The New Genetics

TheNewGenetics
U.S.DEPARTMENTOF HEALTHANDHUMANSERVICES NationalInstitutesofHealth NationalInstituteofGeneralMedicalSciences
WHAT IS NIGM S? TheNationalInstituteofGeneralMedical
Sciences(NIGMS)supportsbasicresearchongenes,proteinsand cells.Italsofundsstudiesonfundamentalprocessessuchashow cellscommunicate,howourbodiesuseenergyandhowwe respondtomedicines.Theresultsofthisresearchincreaseour understandingoflifeandlaythefoundationforadvancesinthe diagnosis,treatmentandpreventionofdisease.TheInstitutes researchtrainingprogramsproducethenextgenerationof scientists,andNIGMShasprogramstoincreasethediversityofthe biomedicalandbehavioralresearchworkforce.NIGMSsupported theresearchofmostofthescientistsmentionedinthisbooklet.
ProducedbytheOfceofCommunicationsandPublicLiaison NationalInstituteofGeneralMedicalSciences NationalInstitutesofHealth U.S.DepartmentofHealthandHumanServices
TheNewGenetics
NIHPublicationNo.10 662 RevisedApril2010 http://www.nigms.nih.gov
Contents
F O RE W O RD C H A P TE R 1: H O W G E N E S W O RK 2
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BeautifulDNA Copycat LetsCallItEven GettingtheMessage NaturesCutandPasteJob AllTogetherNow
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GeneticsandYou:NurseryGenetics
FoundinTranslation RNASurprises AnInterestingDevelopment
TheToolsofGenetics:MightyMicroarrays
C H A P TE R 2: RN A A N D D N A RE VE A LE D : N E W RO LE S , N E W RU LE S
RNAWorld MolecularEditor HealthyInterference DynamicDNA SecretCode
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GeneticsandYou:TheGeneticsofAnticipation
BattleoftheSexes StartingattheEnd TheOtherHumanGenome
TheToolsofGenetics:RecombinantDNAandCloning
C H A P TE R 3: LI F E S G E N E TI C TRE E
EverythingEvolves SelectiveStudy CluesfromVariation
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LivingLaboratories
TheGenomeZoo GenesMeetEnvironment
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GeneticsandYou:YouveGotRhythm!
AnimalsHelpingPeople MyCollaboratorIsaComputer
TheToolsofGenetics:UnlimitedDNA
C H A P TE R 4: G E N E S A RE U S
IndividualizedPrescriptions TheHealingPowerofDNA CauseandEffect Usvs. Them
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GeneticsandYou:EatLess,LiveLonger?
GangWarfare
TheToolsofGenetics:MathematicsandMedicine
C H A P TE R 5: 2 1 S T C E N TU RY G E N E TI C S
NoLab?NoProblem! HardQuestions GoodAdvice
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GeneticsandYou:CrimeFightingDNA
Genetics,Business,andtheLaw CareersinGenetics
TheToolsofGenetics:InformaticsandDatabases
G LO S SA RY
Foreword
ConsiderjustthreeofEarthsinhabitants: a brightyellowdaffodilthatgreetsthe spring,thesinglecelledcreaturecalled Thermococcus thatlivesinboilinghot springs,andyou.Evenasciencection writerinventingastorysetonadistant planetcouldhardlyimaginethreemoredif ferentformsoflife.Yetyou,Thermococcus andthedaffodilarerelated!Indeed,allof the Earthsbillionsoflivingthingsarekin to eachother.
Andeverylivingthing doesonethingthesame way:To makemoreof itself, it first copies its molecularinstruction manualitsgenesandthenpassesthisinfor mationontoitsoffspring.Thiscyclehasbeen repeatedforthreeandahalf billionyears. Buthowdidweandourverydistantrela tivescometolooksodifferentanddevelopso many different ways of getting along in the world?Acenturyago,researchersbegantoanswer thatquestionwiththehelpofasciencecalled genetics.Getarefreshercourseonthebasicsin Chapter1,HowGenesWork. Itslikelythatwhenyouthinkofheredity youthinkrstofDNA,butinthepastfewyears, researchershavemadesurprisingndingsabout
TheNewGenetics I Foreword 3
anothermolecularactorthatplaysastarringrole. CheckoutthemodernviewofRNAinChapter2, RNAandDNARevealed:NewRoles,NewRules. Whengeneticsrststarted,scientistsdidnt havethetoolstheyhavetoday.Theycouldonly lookatonegene,orafewgenes,atatime.Now, researcherscanexamineallofthegenesinaliv ingorganismitsgenomeatonce.Theyare doingthisfororganismsoneverybranchofthe treeoflifeandndingthatthegenomesofmice, frogs,shandaslewofothercreatureshave manygenessimilartoourown. Sowhydoesntyourbrotherlooklikeyour dogortheshinyouraquarium?Itsbecauseof evolution.InChapter3,LifesGeneticTree, ndouthowevolutionworksandhowitrelates togeneticsandmedicalresearch.
CanDNAandRNAhelpdoctorspredict whetherwellgetdiseaseslikecancer,diabetesor asthma?Whatothermysteriesarelockedwithin the6feetof DNAinsidenearlyeverycellinour bodies?Chapter4,GenesAreUs, explainswhat researchersknow,andwhattheyarestilllearning, abouttheroleofgenesinhealthanddisease. Finally,inChapter5,21stCentury Genetics,seeapreviewofthingstocome.Learn howmedicineandsciencearechanginginbig ways,andhowthesechangesinuencesociety. Frommetabolismtomedicinestoagriculture, thescienceofgeneticsaffectsuseveryday.Itis partoflifepartofyour life!
CHAPTER1
HowGenesWork

eoplehaveknownformanyyearsthat
Proteinsdomanyotherthings,too.They providethebodysmainbuildingmaterials, formingthecellsarchitectureandstructural components.Butonethingproteinscantdois makecopiesof themselves.Whenacellneeds moreproteins,itusesthemanufacturinginstruc tionscodedinDNA. TheDNAcodeof agenethe sequenceof its individualDNAbuildingblocks,labeledA (adenine),T(thymine),C(cytosine)andG (guanine)andcollectivelycallednucleotides spellsouttheexactorderof aproteinsbuilding blocks,aminoacids. Occasionally,thereisakindof typographical errorinagenesDNAsequence.Thismistake whichcanbeachange,gaporduplicationis calledamutation.
livingthingsinherittraitsfromtheirparents.
Thatcommonsenseobservationledtoagricul ture,thepurposefulbreedingandcultivationof animalsandplantsfordesirablecharacteristics. Firmingupthedetailstookquitesometime, though.Researchersdidnotunderstandexactly howtraitswerepassedtothenextgeneration untilthemiddleof the20thcentury. Nowitisclearthatgenes arewhatcarryour traitsthroughgenerationsandthatgenesare madeof deoxyribonucleicacid(DNA).But genesthemselvesdontdotheactualwork. Rather,theyserveasinstructionbooksformak ingfunctionalmoleculessuchasribonucleic acid(RNA) andproteins,whichperformthe chemicalreactionsin ourbodies.
GeneticsintheGarden
In1900,threeEuropeanscientistsinde pendentlydiscoveredanobscureresearch paperthathadbeenpublishednearly35 yearsbefore.WrittenbyGregorMendel, anAustrianmonkwhowasalsoascien tist,thereportdescribedaseriesof breedingexperimentsperformedwithpea plantsgrowinginhisabbeygarden. Mendelhadstudiedhowpeaplants inheritedthetwovariantformsofeasytosee traits.Theseincludedowercolor(whiteorpurple) andthetextureofthepeas(smoothorwrinkled). Mendelcountedmanygenerationsofpeaplant
ThemonkGregor
Mendelrstdescribed howtraits areinherited fromonegenerationto thenext.
offspringandlearnedthatthesecharacteristics werepassedontothenextgenerationinorderly, predictableratios. Whenhecrossbredpurpleoweredpeaplants withwhiteoweredones,thenextgenerationhad onlypurpleowers.Butdirectionsformakingwhite owerswerehiddensomewhereinthepeasofthat generation,becausewhenthosepurpleowered
TheNewGenetics I HowGenesWork 5
Amutationcancauseagenetoencodea proteinthatworksincorrectlyorthatdoesnt workatall.Sometimes,theerrormeansthatno proteinismade. ButnotallDNAchangesareharmful.Some mutationshavenoeffect,andothersproduce newversionsofproteinsthatmaygiveasurvival advantagetotheorganismsthathavethem.Over time,mutationssupplytherawmaterialfrom whichnewlifeformsevolve(seeChapter3, LifesGeneticTree).
BeautifulDNA
Upuntilthe1950s,scientistsknewagooddeal aboutheredity,buttheydidnthaveacluewhat DNAlookedlike.Inordertolearnmoreabout DNAanditsstructure,somescientistsexperi mentedwithusingXraysasaformofmolecular photography. RosalindFranklin,aphysicalchemistwork ingwithMauriceWilkinsatKingsCollegein London,wasamongthersttousethismethod toanalyzegeneticmaterial.Herexperiments
plantswerebredtoeachother,someoftheiroff springhadwhiteowers.Whatsmore,the secondgenerationplantsdisplayedthecolorsina predictablepattern.Onaverage,75percentofthe secondgenerationplantshadpurpleowersand 25percentoftheplantshadwhiteowers.Those sameratiospersisted,andwerereproducedwhen theexperimentwasrepeatedmanytimesover. Tryingtosolvethemysteryofthemissingcolor blooms,Mendelimaginedthatthereproductive cellsofhispeaplantsmightcontaindiscrete factors,eachofwhichspeciedaparticulartrait, suchaswhiteowers.Mendelreasonedthatthe
factors,whatevertheywere,mustbephysical materialbecausetheypassedfromparentto offspringinamathematicallyorderlyway.Itwasnt untilmanyyearslater,whentheotherscientists unearthedMendelsreport,thatthefactorswere namedgenes. Earlygeneticistsquicklydiscoveredthat Mendelsmathematicalrulesofinheritanceapplied notjusttopeas,butalsotoallplants,animalsand people.Thediscoveryofaquantitativerulefor inheritancewasmomentous.Itrevealedthata common,generalprinciplegovernedthegrowth anddevelopmentofalllifeonEarth.
National Institute of General Medical Sciences
producedwhatwerereferredtoatthetimeas the mostbeautifulXrayphotographsofany substanceevertaken. Otherscientists,includingzoologistJames WatsonandphysicistFrancisCrick,bothwork ingatCambridgeUniversityintheUnited Kingdom,weretryingtodeterminetheshape of DNAtoo.Ultimately,thislineofresearch revealedoneofthemostprofoundscientic discoveriesofthe20thcentury:thatDNAexists asa doublehelix. The1962NobelPrizeinphysiologyormedi cinewasawardedtoWatson,CrickandWilkins forthiswork.AlthoughFranklindidnotearna shareoftheprizeduetoheruntimelydeathatage 38,sheiswidelyrecognizedashavingplayeda signicantroleinthediscovery. Thespiralstaircaseshapeddouble helixhasattainedglobalstatusas thesymbolforDNA.Butwhat is sobeautifulaboutthe discoveryof thetwisting ladderstructureisntjust itsgoodlooks.Rather,the structureof DNAtaught researchersa fundamental lessonaboutgenetics.Ittaught themthatthetwoconnected strandswindingtogetherlikeparallel
. RosalindFranklins
originalXraydiffraction photorevealedthephysical structureofDNA.
OREGON STATE UNIVERSITY LIBRARIES SPECIAL COLLECTIONS COLD SPRING HARBOR LABORATORY ARCHIVES
. In1953,WatsonandCrickcreatedtheirhistoric
modeloftheshapeofDNA:thedoublehelix.
handrailswerecomplementarytoeachother, andthisunlockedthesecretof howgenetic informationisstored,transferredandcopied. Ingenetics,complementarymeansthatif youknowthesequenceofnucleotidebuilding blocksononestrand,youknowthesequenceof nucleotidebuildingblocksontheotherstrand: AalwaysmatchesupwithTandCalwayslinks toG(seedrawing,page7). Longstringsofnucleotidesformgenes, andgroupsofgenesarepackagedtightlyinto structurescalledchromosomes.Everycellinyour bodyexceptforeggs,spermandredbloodcells containsafullsetofchromosomesinitsnucleus. Ifthechromosomesinoneofyourcellswere uncoiledandplacedendtoend,theDNAwould beabout6feetlong.IfalltheDNAinyourbody wereconnectedinthisway,itwouldstretch approximately67billionmiles!Thatsnearly 150,000roundtripstotheMoon.
