, and genome organ|zat|on and |ntegr|ty. v|s|t
www.genet|cs.org/s|te/m|sc/yeastbook.xhtm| to browse the co||ect|on.
K1*;"<!"#*J" >"9/"))%*# ,#= :/"=%&$%*# -"$1*=) 0??;%"= $* :;,#$ ,#= 0#%J,;
B/""=%#9
Gustavo de |os Oampos, John M. H|ckey, R|cardo Pong-Wong, Hans D. Daetwy|er,
and Mar|o P. |. Oa|us
!"#"$%&' February 2013 193:327-345
!"#*J%& :/"=%&$%*# %# 0#%J,;) ,#= :;,#$)W D%J8;,$%*# *+ (,$,G Z,;%=,$%*#G
>"?*/$%#9G ,#= B"#&1J,/N%#9
Hans D. Daetwy|er, Mar|o P. |. Oa|us, R|cardo Pong-Wong, Gustavo de |os Oampos,
and John M. H|ckey
!"#"$%&' February 2013 193:347-365
5*#9 O*#&*=%#9 >O0)W :,)$G :/")"#$G ,#= H8$8/"
Johnny T. Y. Kung, Dav|d Oo|ognor|, and Jeann|e T. |ee
!"#"$%&' March 2013 193:651-669
-"%*$%& ,#= -%$*$%& >"&*J7%#,$%*# %# -"%*)%)
Kathryn P. Koh| and Jeff Seke|sky
!"#"$%&' June 2013 194:327-334
A="#$%$2 72 (")&"#$W Z,/%,$%*# %# -"%*)%)G 0&/*)) !"#*J")G ,#= %# :*?8;,$%*#)
E||zabeth A. Thompson
!"#"$%&' June 2013 194:301-326
4* !/*C */ O*$ $* !/*CW O8$/%$%*#,; 6*#$/*; *+ ("@";*?J"#$ (8/%#9
6,"#*/1,7=%$%) ";"9,#) 5Y 0//")$
|. Ryan Baugh
!"#"$%&' Ju|y 2013 194:539-555
41" -*;"&8;,/ !"#"$%&) *+ A#)"&$%&%=" >")%)$,#&"
R|chard H. ffrench-Oonstant
!"#"$%&' August 2013 194:807-815
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