DNAStructure
Thelong,stringyDNAthatmakesupgenesis
spooledwithinchromosomesinsidethenucleus ofacell.(Notethatagenewouldactuallybeamuch longerstretchofDNAthanwhatisshownhere.)
Chromosome Nucleus
GC Cell A DNA G C C T G
Bases
Guanine A
GC T C G T A
Cytosine
Thymine
Adenine
Gene Sugar phosphate backbone A G C T
A C G
DNAconsistsoftwolong,twistedchainsmadeup ofnucleotides.Eachnucleotidecontainsonebase, onephosphatemoleculeandthesugarmolecule deoxyribose.ThebasesinDNAnucleotidesare adenine,thymine,cytosineandguanine.
P Nucleotide S C
Copycat
Itsastoundingtothinkthat yourbodyconsistsoftrillions ofcells.Butwhatsmost amazingisthatit allstarts withonecell.Howdoesthis massiveexpansiontakeplace? Asanembryoprogresses throughdevelopment,itscells mustreproduce.Butbefore a celldividesintotwonew, nearlyidenticalcells,itmust copyitsDNAsotherewillbea completesetof genestopassontoeachofthenewcells. Tomakeacopyofitself,thetwisted,com pacteddoublehelixofDNAhastounwindand separateitstwostrands.Eachstrandbecomes a pattern,ortemplate,formakinganewstrand, sothetwonewDNAmoleculeshaveonenew strandandoneoldstrand. Thecopyiscourtesyofacellularprotein machinecalledDNApolymerase,whichreads thetemplateDNAstrandandstitchestogether thecomplementarynewstrand.Theprocess, calledreplication,isastonishinglyfastand accurate,althoughoccasionalmistakes,suchas deletionsor duplications,occur.Fortunately,a cellular spellcheckercatchesandcorrectsnearly alloftheseerrors. Mistakesthatarenotcorrectedcanleadto diseasessuchascancerandcertaingeneticdisor ders.SomeoftheseincludeFanconianemia,early agingdiseasesandotherconditionsinwhich peopleareextremelysensitivetosunlightand somechemicals. DNAcopyingisnottheonlytimewhenDNA damagecanhappen.Prolonged,unprotectedsun exposurecancauseDNAchangesthatleadto skincancer,andtoxinsincigarettesmokecan causelungcancer.
. WhenDNApolymerasemakesanerrorwhilecopyingagenes
DNAsequence,themistakeiscalledamutation.Inthisexample, thenucleotideGhasbeenchangedtoanA.
CYTOGENETICSLABORATORY,BRIGHAMANDWOMENSHOSPITAL
. Humanshave23pairsofchromosomes.MaleDNA(picturedhere)
containsanXandaYchromosome,whereasfemaleDNAcontains twoXchromosomes.
CG AT CG
Itmayseemironic,then,thatmanydrugs usedtotreatcancerworkbyattackingDNA.Thats becausethesechemotherapydrugsdisruptthe DNAcopyingprocess,whichgoesonmuchfaster in rapidly dividing cancer cells than in other cellsofthebody.Thetroubleisthatmostofthese drugs do affect normal cells that grow and dividefrequently,suchascellsoftheimmune systemand haircells.
AT T A
CG TA GC TA TA
C T
A
UnderstandingDNAreplication bettercould beakeytolimitingadrugsactionto cancer cellsonly.

A G C G
T
C G
A
GC Newstrand
T T
LetsCallItEven
AftercopyingitsDNA,acellsnextchallengeis gettingjusttherightamountofgeneticmaterial intoeachofitstwooffspring. Mostofyourcellsarecalleddiploid (dimeanstwo,andploidreferstosetsof chromosomes)becausetheyhavetwosetsof chromosomes(23pairs).Eggsandspermare different;theseareknownashaploid cells.Each haploidcellhasonlyonesetof23chromosomes sothatatfertilizationthemathwillworkout: A haploideggcellwillcombinewithahaploid spermcelltoformadiploidcellwiththeright
AT AT GC CG AT GC AT GC AT
GC A T GC AT
AT GC CG AT
numberofchromosomes:46. Chromosomesarenumbered1to22, accordingtosize,with1beingthelargest chromosome.The23rdpair,knownasthesex chromosomes,arecalledXandY.Inhumans, abnormalitiesofchromosomenumberusually occurduringmeiosis,thetimewhenacell
AT
. DuringDNAreplication,eachstrandofthe
originalmoleculeactsasatemplatefor thesynthesisofanew,complementary DNAstrand.
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Meiosis
Chromosomes fromparents
Cellnucleus
Duringmeiosis,chromosomes
frombothparentsarecopied andpairedtoexchangeportions ofDNA.
Chromosomes replicate
Matching chromosomes pairup
Thiscreatesamixofnewgenetic
materialintheoffspringscells.
Chromosomesswap sectionsofDNA
Nucleusdividesinto daughternuclei
Chromosomepairsdivide
Daughternuclei divideagain
Chromosomesdivide; daughternucleihave singlechromosomes andanewmixof geneticmaterial
reducesitschromosomesfromdiploidtohaploid in creatingeggsorsperm. Whathappensifaneggoraspermcellgets the wrongnumberofchromosomes,andhow oftendoesthishappen? MolecularbiologistAngelikaAmonof the MassachusettsInstituteof Technologyin CambridgesaysthatmistakesindividingDNA betweendaughtercellsduringmeiosisarethe leadingcauseof humanbirthdefectsandmis carriages.Currentestimatesarethat10percent of allembryoshaveanincorrectchromosome number.Mostof thesedontgotofulltermand aremiscarried. Inwomen,thelikelihoodthatchromosomes wontbeapportionedproperlyincreaseswithage. Oneofevery18babiesborntowomenover45 hasthreecopiesofchromosome13,18or21 insteadofthenormaltwo,andthisimproper balancingcancausetrouble.Forexample,three copiesofchromosome21leadtoDown syndrome. Tomakeherworkeasier,Amonlikemany otherbasicscientistsstudiesyeastcells,which separatetheirchromosomesalmostexactlythe samewayhumancellsdo,exceptthatyeastdoit muchfaster.AyeastcellcopiesitsDNAand producesdaughtercellsinabout11/2 hours, comparedtoawholedayforhumancells. Theyeastcellssheusesarethesamekind bakeriesusetomakebreadandbreweriesuse to makebeer!
Amonhasmademajorprogressinunder standingthedetailsofmeiosis.Herresearchshows how,inhealthycells,gluelikeproteincomplexes calledcohesinsreleasepairsofchromosomesat exactlytherighttime.Thisallowsthechromo somestoseparateproperly. Thesendingshaveimportantimplications forunderstandingandtreatinginfertility,birth defectsandcancer.
GettingtheMessage
So,wevedescribedDNAitsbasicproperties and howourbodiesmakemoreofit.Buthow doesDNAserveasthelanguageoflife?Howdo yougetaproteinfromagene?
. Trisomy,thehallmarkofDownsyndrome,results
whenababyisbornwiththreecopiesofchromo some21insteadoftheusualtwo.
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Therearetwomajorstepsinmakinga protein.Therstistranscription,wherethe informationcodedinDNAiscopiedintoRNA. TheRNAnucleotidesarecomplementaryto thoseontheDNA:aContheRNAstrand matchesaGontheDNAstrand. TheonlydifferenceisthatRNApairsa nucleotidecalleduracil(U),insteadofaT,with an AontheDNA. AproteinmachinecalledRNApolymerase readstheDNAandmakestheRNAcopy.This copyiscalledmessengerRNA,ormRNA,because itdeliversthegenesmessagetotheprotein producingmachinery. Atthispointyoumaybewonderingwhyall of thecellsinthehumanbodyarentexactly alike,sincetheyallcontainthesameDNA.What makesalivercelldifferentfromabraincell?How dothecellsintheheartmaketheorgancontract, butthoseinskinallowustosweat? Cellscanlookandactdifferently,anddo entirelydifferentjobs,becauseeachcellturns on,orexpresses,onlythegenesappropriatefor whatitneedstodo. ThatsbecauseRNApolymerasedoesnot workalone,butratherfunctionswiththeaidof manyhelperproteins.Whilethecorepartof RNApolymeraseisthesameinallcells,the helpersvaryindifferentcelltypesthroughout the body.
Youdthinkthatforaprocesssoessentialto life,researcherswouldknowalotabouthow transcriptionworks.Whileitstruethatthe basicsareclearbiologistshavebeenstudying genetranscribingbyRNApolymerasessince these proteinswererstdiscoveredin1960 someof thedetailsareactuallystillmurky.
1
A C A T A T G T
DNA
. RNApolymerasetranscribesDNAto
makemessengerRNA(mRNA).
Thebiggestobstacletolearningmore has beenalackoftools.Untilfairlyrecently, researcherswereunabletogetapictureatthe atomiclevelof thegiantRNApolymerasepro teinassembliesinsidecellstounderstandhow themanypiecesofthisamazing,livingmachine dowhattheydo,anddoitsowell.
Butourunderstandingisimprovingfast, thankstospectaculartechnologicaladvances. We havenewXraypicturesthatarefarmore sophisticatedthanthosethatrevealedthestructure ofDNA.RogerKornbergofStanfordUniversityin Californiausedsuchmethodstodeterminethe structureofRNApolymerase.Thisworkearned
Threonine
Arginine
Aminoacids DNAstrand RNAstrand Tyrosine Threonine
. Aminoacidslinkupto
makeaprotein.
A AT C CG AAT TUA G G C C C G T U A AA T T UA G C G C GC AT A
tRNA Ribosome
AC GU A U CGU A C A Codon1 Codon2 Codon3 Codon4
mRNA
. ThemRNAsequence(darkredstrand)iscom
plementarytotheDNAsequence(bluestrand).
. Onribosomes,transferRNA(tRNA)helps
convertmRNAintoprotein.
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himthe2006Nobel Prizeinchemistry.In addition,verypowerful microscopesandother toolsthatallowusto watch one molecule at a time provide a newlookatRNApoly merasewhileitsatwork readingDNAandpro ducingRNA. Forexample,Steven Block,alsoofStanford, hasusedaphysicstech niquecalledoptical trappingtotrackRNA
. RNApolymerase(green)andoneendofaDNA
strand(blue)areattachedtoclearbeadspinned downintwoopticaltraps.AsRNApolymerase movesalongtheDNA,itcreatesanRNAcopyof a gene,shownhereasapinkstrand.
STEVENBLOCK
NaturesCutandPasteJob
SeveraltypesofRNAplaykeyrolesinmaking a protein.Thegenetranscript(themRNA) transfersinformationfromDNAinthenucleusto theribosomes thatmakeprotein.RibosomalRNA formsabout60percentoftheribosomes.Lastly, transferRNAcarriesaminoacidstothe ribo somes.Asyoucansee,allthreetypesofcellular RNAscometogethertoproducenewproteins. Butthejourneyfromgenetoproteinisnt quiteassimpleaswevejustmadeitouttobe. Aftertranscription,severalthingsneedtohap pentomRNAbeforeaproteincanbemade.For example,thegeneticmaterialofhumansand othereukaryotes (organismsthathavea nucleus)includesalotofDNAthatdoesnt encodeproteins.SomeofthisDNAisstuckright inthemiddleofgenes. TodistinguishthetwotypesofDNA,scien tistscallthecodingsequencesofgenesexons and thepiecesinbetweenintrons (forintervening sequences). IfRNApolymeraseweretotranscribeDNA fromthestartofanintroncontaininggeneto theend,theRNAwouldbecomplementaryto theintronsaswellastheexons. TogetanmRNAmoleculethatyieldsawork ingprotein,thecellneedstotrimouttheintron sectionsandthenstitchonlytheexonpieces together(seedrawing,page15).Thisprocessis called RNAsplicing.
polymeraseasitinches alongDNA.Blockand histeamperformed thisworkby designing aspecializedmicroscope
sensitiveenoughtowatchtherealtimemotionof asingle polymerase traveling down a gene on one chromosome. Theresearchersdiscoveredthatmoleculesof RNApolymerasebehavelikebatterypowered spidersastheycrawlalongtheDNAladder, addingnucleotidesoneatatimetothegrowing RNAstrand.Theenzyme worksmuchlikea motor,Blockbelieves,poweredbyenergyreleased duringthechemicalsynthesisofRNA.
RNASplicing
Gene
DNA
Exon1
Intron1
Exon2
Genesareofteninterrupted
Intron2 Exon3 bystretchesofDNA (introns,blue)thatdonot containinstructionsfor makingaprotein.TheDNA segmentsthatdocontain protein akinginstructions m areknownasexons(green).
Transcription (RNAsynthesis)
NuclearRNA
Exon1
Intron1
Exon2
Intron2
Exon3
RNAsplicing
MessengerRNA
Exon1
Exon2
Exon3 Translation (proteinsynthesis)
Protein
Gene
DNA
Exon1
Exon2
Exon3
Exon4
Arrangingexonsindifferent
patterns,calledalternative splicing,enablescellsto makedifferentproteins fromasinglegene.
Exon1
Exon2
Exon3
Exon4
Alternativesplicing
Exon1
Exon2
Exon3
Exon1
Exon2
Exon4
Translation ProteinA ProteinB
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Splicinghastobeextremelyaccurate.An errorinthesplicingprocess,evenonethatresults inthedeletionofjustonenucleotideinanexon ortheadditionofjustonenucleotideinan intron,willthrowthewholesequenceoutof alignment.Theresultisusuallyanabnormal proteinornoproteinatall.Oneformof Alzheimersdisease,forexample,iscausedby this kindofsplicingerror. MolecularbiologistChristineGuthrieofthe UniversityofCalifornia,SanFrancisco,wants to understandmorefullythemechanismfor removingintronRNAandndouthowitstays soaccurate. Sheusesyeastcellsfortheseexperiments. Just likehumanDNA,yeastDNAhasintrons, but theyarefewerandsimplerinstructureand arethereforeeasiertostudy.Guthriecanidentify whichgenesarerequiredforsplicingbynding abnormalyeastcellsthatmanglesplicing. Sowhydointronsexist,iftheyrejustgoingto bechoppedout?Withoutintrons,cellswouldnt needtogothroughthesplicingprocessandkeep monitoringittobesureitsworkingright. Asitturnsout,splicingalsomakesitpossible forcellstocreatemoreproteins. Thinkaboutalltheexonsinagene.Ifacell stitchestogetherexons1,2and4,leavingout exon3,themRNAwillspecifytheproduction of aparticularprotein.Butinstead,ifthecell stitchestogetherexons1,2and3,thistimeleav ingoutexon4,thenthemRNAwillbetranslated intoadifferentprotein(seedrawing,page15).
Bycuttingandpastingtheexonsindifferent patterns,whichscientistscallalternativesplicing, acellcancreatedifferentproteinsfromasingle gene.Alternative splicing is one of the reasons why human cells, which have about 20,000 genes, can make hundreds of thousands of different proteins.
AllTogetherNow
Untilrecently,researcherslookedatgenes,and theproteinstheyencode,oneatatime.Now,they canlookathowlargenumbersofgenesandpro teinsact,aswellashowtheyinteract.Thisgives themamuchbetterpictureofwhatgoesonina livingorganism. Already,scientistscanidentifyallofthegenes thataretranscribedinacellorinanorgan,like theheart.Andalthoughresearcherscanttellyou, rightnow,whatsgoingonineverycellofyour bodywhileyoureadabookorwalkdownthe street,theycandothissortofwholebodyscan forsimpler,singlecelledorganismslikeyeast. Usingatechniquecalledgenomewide locationanalysis,RichardYoungofthe MassachusettsInstituteofTechnologyunraveled aregulatorycodeoflivingyeastcells,which havemorethan6,000genesintheirgenome. Youngstechniqueenabledhimtodetermine the exactplaceswhereRNApolymeraseshelper proteinssitonDNAandtellRNApolymerase to begintranscribingagene. Sincehedidtheexperimentwiththeyeast exposedtoavarietyofdifferentconditions,
GENETICS AND YOU:
NurseryGenetics
Newbornscreeningisgovernedby individualstates.Thismeansthatthe stateinwhichababy isborndeterminesthe geneticconditionsfor which heorshewillbe screened.Currently, statestestforbetween 28and54conditions.Allstatestest for PKU. Althoughexpandedscreeningfor geneticdiseasesinnewbornsisadvo catedbysome,othersquestionthe valueofscreeningforconditionsthat arecurrentlyuntreatable.Another issueisthatsomechildrenwithmild versionsofcertaingeneticdiseases may betreatedneedlessly. In2006,theAdvisoryCommittee on HeritableDisordersinNewborns and Children,whichassiststheSecretary of theU.S.DepartmentofHealthand HumanServices,recommendeda standard,nationalsetofnewborn tests for29conditions,rangingfrom relativelycommonhearingproblems to veryrare metabolicdiseases.
hilemostgeneticresearch useslaborganisms,test tubesandpetridishes,
the resultshaverealconsequencesfor people.Yourfirstencounterwith geneticanalysisprobablyhappened shortlyafteryouwereborn,whena doctorornursetookadropofblood fromtheheelofyourtinyfoot. Labtestsperformedwiththatsingle dropofbloodcandiagnosecertainrare geneticdisordersaswellasmetabolic
problemslikephenylketonuria(PKU). Screeningnewbornsinthisway beganinthe1960sinMassachusetts withtestingforPKU,adiseaseaffecting 1in14,000people.PKUiscausedbyan enzymethatdoesntworkproperlydue toageneticmuta tion.Thoseborn withthisdisorder cannotmetabolize theaminoacid phenylalanine, whichispresent in manyfoods.Leftuntreated,PKUcan leadtomentalretardationandneurolog icaldamage,butaspecialdietcan preventthese utcomes.Testingforthis o conditionhasmadeahugedifferencein manylives.
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Youngwasabletogureouthowtranscription patternsdifferwhentheyeastcellisunderstress (say,inadryenvironment)orthrivinginasugary richnutrientsolution.Doneonegeneatatime, usingmethodsconsideredstateoftheartjusta fewyearsago,thiskindofanalysiswouldhave takenhundredsofyears. Afterdemonstratingthathistechnique workedinyeast,Youngthentookhisresearch a stepforward.Heusedavariationoftheyeast
methodtoscantheentirehumangenomein smallsamplesofcellstakenfromthepancreases andliversofpeoplewithtype2diabetes.He used theresultstoidentifygenesthatarenttran scribedcorrectlyinpeoplewiththedisease. Thisinformationprovidesresearcherswith an importanttoolforunderstandinghowdia betesandotherdiseasesareinuencedby defectivegenes.Bybuildingmodelstopredict howgenesrespondindiversesituations, researchersmaybeabletolearnhowtostopor jumpstartgenesondemand,changethecourse ofadiseaseorpreventitfromeverhappening.
FoundinTranslation
AfteragenehasbeenreadbyRNApolymerase andtheRNAisspliced,whathappensnextin thejourneyfromgenetoprotein?Thenextstep isreadingtheRNAinformationandttingthe buildingblocksofaproteintogether.Thisis calledtranslation,anditsprincipalactorsare theribosomeandaminoacids. Ribosomesareamongthebiggestandmost intricatestructuresinthecell.Theribosomesof bacteriacontainnotonlyhugeamountsofRNA, butalsomorethan50differentproteins.Human ribosomeshaveevenmoreRNAandbetween70 and80differentproteins! HarryNolleroftheUniversityofCalifornia,
.Aribosomeconsistsoflargeandsmall
proteinsubunitswithtransferRNAs nestledinthemiddle.
RIBOSOMESTRUCTURECOURTESYOFJAMIECATE,MARATYUSUPOV, GULNARAYUSUPOVA,THOMASEARNESTANDHARRYNOLLER.GRAPHIC COURTESYOFALBIONBAUCOM,UNIVERSITYOFCALIFORNIA,SANTACRUZ.
SantaCruz,hasfoundthataribosomeperforms severalkeyjobswhenittranslatesthegenetic codeofmRNA.AsthemessengerRNAthreads throughtheribosomeproteinmachine,the
ribosomereadsthemRNAsequenceandhelps recognizeandrecruitthecorrectaminoacid carryingtransferRNAtomatchthemRNAcode. Theribosomealsolinkseachadditionalamino acidintoagrowingproteinchain(seedrawing, page13). Formanyyears,researchersbelievedthateven thoughRNAsformedapartoftheribosome,the proteinportionoftheribosomedidallofthe work.Nollerthought,instead,thatmaybeRNA, notproteins,performedtheribosomesjob.His ideawasnotpopularatrst,becauseatthattime itwasthoughtthatRNAcouldnotperformsuch complexfunctions. Sometimelater,however,theconsensus changed.SidneyAltmanofYaleUniversityin New Haven,Connecticut,andThomasCech, who wasthenattheUniversityofColoradoin Boulder,eachdiscoveredthatRNAcanperform workascomplexasthatdonebyproteinenzymes. TheirRNAasanenzymediscoveryturnedthe researchworldonitsheadandearnedCechand Altmanthe1989NobelPrizeinchemistry. Nollerandotherresearchershavecontinued thepainstakingworkofunderstandingribo somes.In1999,heshowedhowdifferentparts of a bacterial ribosome interact with one anotherandhowtheribosomeinteractswith moleculesinvolvedinproteinsynthesis. Thesestudies providednearproof thatthe fundamental mechanismof translationis performed by RNA, not by the proteins of theribosome.
.Somerstaidointmentscontaintheantibioticneomycin,
whichtreatsinfectionsbyattackingribosomesinbacteria.
RNASurprises
ButwhichribosomalRNAsaredoingthework? MostscientistsassumedthatRNAnucleotides burieddeepwithintheribosomecomplexthe onesthathavethesamesequenceineveryspecies frombacteriatopeopleweretheimportant onesforpiecingthegrowingproteintogether. However,recentresearchbyRachelGreen, who worked with Noller before moving toJohns Hopkins University in Baltimore, Maryland,showedthatthisisnotthecase. Green discoveredthatthoseRNAnucleotides arenotneededforassemblingaprotein.Instead, shefound,thenucleotidesdosomethingelse entirely:Theyhelpthegrowingproteinslipoff theribosomeonceitsnished. Noller,Greenandhundredsofotherscientists workwiththeribosomesofbacteria.Whyshould youcareabouthowbacteriacreate proteinsfrom theirgenes?
20
Onereasonisthatthisknowledgeisimpor tantforlearninghowtodisrupttheactionsof diseasecausingmicroorganisms.Forexample, antibioticslikeerythromycinandneomycinwork byattackingtheribosomesofbacteria,whichare differentenoughfromhumanribosomesthatour cellsarenotaffectedbythesedrugs. Asresearchersgainnewinformationabout bacterialtranslation,theknowledgemayleadto moreantibioticsforpeople. Newantibioticsareurgentlyneededbecause manybacteriahavedevelopedresistancetothe currentarsenal.Thisresistanceissometimesthe resultofchangesinthebacteriasribosomalRNA. Itcanbedifculttondthosesmall,butcritical, changesthatmayleadtoresistance,soitis importanttondcompletelynewwaystoblock bacterialtranslation. Greenisworkingonthatproblemtoo.Her strategyistomakerandommutationstothe genesinabacteriumthataffectitsribosomes. But whatifthemutationdisablestheribosome so muchthatitcantmakeproteins?Thenthe bacteriumwontgrow,andGreenwouldntndit. Usingclevermoleculartricks,Greengured outawaytorescuesomeofthebacteriawith defectiveribosomessotheycouldgrow.While someoftherescuedbacteriahavechangesin theirribosomalRNAthatmakethemresistant to certainantibiotics(andthuswouldnotmake goodantibiotictargets)otherRNAchangesthat dontaffectresistancemaypointtopromising ideasfornewantibiotics.
AnInterestingDevelopment
Inthehumanbody,oneofthemostimportant jobsforproteinsistocontrolhowembryos develop.Scientistsdiscoveredahugelyimportant setofproteinsinvolvedindevelopmentbystudy ingmutationsthatcausebizarremalformations infruities. Themostfamoussuchabnormalityisafruit ywithaleg,ratherthantheusualantenna, growingoutofitshead(seepage21).According toThomasC.KaufmanofIndianaUniversity inBloomington,thelegisperfectlynormalits justgrowinginthewrongplace. Inthistypeofmutationandmanyothers, somethinggoeswrongwiththegeneticprogram thatdirectssomeofthecellsinanembryoto followdevelopmentalpathways,whichare a seriesofchemicalreactionsthatoccurina specicorder.Intheantennaintolegproblem, it is asifthecellsgrowingfromtheyshead, whichnormallywouldbecomeanantenna, mistakenlybelievethattheyareintheys thorax,andthereforeoughttogrowintoaleg. Andsotheydo. Thinkingaboutthisoddsituationtaught scientistsanimportantlessonthattheproteins madebysomegenescanactasswitches.Switch genesaremastercontrollersthatprovideeach bodypartwithakindofidenticationcard.Ifa proteinthatnormallyinstructscellstobecome an antennaisdisrupted,cellscanreceivenew instructionstobecomealeginstead.
FLYBASE; R. TURNER
. Normalfruityhead.
. FruityheadshowingtheeffectsoftheAntennapedia
gene.Thisyhaslegswhereitsantennaeshouldbe.
Scientistsdeterminedthatseveraldifferent genes,eachwithacommonsequence,provide theseanatomicalidenticationcardinstructions. Kaufmanisolatedanddescribedoneofthese genes,whichbecameknownasAntennapedia, a wordthatmeansantennafeet. Kaufmanthenbeganlookingalotmore closelyatthemolecularstructureofthe
genesof differentorganisms,itsagoodclue thatthesegenesdosomethingsoimportantand usefulthatevolutionusesthesamesequence overandoverandpermitsveryfewchangesin itsstructureasnewspeciesevolve. Researchersquicklydiscoverednearly identicalversionsofhomeoboxDNAinalmost everynonbacterialcelltheyexaminedfrom yeasttoplants,frogs,worms,beetles,chickens, miceandpeople. Hundredsofhomeoboxcontaininggenes havebeenidentied,andtheproteinsthey maketurnouttobeinvolvedintheearlystages ofdevelopmentofmanyspecies.Forexample, researchershavefoundthatabnormalitiesin thehomeoboxgenescanleadtoextrangersor toesinhumans.
Antennapedia gene.Intheearly1980s,heand
otherresearchersmadeadiscoverythathasbeen fundamentaltounderstandingevolutionaswell asdevelopmentalbiology. ThescientistsfoundashortsequenceofDNA, nowcalledthehomeobox,thatispresentnotonly inAntennapediabutintheseveralgenesnextto itandingenesinmanyotherorganisms.When geneticistsndverysimilarDNAsequencesinthe
22
TheToolsofGenetics:MightyMicroarrays
Wenowhavetheabilitytoattachapieceofevery geneinagenome (allof anorganismsgenes)to apostagestampsizedglassmicroscopeslide. Thisorderedseriesof DNAspotsiscalledaDNA microarray,agenechip ora DNAchip. Whichevernameyouprefer,the chipcould alsobecalledrevolutionary.This technologyhas changedthewaymanygeneticistsdotheirwork bymakingitpossibletoobservetheactivityof thousandsof genesatonce. Inrecentyears,microarrayshavebecome standardequipmentformodernbiologists, but teachersandstudentsareusingthem,too. TheGenomeConsortiumforActiveTeaching program(www.bio.davidson.edu/GCAT)pro videsresourcesandinstructionsforhighschool andcollegestudentstodogenechipexperiments inclass. Microarraysareusedtogetcluesabout which genesareexpressedtocontrolcell,tissue ororganfunction.BymeasuringthelevelofRNA productionforeverygeneatthesametime, researcherscanlearnthegeneticprogramming thatmakescelltypesdifferentanddiseasedcells differentfromhealthyones. ThechipsconsistoflargenumbersofDNA fragmentsdistributedinrowsinaverysmall space.Thearraysarelaidoutbyrobotsthatcan
DNAfragments
DNAfragmentsareattachedto
glassorplastic,thenuorescently taggedmoleculesarewashedover thefragments.
T Theresultingpatternofuorescenceindicates
whichgenesareactive.
ComplementarymRNA
Somemolecules(green)bindtotheir
complementarysequence.Thesemol eculescanbeidentiedbecausethey glowunderuorescentlight.
GotIt?
Whyaresomeinfectionshard totreatwithantibiotics?What aresomethingsresearchers mightdotosolvethispublic healthproblem?
positionDNAfragmentssopreciselythat more than20,000ofthemcantononemicro scopeslide. ScientistsisolatemRNAfromcellsgrown undertwoconditionsandtagthetwosources of RNAwithdifferentcolorsofuorescentmole cules.ThetwocolorsofRNAarethenplaced on thechip,wheretheyattachtocomplementary DNAfragmentsanchoredtothechipssurface. Next, a scanner measures the amount of fluorescence at each spot on the chip, revealing how active each gene was (how much mRNA each gene produced).A computer analyzes the patterns of gene activity, providing a snapshot ofa genomeundertwoconditions(e.g.,healthy or diseased).
InDecember2004,theU.S.Foodand DrugAdministrationclearedtherst gene chipformedicaluse.TheAmplichip CYP450,madebyRocheMolecularSystems Inc.ofPleasanton,California,analyzesvaria tionsintwogenesthatplayamajorrolein thebodysprocessingofmanywidelypre scribeddrugs.Thisinformationcanhelp doctorschoosetheproperdoseofcertain medicinesforanindividualpatient.
HowdoesDNAworkasaform ofinformationstorage?
Howcan20,000humangenes providetheinstructionsfor makinghundredsofthousands ofdifferentproteins?
Whatnewborntestsdoesyour areahospitalroutinelydo?
CHAPTER2
RNAandDNARevealed:NewRoles,NewRules
ormanyyears,whenscientiststhought aboutheredity,DNAwastherstthing
to cometomind.ItstruethatDNAisthebasic ingredientofourgenesand,assuch,itoften stealsthelimelightfromRNA,theotherform

G C U C U C G A C U C G G A U U
of geneticmaterialinsideourcells. But,whiletheyarebothtypesofgenetic material,RNAandDNAareratherdifferent. ThechemicalunitsofRNAarelikethoseof DNA,exceptthatRNAhasthenucleotideuracil (U)insteadofthymine(T).Unlikedouble strandedDNA,RNAusuallycomesasonlyasingle strand.AndthenucleotidesinRNAcontainribose sugarmoleculesinplaceofdeoxyribose. RNAisquiteexibleunlikeDNA,whichis a rigid,spiralstaircasemoleculethatisverystable. RNAcantwistitselfintoavarietyofcomplicated, threedimensionalshapes.RNAisalsounstablein thatcellsconstantlybreakitdownandmustcon tinuallymakeitfresh,whileDNAisnotbroken
Sugar phosphate backbone
Base
G C U C
C A
downoften.RNAsinstabilityletscellschange their patternsofproteinsynthesisveryquickly

A C
in responsetowhatsgoingonaroundthem. ManytextbooksstillportrayRNAasapassive molecule,simplyamiddlestepinthecells genereadingactivities.Butthatviewisnolonger accurate.Eachyear,researchersunlocknew secretsaboutRNA.Thesediscoveriesrevealthat itistrulyaremarkablemoleculeandamulti talentedactorinheredity.
C A U
Ribonucleicacid(RNA)has
thebases adenine(A), cytosine(C),guanine(G) anduracil(U).
RNARNARNARNARNARNARNARNARNARNARNARNARNARNARNARNARNARNARNARNARNARNARNARNARNARNARNA
TheNewGenetics I RNAandDNARevealed:NewRoles,NewRules 25
RONALDBREAKER
Riboswitches are RNA sequences that control gene activity.Theriboswitch shown here bends into a specialshapewhenitgrips tightly onto a molecule calledametabolite(colored balls)thatbacterianeed to survive.
Today,manyscientistsbelievethatRNA evolvedontheEarthlongbeforeDNAdid. Researchershypothesize obviously,noone wasaroundtowritethisdown thatRNAwas amajorparticipantinthechemicalreactions thatultimatelyspawnedtherstsignsof life on theplanet.
becauseofitsabilitytoleadadoublelife:tostore informationandtoconductchemicalreactions. Inotherwords,inthisworld,RNAservedthe functionsof bothDNAandproteins. Whatdoesanyofthishavetodowithhuman health?Plenty,itturnsout. Todaysresearchersareharnessingsomeof RNAsexibilityandpower.Forexample,through
RNAWorld
Atleasttwobasicrequirementsexistformaking a cell:theabilitytohookmoleculestogetherand breakthemapart,andtheabilitytoreplicate,or copyitself,fromexistinginformation. RNAprobablyhelpedtoformtherstcell. The rstorganicmolecules,meaningmolecules containingcarbon,mostlikelyaroseoutofrandom collisionsofgasesintheEarthsprimitiveatmos phere,energyfromtheSun,andheatfromnaturally occurringradioactivity.Somescientiststhinkthat inthisprimitiveworld,RNAwasa molecule critical
astrategyhecallsdirectedevolution,molecular engineerRonaldR.Breakerof Yale Universityis developingwaystocreateentirely newformsof RNAandDNAthatbothworkasenzymes. Breakerandothershavealsouncovered ahiddenworldof RNAsthatplayamajor roleincontrollinggeneactivity,ajobonce thoughttobeperformedexclusivelybyproteins. These RNAs, which the scientists named riboswitches,arefoundinawidevarietyof bacteriaandotherorganisms.
26
ThisdiscoveryhasledBreakertospeculate thatnewkindsofantibioticmedicinescouldbe developedtotargetbacterialriboswitches.
MolecularEditor
Scientistsarelearningof anotherwaytocus tom ze proteins:byRNAediting.AlthoughDNA i
RNAcomesinavarietyof differentshapes(above andright).
sequencesspelloutinstructionsforproducing RNAandproteins,theseinstructionsarent alwaysfollowedprecisely.Editing agenesmRNA,evenbyasingle chemicalletter,canradicallychange
DoublestrandedDNA
(left)isastaircaselike
molecule.
theresultingproteinsfunction. NaturelikelyevolvedtheRNA editingfunctionasawaytogetmore proteinsoutofthesamenumberof
SmallButPowerful
LargerRNA
Dicer enzyme
MicroRNA
mRNA Nearperfectcomplementarity totargetmRNA Notranslation Noprotein
Recently,moleculescalledmicroRNAs havebeen foundinorganismsasdiverseasplants,worms andpeople.Themoleculesaretrulymicro,con sistingofonlyafewdozennucleotides,compared totypicalhumanmRNAsthatareafewthousand nucleotideslong. WhatsparticularlyinterestingaboutmicroRNAs isthatmanyofthemarisefromDNAthatused tobeconsideredmerelyfillermaterial(see page14). HowdothesesmallbutimportantRNAmole culesdotheirwork?Theystartoutmuchbigger butgettrimmedbycellularenzymes,including oneaptlynamedDicer.Liketinypiecesof
TheenzymeDicergeneratesmicroRNAsby
choppinglargerRNAmoleculesintotiny Velcrolikepieces.MicroRNAssticktomRNA moleculesandpreventthemRNAsfrombeing madeintoproteins.
genes.Forexample,researchershavefoundthat themRNAsforcertainproteinsimportantforthe properfunctioningofthenervoussystemare particularlypronetoediting.Itmaybe thatRNA editinggivescertainbraincellsthecapacityto reactquicklytoachanging environment. Whichmoleculesserveastheeditorandhow doesthishappen?BrendaBassoftheUniversityof UtahSchoolofMedicineinSaltLakeCitystudies oneparticularclassofeditorscalledadenosine deaminases.TheseenzymesretypeRNAletters atvariousplaceswithinanmRNAtranscript. Theydotheirjobbysearchingforcharacteris ticRNAshapes.Telltaletwistsandbendsinfolded RNAmoleculessignaltheseenzymestochange
theRNAsequence,whichinturnchangesthe proteinthatgetsmade. BassexperimentsshowthatRNAediting occursinavarietyoforganisms,includingpeo ple.Anotherinterestingaspectofeditingisthat certaindiseasecausingmicroorganisms,suchas someformsofparasites,useRNAeditingtogain asurvivaledgewhenlivinginahumanhost. Understandingthedetailsofthisprocessisan importantareaofmedicalresearch.
AMYPASQUINELLI
Velcro,microRNAssticktocertainmRNAmole culesandstopthemfrompassingontheir proteinmakinginstructions. Firstdiscoveredinaroundwormmodelsystem (seeLivingLaboratories,page49),somemicroRNAs helpdeterminetheorganismsbodyplan.Intheir absence,verybadthingscanhappen.Forexam ple,wormsengineeredtolackamicroRNAcalled let7developsoabnormallythattheyoftenrupture andpracticallybreakinhalfasthewormgrows. PerhapsitisnotsurprisingthatsincemicroRNAs helpspecifythetimingofanorganismsdevelop mentalplan,theappearanceofthemicroRNAs themselvesiscarefullytimedinsideadeveloping organism.Biologists,includingAmyPasquinelli oftheUniversityofCalifornia,San Diego,arecur rently guring out how microRNAs are made andcuttosize,aswellashowtheyareproduced atthepropertimeduringdevelopment.
WormswithamutatedformofthemicroRNAlet7 (right)haveseveregrowthproblems,rupturingas theydevelop.
MicroRNAmoleculesalsohavebeenlinkedto cancer.Forexample,GregoryHannonoftheCold SpringHarborLaboratoryonLongIsland,New York,foundthatcertainmicroRNAsareassoci atedwiththeseverityofthebloodcancerBcell lymphomainmice. Since the discovery of microRNAs in the first years of the 21st century, scientists have identified hundreds of them that likely exist as part of a large family with similar nucleotide sequences. New roles for these molecules are still being found.
28
RNAInterference(RNAi)
Dicerenzyme
dsRNA
DoublestrandedRNA(dsRNA)ischopped
intoshortinterferingRNAs(siRNAs)bythe enzymeDicer.
Shortinterfering RNAs(siRNAs)
RISC TheRNAinducedsilencing complex(RISC)enzyme attachestosiRNA.
C
G
G
C
U
A
A
U
G
C
ThesiRNARISCcomplex attachestotargetmRNA andchopsthemRNAinto smallpieces.
mRNA
ChoppedmRNA (nolongerfunctional)
HealthyInterference
RNAcontrolsgenesinawaythatwasonlydiscov eredrecently:aprocesscalledRNAinterference, orRNAi.AlthoughscientistsidentiedRNAiless than10yearsago,theynowknowthatorganisms havebeenusingthistrickformillionsofyears. ResearchersbelievethatRNAiaroseasawayto reducetheproductionofagenesencodedprotein forpurposesofnetuninggrowthorselfdefense. Whenvirusesinfectcells,forexample,theycom mandtheirhosttoproducespecializedRNAs that allowthevirustosurviveandmakecopies of itself.ResearchersbelievethatRNAieliminates unwantedviralRNA,andsomespeculatethat it mayevenplayaroleinhumanimmunity. Oddlyenough,scientistsdiscoveredRNAi fromafailedexperiment!Researchersinvesti gatinggenesinvolvedinplantgrowthnoticed somethingstrange:Whentheytriedtoturn petuniaowerspurplebyaddinganextra purplegene,theowersbloomedwhiteinstead. Thisresultfascinatedresearchers,whocould notunderstandhowaddinggeneticmaterial couldsomehowgetridofaninheritedtrait.The mysteryremainedunsolveduntil,afewyears later,twogeneticistsstudyingdevelopmentsaw a similarthinghappeninginlabanimals. Theresearchers,AndrewZ.Fire,thenofthe CarnegieInstitutionofWashingtoninBaltimore andnowatStanfordUniversity,andCraigMello oftheUniversityofMassachusettsMedicalSchool inWorcester,weretryingtoblocktheexpression of genes that affect cell growth and tissue formationinroundworms,usingamolecular tool calledantisenseRNA. Totheirsurprise,MelloandFirefound thattheirantisenseRNAtoolwasntdoing muchatall.Rather,theydetermined,adouble strandedcontaminantproducedduringthe synthesisofthesinglestrandedantisenseRNA interferedwithgeneexpression.Melloand FirenamedtheprocessRNAi,andin2006were awardedtheNobelPrizeinphysiologyor medicinefortheirdiscovery. Furtherexperimentsrevealedthatthedouble strandedRNAgetschoppedupinsidethecell intomuchsmallerpiecesthatsticktomRNAand blockitsaction,muchlikethemicroRNApieces ofVelcrodiscussedabove(seedrawing,page28). Today,scientistsaretakingacuefromnature andusingRNAitoexplorebiology.Theyhave learned,forexample,thattheprocessisnotlimited towormsandplants,butoperatesinhumanstoo. Medicalresearchersarecurrentlytestingnew typesofRNAibaseddrugsfortreatingcondi tionssuchasmaculardegeneration,theleading causeofblindness,andvariousinfections,includ ingthosecausedbyHIVandtheherpesvirus.
30
DNA
Histoneproteinslooptogether
withdoublestrandedDNAto formastructurethatresembles beadsonastring. Histones
Chromatin
DynamicDNA
Agoodpartofwhoweareiswritteninour genes,inheritedfromMomandDad.Many traits,likeredorbrownhair,bodyshapeand evensomepersonalityquirks,arepassedonfrom parenttooffspring. Butgenesarenotthewholestory.Wherewe live,howmuchweexercise,whatweeat:These andmanyotherenvironmentalfactorscanall affecthowourgenesgetexpressed. YouknowthatchangesinDNAandRNAcan producechangesinproteins.Butadditionalcon trolhappensatthelevelofDNA,eventhough thesechangesdonotalterDNAdirectly.Inherited factorsthatdonotchangetheDNAsequenceof nucleotidesarecalledepigenetic changes,andthey toohelpmakeeachofusunique. Epigeneticmeans,literally,uponorover genetics.Itdescribesatypeofchemicalreaction thatcanalterthephysicalpropertiesofDNA
withoutchangingitssequence.Thesechanges makegeneseithermoreorlesslikelytobe expressed(seedrawing,page31). Currently,scientistsarefollowinganintrigu ingcourseofdiscoverytoidentifyepigenetic factorsthat,alongwithdietandotherenviron mentalinuences,affectwhoweareandwhat typeof illnesseswemightget.
SecretCode
DNAisspooledupcompactlyinsidecellsinan arrangementcalledchromatin.Thispackaging iscriticalforDNAtodoitswork.Chromatin consistsoflongstringsofDNAspooledaround acompactassemblyofproteinscalledhistones. Oneofthekeyfunctionsofchromatinisto controlaccesstogenes,sincenotallgenesare turnedonatthesametime.Improperexpression ofgrowthpromotinggenes,forexample,canlead tocancer,birthdefectsorotherhealth concerns.
DNADNADNADNADNADNADNADNADNADNADNADNADNADNADNADNADNADNADNADNADNADNADNADNADNADNADNA
DNA
ManyyearsafterthestructureofDNA wasdetermined,researchersusedapowerful deviceknownasanelectronmicroscopeto takepicturesofchromatinbers.Upon viewingchromatinupclose,theresearchers describeditasbeadsonastring,animage stillusedtoday.Thebeadswerethehistone balls,andthestringwasDNAwrapped aroundthehistonesandconnectingone beadtothenext. Decadesofstudyeventuallyrevealedthat histoneshavespecialchemicaltagsthatact likeswitchestocontrolaccesstotheDNA. Flippingtheseswitches,calledepigenetic markings,unwindsthespooledDNAsothe genescanbetranscribed. Theobservationthatacellsgenereading machinerytracksepigeneticmarkingsled C. DavidAllis,whowasthenattheUniversity of Virginia Health Sciences Center in Charlottesville and now works at the Rockefeller University in NewYork City, to coin a new phrase, thehistone code. He and others believe that the histone code plays a major role in determining which proteins get made in a cell. Flawsinthehistonecodehavebeen associatedwithseveraltypesofcancer,and researchersareactivelypursuingthedevelop mentofmedicinestocorrectsucherrors.
Theepigeneticcodecontrolsgeneactivitywith chemicaltagsthatmarkDNA(purplediamonds) andthetailsofhistoneproteins(purpletriangles). Thesemarkingshelpdeterminewhethergeneswill betranscribedbyRNApolymerase.Geneshidden fromaccesstoRNApolymerasearenotexpressed. Chromosome Histones Histonetails
32
GENETICS AND YOU:
TheGeneticsofAnticipation
Thenumberoftripletrepeatsseems toincreaseasthechromosomeis passeddownthroughseveralgenera tions.Thus,thegrandsonsofaman withafragileXchromosome,whois nothimselfaffected,havea40percent riskofretardationiftheyinheritthe repeatcontainingchromosome.The risk forgreatgrandsonsisevenhigher: 50percent. Intriguedbytheevidencethattriplet repeatscancausegeneticdisease,scien tistshavesearchedforotherexamples of disordersassociatedwiththeDNA expansions.Todate,morethanadozen suchdisordershavebeenfound,andall ofthemaffectthenervoussystem. Analysisoftherarefamiliesin whichsuchdiseasesarecommonhas revealedthatexpansionofthetriplet repeatsislinkedtosomethingcalled geneticanticipation,whenadiseases symptomsappearearlierandmore severelyineachsuccessivegeneration.
ccasionally,unusualfactors inuencewhetherornota childwillbebornwitha
geneticdisease. Anexampleisthemolecularerror
thatcausesFragileXsyndrome,arare conditionassociatedwithmentalretar dation.Themutationleadingtoafragile XchromosomeisnotatypicalDNAtyp ingmistake,inwhichnucleotidesare switchedaroundordropped,oroneof themisswitchedfor anothernucleotide. Instead,itisakind of stutterbytheDNA polymeraseenzyme thatcopiesDNA.This stuttercreatesastringofrepeatsofa DNAsequencethatiscomposedofjust threenucleotides,CGG. Somepeoplehaveonlyonerepeat oftheCGGnucleotidetriplet.Thus,they havetwocopiesoftherepeatinagene, andtheextrasequencereadsCGGCGG. Othershavemorethanathousand copiesoftherepeat.Thesepeopleare themostseverelyaffected.
NormalIgf2genevariant (expressed) Paternal
Igf2isanimprintedgene.A
singlecopyoftheabnormal, ormutant,formoftheIgf2 gene(red)causesgrowth defects, but only if the abnormal gene variant is inherited from the father.
Maternal MutantIgf2genevariant (notexpressed)
Normalsizemouse
MutantIgf2genevariant (expressed) Paternal
Maternal NormalIgf2genevariant (notexpressed) Dwarfmouse
BattleoftheSexes
Aprocesscalledimprinting,whichoccursnatu rallyinourcells,providesanotherexampleof howepigeneticsaffectsgeneactivity. Withmostgenes,thetwocopiesworkexactly thesameway.Forsomemammaliangenes,how ever,onlythemothersorthefatherscopyis switchedonregardlessofthechildsgender.This isbecausethegenesarechemicallymarked,or imprinted,duringtheprocessthatgenerateseggs andsperm. Asaresult,theembryothatemergesfromthe joiningofeggandspermcantellwhetheragene copycamefromMomorDad,soitknowswhich copyofthegenetoshutoff. Oneexampleofanimprintedgeneisinsulin likegrowthfactor2(Igf2),agenethathelpsa mammalianfetusgrow.Inthiscase,onlythe
fatherscopyofIgf2isexpressed,andthemothers copyremainssilent(isnotexpressed)throughout thelife oftheoffspring. Scientistshavediscoveredthatthisselective silencingofIgf2andmanyotherimprintedgenes occursinallplacentalmammals(allexceptthe platypus,echidnaandmarsupials)examined sofar,butnotinbirds. Whywouldnaturetolerateaprocessthatputs anorganismatriskbecauseonlyoneoftwo copiesofageneisworking?Thelikelyreason, manyresearchersbelieve,isthatmothersand fathershavecompetinginterests,andthebattle eldisDNA! Thescenariogoeslikethis:Itisinafathers interestforhisembryostogetbiggerfaster, becausethatwillimprovehisoffspringschances ofsurvivalafterbirth.Thebetteranindividuals
34
chanceofsurvivinginfancy,thebetteritschance ofbecominganadult,matingandpassingits genesontothenextgeneration. Ofcoursemotherswantstrongbabies,but unlikefathers,mothersprovidephysicalresources toembryosduringpregnancy.Overherlifetime, afemaleislikelytobepregnantseveraltimes,so sheneedstodivideherresourcesamonganum berofembryosindifferentpregnancies. Researchershavediscoveredover200imprinted genesinmammalssincetherstonewasidentied in1991.Wenowknowthatimprintingcontrols someofthegenesthathaveanimportantrolein regulatingembryonicandfetalgrowthandallocat ingmaternalresources.Notsurprisingly,mutations inthesegenescauseseriousgrowthdisorders. MarisaBartolomeioftheUniversityof PennsylvaniaSchoolofMedicineinPhiladelphia istryingtogureouthowIgf2andothergenes becomeimprintedandstaysilentthroughoutthe lifeofanindividual.Shehasalreadyidentied sequenceswithingenesthatareessentialfor imprinting.Bartolomeiandotherresearchers haveshownthatthesesequences,calledinsula tors,serveaslandingsitesforaproteinthat keepstheimprintedgenefrombeingtranscribed.
StartingattheEnd
WhenwethinkofDNA,wethinkofgenes. However,someDNAsequencesaredifferent: TheydontencodeRNAsorproteins.Introns, describedinChapter1,areinthiscategory. Anotherexampleistelomerestheendsof chromosomes.Therearenogenesintelomeres, but theyserveanessentialfunction.Like shoelaceswithouttheirtips,chromosomeswith outtelomeresunravelandfray.Andwithout telomeres,chromosomessticktoeachotherand causecellstoundergoharmfulchangeslikedivid ingabnormally. Researchersknowagooddealabouttelo meres,datingbacktoexperimentsperformed inthe1970sbyElizabethBlackburn,abasic researcherwhowascuriousaboutsomeofthe fundamentaleventsthattakeplacewithincells.
HESEDPADILLANASHANDTHOMASRIED
Telomeres,repeatednucleotidesequencesatthe tipsofchromosomes,appearwhiteinthisphoto.
Atthetime,Blackburn,nowattheUniversity ofCalifornia,SanFrancisco,wasworkingwith JosephGallatYaleUniversity.Forherexperi mentalsystem,shechoseasinglecelled, ponddwellingorganismnamedTetrahymena. Thesetiny,pearshapedcreaturesarecovered withhairlikeciliathattheyusetopropelthem selvesthroughthewaterastheydevourbacteria andfungi.

Molecular biologist Carol Greider discovered the enzyme telomerase. This license plate, which was onhercarwhensheworkedatColdSpringHarbor Laboratory on Long Island, New York, advertises her research interest!
CAROLGREIDER
Tetrahymena wasagoodorganismfor
Blackburnsexperimentsbecauseithasalarge numberofchromosomeswhichmeansithas a lotoftelomeres! Herresearchwasalsoperfectlytimed,because methodsforsequencingDNAwerejustbeing developed.BlackburnfoundthatTetrahymenas telomereshadanunusualnucleotidesequence: TTGGGG,repeatedabout50timespertelomere. Sincethen,scientistshavediscoveredthatthe telomeresofalmostallorganismshaverepeated sequencesofDNAwithlotsofTsandGs.In humanandmousetelomeres,forexample,the repeatedsequenceisTTAGGG. Thenumberoftelomererepeatsvariesenor mously,notjustfromorganismtoorganismbut indifferentcellsofthesameorganismandeven withinasinglecellovertime.Blackburnreasoned thattherepeatnumbermightvaryifcellshad
an enzymethataddedcopiesoftherepeated sequencetothetelomeresofsomebutnotall chromosomes. WithherthengraduatestudentCarol Greider, now at Johns Hopkins University, Blackburnhuntedfortheenzyme.Theteam founditandGreidernamedittelomerase. Blackburn,GreiderandJackSzostakofHarvard MedicalSchoolinBostonsharedthe2009Nobel Prizeinphysiologyormedicinefortheirdiscov eriesabouttelomeresandtelomerase. Asitturnsout,thetelomeraseenzymecon sistsofaproteinandanRNAcomponent,which theenzymeusesasatemplateforcopyingthe repeatedDNAsequence.
36
Whatisthenaturalfunctionoftelomerase? Ascellsdivideagainandagain,theirtelomeres getshorter.Mostnormalcellsstopdividingwhen theirtelomeresweardowntoacertainpoint,and eventuallythecellsdie.Telomerasecancounter acttheshortening.ByaddingDNAtotelomeres, telomeraserebuildsthetelomereandresetsthe cellsmolecularclock. Thediscoveryoftelomerasetriggerednew ideasandliterallythousandsof newstudies. Manyresearchersthoughtthattheenzyme mightplayimportantrolesincancerandaging. Researcherswerehopingtondwaystoturn telomeraseon sothatcellswouldcontinueto divide(togrowextracellsforburnpatients, forexample), or off sothatcellswouldstop dividing(tostopcancer, forinstance). Sofar,theyhavebeenunsuccessful.Although it isclearthattelomeraseandcellularagingare related,researchersdonotknowwhethertelo meraseplaysaroleinthenormalcellularaging processorindiseaseslikecancer. Recently,however,Blackburnandateamof otherscientistsdiscoveredthatchronicstressand theperceptionthatlifeisstressfulaffecttelomere lengthandtelomeraseactivityinthecellsof healthywomen.Blackburnandhercoworkers are currentlyconductingalongterm,followup studytoconrmtheseintriguingresults.
TheOtherHumanGenome
Beforeyouthinkeverythingsbeensaidabout DNA,theresonelittlethingwedidntmention: SomeoftheDNAineverycellisquitedifferent fromtheDNAthatwevebeentalkingaboutup to thispoint.ThisspecialDNAisntinchromo somesitisnteveninsidethecellsnucleus whereallthechromosomesare! SowhereisthisspecialDNA?Itsinsidemito chondria,theorganellesinourcellsthatproduce theenergyrichmoleculeadenosinetriphosphate, orATP.Mendelknewnothingofmitochondria, sincetheywerentdiscovereduntillateinthe 19th century.Anditwasntuntilthe1960sthat researchersdiscoveredthemitochondrialgenome, whichiscircularlikethegenomesofbacteria. Inhumancells,mitochondrialDNAmakes up lessthan1percentofthetotalDNAineach of ourcells.Themitochondrialgenomeisvery smallcontainingonlyaboutthreedozengenes. Theseencodeafewoftheproteinsthatareinthe mitochondrion,plusasetofribosomalRNAs usedforsynthesizingproteinsfortheorganelle. Mitochondrianeedmanymoreproteins though,andmostoftheseareencodedbygenes in thenucleus.Thus,theenergyproducingcapa bilitiesofhumanmitochondriaavitalpartof anycellseverydayhealthdependoncoordi natedteamworkamonghundredsofgenesin two ellularneighborhoods:thenucleusandthe c m itochondrion.
MitochondrialDNAgetstranscribedand theRNAistranslatedbyenzymesthatarevery differentfromthosethatperformthisjobfor genesinourchromosomes.Mitochondrial enzymeslookandactmuchmorelikethose frombacteria,whichisnotsurprisingbecause mitochondriaarethoughttohavedescended fromfreelivingbacteriathatwereengulfedby anothercelloverabillionyearsago. ScientistshavelinkedmitochondrialDNA defectswithawiderangeofagerelateddiseases includingneurodegenerativedisorders,some formsofheartdisease,diabetesandvarious cancers.Itisstillunclear,though,whetherdam agedmitochondriaareasymptomoracauseof thesehealthconditions. ScientistshavestudiedmitochondrialDNA foranotherreason:tounderstandthehistoryof thehumanrace.UnlikeourchromosomalDNA, whichweinheritfrombothparents,wegetall of ourmitochondrialDNAfromourmothers. Thus,itispossibletodeducewhoourmater nalancestorswerebytrackingtheinheritanceof mutationsinmitochondrialDNA.Forreasons thatarestillnotwellunderstood,mutations accumulateinmitochondrialDNAmorequickly thaninchromosomalDNA.So,itspossibleto traceyourmaternalancestrywaybackbeyond
ALISONDAVIS
Mitochondria(labeled
withareddye)are scatteredthroughout thecytoplasmofthis humancancercell.
Thecellhasalsobeen
treatedwithadyethat colorsthemitochondrial DNAgreen.
Acomputerizedoverlay
ofthesetwoimagesof thesamecellshowsthat mitochondriaandits DNAappeartogether (yellowregions).
anyrelativesyoumayknowbynameallthe waybacktoAfricanEve,theancestorofusall!
38
TheToolsofGenetics:RecombinantDNAandCloning
E.coli bacteria,taken fromhumanintestine
Nucleus
Humancell
Plasmid E.coli chromosome StrandofDNAfromhumancell
Plasmidremoved fromE.coli Plasmidcutopenby restrictionenzymeat aspecicsite RecombinantDNA.Tospliceahuman gene(inthiscase,theoneforinsulin) intoaplasmid,scientiststaketheplas midoutofanE.coli bacterium,cutthe plasmidwitharestrictionenzymeand spliceininsulinmakinghumanDNA. Theresultinghybridplasmidcanbe insertedintoanotherE.coli bacterium, whereitmultipliesalongwiththebac terium.There,itcanproducelarge quantitiesofinsulin.
HumanDNAcutintopieces byrestrictionenzyme
Humaninsulingene
Twopiecessplicedtogether
RecombinantDNA (hybridplasmid)
Humaninsulingene
Humanplasmid insertedintoE.coli cell
Bacteriawithhybridplasmidreplicate,creating clonecapableofproducinghumaninsulin
ROSLININSTITUTE,EDINBURGH
ScientistsinScotlandwerethe
rsttocloneananimal,thissheep namedDolly.Shelatergavebirth toBonnie,thelambnexttoher.
Intheearly1970s,scientists discoveredthattheycould changeanorganismsgenetic traitsbyputtinggenetic materialfromanotherorgan ismintoitscells.Thisdiscovery,whichcaused quiteastir,pavedthewayformanyextraordinary accomplishmentsinmedicalresearchthathave occurredoverthepast35years. Howdoscientistsmovegenesfromone organismtoanother?Thecuttingandpasting getsdonewithchemicalscissors:enzymes,tobe specic.Takeinsulin,forexample.Letssayasci entistwantstomakelargequantitiesof this proteintotreatdiabetes.Shedecidestotransfer thehumangeneforinsulinintoabacterium,
sequence.Mostrestrictionendo nucleasesmakeslightlystaggered incisions,resultinginstickyends, outofwhichonestrandprotrudes. Thenextstepinthisexampleis tosplice,orpaste,thehumaninsulingeneinto acircleofbacterialDNAcalledaplasmid. Attachingthecutendstogetherisdonewith a differentenzyme(obtainedfromavirus), calledDNAligase.Thestickyendsjoinback togetherkindoflikejigsawpuzzlepieces.The result:acutandpastedmixtureofhuman and bacterialDNA. Thelaststepisputtingthenew,recombi nantDNA backintoE.coli andlettingthe bacteriareproduceinapetridish.Now,the scientisthasagreattool:aversionof E.coli thatproduceslotsofhumaninsulinthatcan beusedfortreatingpeoplewithdiabetes. So,whatiscloning?Strictlyspeaking,its makingmanycopies.However,thetermis morecommonlyusedtorefertomaking manycopiesofagene,asintheE.coli exampleabove.Researcherscanalsoclone entireorganisms,likeDollythesheep,which containedtheidenticalgeneticmaterialof anothersheep.
Howiscloningagene differentfromcloningan animaloraperson?How doresearchersusegene cloningtostudyhealth anddisease? Canyouimaginetreat mentsotherthan vaccinesandcurrent medicinescraftedfrom geneticinformationand newmoleculartools? Besidesthesequenceof nucleotidesingenes,what aresomeotherchangesto DNAandRNAthatcan affectourhealthandwho weare?
GotIt?
Escherichiacoli,orE.coli,whichiscommonly
usedforgeneticresearch(seeLivingLaboratories, page46).ThatsbecauseE.coli reproducesreally fast,soafteronebacteriumgetsthehuman insulingene,itdoesnttakemuchtimetogrow millionsofbacteriathatcontainthegene. Therststepistocuttheinsulingeneoutof acopied,orcloned,versionofthehumanDNA usingaspecialbacterialenzymefrombacteria calledarestrictionendonuclease.(Thenormalrole oftheseenzymesinbacteriaistochewupthe DNAofvirusesandotherinvaders.)Eachrestric tionenzymerecognizesandcutsata different nucleotidesequence,soitspossibletobeverypre ciseaboutDNAcuttingbyselectingoneofseveral hundredoftheseenzymesthatcutsatthedesired
Doyouhaveanyrecurring illnessesinyourextended family?
Today
CHAPTER3
LifesGeneticTree
nallofbiology,thereisonethingthatalways staysthesame.Thatthing,believeitornot,
ischangeitself! Themillionsofdifferentlivingthingson Earthplants,bacteria,insects,chimps,people andeverythingelseallcametobebecauseof a processcalledbiologicalevolution,inwhich organismschangeovertime. Becauseofbiologicalevolution,earlyhumans gainedtheabilitytowalkontwofeet.Becauseof evolution,airbreathingwhalescanliveinthe oceandespitebeingmammalslikeus.Becauseof evolution,somebacteriacanliveinscaldingwater, otherscansurviveinsolidiceandstillotherscan livedeepintheEartheatingonlyrocks! Evolutionhappenseveryday,anditaffects everyspeciesincludingus.Itchangesentire populations,notindividuals.Andithasabig impactonmedicalresearch.
Time
EverythingEvolves
Tounderstandevolution,letsgobackintime a centuryandahalfto1854,when theBritish n aturalistCharles DarwinpublishedThe Origin
Firstlivingspecies
TheNewGenetics I LifesGeneticTree 41
CharlesDarwindescribed evolutioninhisclassictext, TheOriginofSpecies.
ofSpecies,abookthat
proposedanexplanationfor howevolutionworks. Themainconceptinevolutionisthatall livingthingsshareacommonancestor.Thevery earliestancestorofalllifeformsonEarthlived about4billionyearsago.Fromthatearlyorgan ism,millionsoftypesofcreaturessomeliving andsomenowextincthaveevolved. Evolutionrequiresdiversity.Youcantellthat livingthingsarediversejustbywalkingdownthe streetandlookingaroundyou.Individualpeople areverydifferentfromoneanother.Chihuahuas aredifferentfromGreatDanes,andSiamesecats aredifferentfromtabbies. Evolutionalsodependsoninheritance.Many ofouruniquecharacteristicsareinheritedthey arepassedfromparenttooffspring.Thisiseasy tosee:DalmatianpuppieslooklikeDalmatians, notChihuahuas.Petuniasgrowdifferentlyfrom pansies.Evolutionworksonly ontraitsthatare inherited. Finally,asyouprobablyalreadyknow, evolutionfavorsthettest.Throughaprocess callednaturalselection,onlysomeoffspring withinagivengenerationwillsurvivelong enoughtoreproduce. Asanexample,considerhouseies,eachof whichlaysthousandsofeggseveryyear.Why haventtheytakenovertheworld?Because almostallofthebabyhouseiesdie.Theiesthat survivearetheonesthatcanndsomethingto eatanddrinktheonesthatavoidbeingeaten, steppedonorswattedandtheonesthatdont freeze,drownorlandonabugzapper. Theiesthatsurviveallthesewaystodiehave whatittakestooutlivemostoftheirbrothersand sisters.Theseinheritedtraitsgiveanorganisma survivaledge.Thosewhosurvivewillmatewith eachotherandwillpassontothenextgeneration someoftheirDNAthatencodedtheseadvanta geoustraits. Ofcourse,notallaspectsofsurvivalare determinedbygenes.Whetheraygetsswatted
42
dependsongenesthataffectitsreexeswhether itsfastenoughtoavoidtheswatter butalso on theenvironment.Iftheresnohumanaround wavingtheswatter,theyisquitelikelytosur vive,regardlessofitsreexes. Evolutionoftentakesalongtimetomakea difference.Butitcanalsohappenveryquickly, especiallyinorganismswithshortlifespans.For example,asyoureadearlier,somebacteriahave molecularfeaturesthatletthemsurviveinthe presenceofantibiotics.Whenyoutakean antibioticmedicine,antibioticresistantbacteria ourishwhileantibioticsensitivebacteriadie. Becauseantibioticresistanceisagrowing publichealththreat,itsimportanttotakethe wholecourseofantibioticmedicine,notstop whenyoufeelbetter.Andyoushouldtakeantibi oticsonlywhentheyreneeded,notforcolds or otherviralinfections,whichantibiotics cant treat.
discoveredararegeneticvariant thatprotects peoplefromgettingAIDS.Ageneticvariantisa differentversionofagene,onethathasaslightly differentsequenceofnucleotides. Scientiststhinkthattherarevariantofagene calledCCR5originallymayhavebeenselected duringevolutionbecauseitmadepeopleresistant toanorganismunrelatedtoHIV. MontgomerySlatkinoftheUniversityof California,Berkeley,hasusedmathematical modelingtechniquestoshowthatnaturalselec tionovertimecouldexplainthefrequencyofthe CCR5variantinhumanpopulations.Thework indicatesthattheCCR5genevariantsabilityto protectagainstAIDSmaycontributetokeepingit inthehumangenepool. So,throughevolution,livingthingschange. Sometimes,thatsgoodforus,aswhenhumans understandHIVresistanceinhopesofpreventing AIDS.Butsometimesthechangesarentsogreat
SelectiveStudy
Scientistsdoingmedicalresearchareveryinter estedingeneticvariantsthathavebeenselected byevolution.Forexample,researchershave
fromahumanperspective,anywayaswhen bacteriabecomeresistanttoantibiotics. Whethertheconsequencesofevolutionary changearegoodorbad,understandingthe
Differentnucleotides (inthisexample,Aor G)canappearinthe DNAsequenceofthe samechromosome fromtwodifferent individuals,creating asinglenucleotide polymorphism(SNP).
TCG A TAA TG CA TG CA TA
OnepersonsDNA
TCG A TA G TG CA TG CA TA
AnotherpersonsDNA
Haplotypesarecombina
Originalhaplotype onchromosome TAT CAT tionsofgenevariants,or SNPs,thatarelikelytobe inheritedtogetherwithin thesamechromosomal region.Inthisexample,an originalhaplotype(top) evolvedovertimetocreate threenewerhaplotypes thateachdifferbyafew nucleotides(red).
10,000nucleotides
Haplotype1 C Haplotype2 TAT Haplotype3 TAT Haplotype4 CG T CAT C CA CA A AT CAT
process canhelpusdevelopnewstrategiesfor ghting disease.
polymorphisms(abbreviatedSNPsandpro nouncedsnips). Forexample,letssaythatacertainnucleotide
CluesfromVariation
Scientistsknowquiteabitabouthowcells reshufegeneticinformationtocreateeachper sonsuniquegenome.Butmanydetailsare missingabouthowthisgeneticvariationcon tributestodisease,makingforaveryactivearea ofresearch. Whatscientistsdoknowisthatmostofthe humangenomeisthesameinallofus.Alittle bitofgeneticvariationdifferencesthat accountformuchlessthan1percentofour DNAgiveseachof usauniquepersonality, appearanceandhealthprole. Thepartsofthehumangenomewherethe DNAsequencesofmanyindividualsvarybya singlenucleotideareknownassinglenucleotide
inoneofyourgenesisA.Inyouruncle,however, thenucleotideinthesameplaceonthesame genemightbeG.Youandyourunclehaveslightly differentversionsofthatgene.Scientistscallthe differentgeneversionsalleles. Iftwogenessitrightnexttoeachotherona chromosome,theSNPsinthosegenestendtobe inheritedtogether.ThissetofneighboringSNPs is calledahaplotype (seedrawingabove). Mostchromosomeregionshaveonlyafew, commonhaplotypesamongallhumans.Asit turnsout,thesefewhaplotypesindifferent combinationsineachpersonappeartoaccount formostofthevariationfrompersontoperson in apopulation.
44
Scientistscanusehaplotypeinformation to comparethegenesofpeopleaffectedbya diseasewiththoseofunaffectedpeople.For example,thisapproachrevealedageneticvaria tionthatsubstantiallyincreasestheriskof agerelatedmaculardegeneration,theleading causeofseverevisionlossintheelderly.Scientists discoveredthatasingleSNPonenucleotidein the3billionnucleotidehumangenomemakes somepeoplemorelikelytogetthiseyedisease. Thediscoverypavesthewayforbetterdiagnostic testsandtreatments. Whataboutotherdiseases?In2007,an internationalscienticteamcompleteda catalog ofcommonhumanhaplotypes.Sincethen, researchershavebeenusingthecatalogtoidentify genesassociatedwithsusceptibilitytomanycom mondiseases,includingasthma,diabetes,cancer andheartdisease. ButnotallSNPsareingenes.Scientistsstudy inggeneticvariationhavealsofoundSNPsin DNAthatdoesntencodeproteins.Nonetheless, someoftheseSNPsappeartoaffectgeneactivity. Someresearcherssuspectthatthecryptic (hidden)variationassociatedwithSNPsin noncodingDNAplaysanimportantrolein determiningthephysicalcharacteristicsand behaviorsofanorganism. LorenRiesebergofIndianaUniversityin Bloomingtonisonescientistwhowouldlove to takethemysteryoutofcrypticvariation.He wantstoknowhowthisnoncodinggenetic variationcanhelporganismsadapttonew environments.Hesalsocuriousaboutwhether it cancreateproblemsforsomeindividuals. Youmightbesurprisedtolearnthat Riesebergsprincipalresearchsubjectisthesun ower.Althoughmanyplantsproduceonlyone generationayear,plantslikesunowerscanbe veryusefultoolsforresearchersaskingfunda mentalquestionsaboutgenetics.Becausetheir geneticmaterialismoremalleablethanthatof manyanimals,plantsareexcellentmodelsfor studyinghowevolutionworks. WildsunowersappealedtoRieseberg becausethereareseveralspeciesthatlivein differenthabitats.Twoancientspeciesofwild sunowersgrowinmoderateclimatesandare broadlydistributedthroughoutthecentraland westernUnitedStates. Threerecentlyevolvedsunowerspecieslive inmorespecializedenvironments:Oneofthe newspeciesgrowsonsanddunes,anothergrows
indrydesertsoilandthethirdspeciesgrowsin a saltmarsh. Toseehowquicklynewplantspeciescould evolve,Riesebergforcedthetwoancientsunow erstointerbreedwitheachother,something plantsbutnototherorganismscando.Among thehybridprogenyweresunowersthatwerejust likethethreerecentlyevolvedspecies!Whatthat meansisthatRieseberghadstimulatedevolution inhislab,similartowhatactuallyhappenedin naturesome60,000to200,000yearsago,when thenewerspeciesrstarose. ThatRiesebergcoulddothisisprettyamaz ing,butthereallyinterestingpartishowit happened.Scientistsgenerallyassumethat,fora newspecieswithverydifferentcharacteristicsto evolve,alotofnewmutationshavetooccur.
ButwhenRieseberglookedatthegenomes of hishybridsunowers,hewassurprisedto nd thattheywerejustcutandpastedversions of theancientsunowerspeciesgenomes: largechunkshadbeen movedratherthanmany newSNPscreated. Riesebergreasons thatplantsstashaway unusedgeneticmaterial, givingthemaready supplyof ingredientstheycanusetoadapt quicklyto anewenvironment.Itmaybethat humangenomescanrecycleunusedgenetic materialtoconfrontnewchallenges,aswell.
Plantslikethesesunowers
makegreatmodelsforstudy inghow volutionworks. e
ALISONDAVIS
46
Living Laboratories
Likemostpeople,youprobablythinkoffruities askitchennuisances.Butdidyouknowthatsci entistsusetheseorganismsformedicalresearch? Fruitiesandothermodelorganismsas differentasmice,plantsandzebrashpermit scientiststoinvestigatequestionsthatwouldnot bepossibletostudyin anyotherway.These livingsystemsare,relativelyspeaking,simple, inexpensiveandeasytoworkwith. Modelorganismsareindispensabletoscience becausecreaturesthatappearverydifferentfrom usandfromeachotheractuallyhavealotin commonwhenitcomestobodychemistry.Even organismsthatdonthaveabodymoldand yeast,forexamplecangivescientistscluesto theworkingsofthetissuesandorgansofpeople. Thisisbecausealllivingthingsprocessthe nutrientstheyconsumeintothesamechemicals, moreorless.Thegenesfortheenzymesinvolved inmetabolismaresimilarinallorganisms.
REX L. CHISHOLM
Belowisasamplingofthewidevarietyof livinglaboratoriesthatscientistsareusingto advancehumanhealth.
1 Escherichiacoli:Bacterium Onceweunderstandthebiologyof Escherichia

coli, wewillunderstandthebiologyofanele
phant. SosaidJacquesMonod,aFrenchscientist
whowonthe1965NobelPrizeinphysiologyor medicineforhisworkongeneregulation.Monod wasanearlyproponentofthevalueofexperi mentingwithsimpleorganismslikebacteria.Are allbacteriabad?IfallyouveeverheardaboutE.
coli isitsnotoriouslinktotaintedhamburger
meat,youmaynotrealizethatnondiseasecausing strainsofthebacteriumliveinthe intestinaltracts ofhumansandotheranimals,helpingthemina varietyofways.Foronething,these bacteriaare a mainsourceofvitaminKandBcomplex vitamins.Theyalsoaiddigestionandprotect againstinfectionbyharmfulbacteria.
NAMBOORI B. RAJU
Scientistsallovertheworldhavebanded togethertosequencedifferentversionsofthe
Dicty normallygrowsasseparate,independent
cells.However,whenfoodislimited,neighboring cellspileontopofeachothertocreatealarge, multicelledstructurecontainingupto100,000 cells.Thisblobamblesalonglikeaslug,leaving a trailofslimebehind.Aftermigratingtoamore suitableenvironment,theblobrmsupintoa
E.coli genome.Amongotherthings,thesestudies
willhelpdistinguishthegeneticdifferences betweenbacteriainahealthyhumangutand thosethatcausefoodpoisoning.
2 Dictyosteliumdiscoideum: Amoeba
Thismicroscopicamoeba100,000ofthem form amoundasbigasagrainofsandisan importanttoolforhealthstudies.Scientistshave determinedthatDictyosteliumdiscoideum(Dicty) hassomewherebetween8,000and10,000genes, manyofwhichareclosecopiesofthoseinpeople andanimalsbutaremissinginanothersingle celledorganism,yeast.Dicty wasrstdiscovered in the1930sinaNorthCarolinaforestandhas sincebeenfoundinmanysimilarhabitatsaround theworld.
towerlikestructurethatdispersesspores,each capableofgeneratinganewamoeba.Becauseof itsunusualpropertiesandabilityto livealoneor inagroup,Dicty intriguesresearcherswhostudy celldivision,movementandvariousaspectsof organandtissuedevelopment.
3 Neurosporacrassa:BreadMold
Chancesareyoudontthinkofamoldybread crustasapotentialscience experiment,but thousandsofresearchersaroundtheworlddo!
Neurosporacrassa(Neurospora),whichis
a speciesofmoldthatthriveson bread,isawidely usedmodelorganismforgeneticresearch.
48
GARY DITTA
ALAN WHEALS
BiologistsliketouseNeurospora because itissimpleto growandhasfeaturesthatmake itverysuitableforansweringquestionsabout howspeciesariseandadapt, aswellashowcells and tissues change their shape in different environments.SinceNeurospora producesspores ona24hourcycle,theorganismisalsouseful for studying the biological clocks that govern sleep, wakefulness and other rhythms of life.
likeyeastbecauseitgrowsfast,ischeaptofeed andsafetohandle,anditsgenesareeasytowork with.Weknowalotaboutmammaliangenes becausescientistscaneasilyinsertthemintoyeast andthenstudyhowtheyworkandwhathappens whentheydontwork.
5 Arabidopsisthaliana:MustardPlant
Researcherswhostudyplantgrowthoftenuse
Arabidopsisthaliana(Arabidopsis),asmall, 4 Saccharomycescerevisiae:Yeast
Therearehundredsofdifferentkindsofyeast,but oweringplantrelatedtocabbageandmustard. This organismisappealingtobiologistsbecause
Saccharomyces cerevisiae,theone scientistsstudy

mostoften,isanimportantpartofhumanlife outsidethelab,too.Itistheyeastthatbakersuse tomakebreadandbrewersuseforbeer. LikeNeurospora,yeastis actuallyafungus nota plant,notananimal,butrelatedtoboth. It isalsoaeukaryote(asisNeurospora)a higherorganismwithanorganized,protective nucleusthatholdsitschromosomes.Researchers
Arabidopsis hasalmostallofthesamegenesas
otheroweringplantsandhasrelativelylittle DNA thatdoesnotencodeproteins,simplifying thestudyofitsgenes.Likepeopleandyeast, plantsare alsoeukaryotes.Arabidopsis grows quickly,goingfromseedtomatureplantinonly 6weeksanotherplusforresearcherswhostudy howgenesaffectbiology.
7
Whatdoyouhaveincommonwithamustard plant?Plantcells,andpartsofplantcells,com municatewitheachotherinmuchthesameway thathumancellsdo.Forthatreason,plantsare goodmodelsforgeneticdiseasesthataffect cell communication. hasalotofgenesmorethan19,000(humans haveabout20,000).DecodingtheC.elegans genomewasahugemilestoneforbiology,since it wastherstanimalgenometobesequenced completely.Scientistsquicklylearnedthatavast numberofgenesinC.elegans arevery similar to genesinotherorganisms,includingpeople.
6 Caenorhabditiselegans:Roundworm Caenorhabditiselegans(C.elegans) isacreature

thatisalotsmallerthanitsname!Severalof theseharmlessroundwormswouldtonthe headofapin,althoughtheirusualhabitatis dirt.Inthelab,theyliveinpetridishesandeat bacteria.C.eleganscontainsjust959cells, almostathirdofthemformingitsnervous system.Researchersknowthe fateofeveryone ofthesecells! Thiswormisparticularlyprizedbybiologists becauseitistransparent,sowhatgoesoninits tinybodyisinplainviewunderamicroscope. But forsuchasmall,simpleanimal,C.elegans
7 Drosophilamelanogaster: FruitFly
Thefruityspeciesmostcommonlyusedfor researchisnamedDrosophilamelanogaster
(Drosophila).Ageneticistsfruityispretty
muchthesameastheonesthatyaroundyour overripebananas.Inthelab,though,someof theiesareexposedtodamagingchemicalsor radiation,whichchangesthesequenceoftheir DNA.Researchersallowtheiestomate,then searchamongtheoffspringforieswith abnormalities.Themutantiesarethenmated toproducemoreoffspringwiththeabnormality, enablingresearcherstocloseinonthedefective genesinvolved.
50
MONTE WESTERFIELD
Fruitieshavebeenafavoriteexperimental organismamonggeneticistssinceearlyinthe 20thcentury.Hundredsofthemcanliveina pintsizedmilkbottleorevenasmallvial,and theyreproducesoquicklythatkeepingtrack ofaparticulargeneasitpassesthroughacouple ofDrosophila generationstakesonlyabouta month.Itsalsorelativelyeasytocreateieswith mutationsinmanygenes,enablingscientiststo studyhowthegenesworktogether.
Manyresearchersaredrawntozebrash becausetheireggsandembryosaretransparent, makingitpossibletowatchdevelopmentunfold. Inaspanof2to4days,zebrashcellssplitand formdifferentpartsofthebabyshsbody:eyes, heart,liver,stomachandsoon.Sometimes, researcherswillmoveacelltoanotherspottosee ifitwillstillgoontoformthesamepartofthe bodyorifitwilldosomethingdifferent.This researchhastaughtscientistsaboutarangeof healthrelatedmattersinpeople,includingbirth
8 Daniorerio:Zebrash
Zebrashwereoriginallyfoundinslowstreams, ricepaddiesandtheGangesRiverinEastIndia andBurma.Theycanalsobefoundinmostpet storesandareahomeaquariumfavorite. Althoughtheshhavebeenusedbysome geneticistsforresearchsincetheearly1970s,in recentyearstheyhavebecomeanespecially popularmodelorganism.
defectsandtheproperdevelopmentofblood,the heartandtheinnerear.
9 Musmusculus:Mouse
Thebranchesoflifesgenetictreethatledeventu allytomiceandtohumanbeingssplitofffrom eachother75millionyearsago,backinthe dinosaurage.Butwearebothmammals,andwe share85percentofourgenes.Becausesome mousediseasesareverysimilarsometimes
10
identicaltohumandiseases,miceare exceptionallyvaluableforresearch. Sincethelate1980s,researchershavebeen abletoengineermicewithmissinggenes. Scientistsmaketheseknockoutmicetolearn whatgoeswrongwhena particulargeneis removed.Thisgivesthemvaluablecluesabout thegenesnormalfunction.Identifyingthese genesinhumanshashelpeddenethemolecular basisformanyillnesses.
Althoughratsaremammalsjustlikemice, theydifferinimportantways.Ratsaremuch biggerthanmice,makingiteasierforscientists todoexperimentsthatinvolvethebrain.For example,ratshavetaughtscientistsalotabout substanceabuseandaddiction,learning,memory andcertainneurologicaldiseases.Ratsarealso much bettermodelsthanmiceforstudying asthmaandlunginjury.Andsince,inpeople,the diseasearthritisismorecommoninwomen, studyingratsmakesmoresensebecausefemale
10 Rattusnorvegicus:Rat
TheNorwayrat,orlabrat,wastherstanimal domesticatedforuseinscienticresearch. Currently,theymakeupaboutonefourthofall researchanimalsintheUnitedStates.Labratshave beenusedformanydecadesfortestingdrugs,and muchofwhatweknowaboutcancercausing moleculeswaslearnedinbasicresearchwithrats.
ratsappeartobemoresusceptibletoarthritis thanmalerats.Theoppositeistruewithmice.
ThisLivingLaboratories sectionis availableasaposter.Toorderafreecopy, visithttp://publications.nigms.nih.gov/order.
52
TheGenomeZoo
Scientistsoftenuseanimageofatreetodepict howallorganisms,livingandextinct,arerelated to acommonancestor.Inthistreeoflife,each branchrepresentsaspecies,andtheforksbetween branchesshowwhenthespeciesrepresentedby thosebranchesbecamedifferentfromoneanother. Forexample,researchersestimatethatthe com monancestorofhumansandchimpanzeeslived about6millionyearsago. Whileitisobviousjustbylookingthatpeople havealotincommonwithourclosestlivingrela tives,chimpanzees,whataboutmoredistant species?Ifyoulookatanevolutionarytree,youll seethathumansarerelatedtomice,wormsand evenbacteria.Theancestralspeciesthatgaverise tobothhumansandbacteriawasalivealot
longeragothantheancestorof humansand chimpanzees,yetwestillsharehundredsofgenes withbacteria. Scientistsusethetermcomparativegenomics todescribewhattheyredoingwhentheycom parethegenomesofdifferentspeciestoseehow similar(orhowdifferent!)thespeciesDNA sequencesare.Sequencesthatthespecieshavein commonarethemolecularfootprintsofan ancestorofthosespecies. WhyareoldDNAsequencesstillinour genomes?Itturnsoutthatnatureisquiteeco nomical,soDNAsequencesthatareresponsible forsomethingascomplicatedandimportantas controllinggeneactivitymaystayintactfor millionsofyears. Comparativegenomicstudiesalsohavemed icalimplications.Whatwouldyoudoifyou wantedtodevelopnewmethodsofpreventing, diagnosingortreatingahumandiseasethat animalsdontget?
StartingAllOverAgain
Stemcells whatembryos aremadeupofjustdays afteraneggisfertilizedby a spermhavetheamazing abilitytodevelopintoany kindofcellinthebody, fromskintoheart,muscle andnerve. Intriguedbythepotential ofthesemasterfulcells, researcherswanttoknow whatgivesstemcellstheir
abilitytochangeintoaspeciccelltypeupon thebodysrequest,butstayintheIcando anythingstateuntilasked. Someresearchersaretryingtogureouthow stemcellsworkbyusingauniquemodelsystem: tiny,freshwaterwormscalledplanarians.These wormsarelikestemcellsinthesensethatthey canregenerate.Youcancutaplanarianinto hundredsofpieces,andeachpiecewillgrow intoacompleteworm. Planariansresemblancetostemcellsisnt justcoincidental.Scientistshavediscovered
PHILLIPNEWMARK
Ifpeoplehaveagenethatinuencestheirrisk foradisease,andmicehavethegenetoo,you couldstudysomeaspectofthediseaseinmice, eventhoughtheydonteverhavethesymptoms of thedisease.Youcouldevenstudythedisease in yeast,ifithasthegene,aswell.
cytochromeP450family,abbreviated3A4and 3A5,encodeproteinsthatprocessmorethanhalf ofallofthemedicinesthataresoldtoday. Sincethechemicalstowhichpeopleare exposedvarysowidely,ascientistmightpre dict thattherewouldbedifferentvariants of cytochromeP450genesindifferenthuman
GenesMeetEnvironment
If toxinsfromtheenvironmentgetintoour bodies,theydontalwaysmakeussick.Thats becauseliverenzymescometoourrescueto makethechemicalslessharmful.Thegenesthat encodethoseenzymesareunderconstantevolu tionarypressuretoadaptquicklytonewtoxins. Forexample,certainliverenzymescalled cytochromeP450proteinsmetabolize,orbreak down,hormonesthatourbodiesmakeaswellas manyoftheforeignsubstancesthatweencounter. These include harmful molecules like cancer causing agents as well as beneficial ones, like medicines. In fact, just two genes within the
populations.Usingcomparativegenomics, researcherssuchasAnnaDi Rienzoofthe UniversityofChicagohave shownthatthisis indeedthecase.DiRienzohasfoundmany sequencedifferenceswithinthesegenesinpeople livingthroughoutthe world. Itturnsoutthatonevariantofthegenethat encodesthecytochromeP4503A5proteinmakes thisenzymeveryefcientatbreakingdown cortisol,ahormonethatraisessaltlevelsinthe kidneysandhelpsthebodyretainwater.DiRienzo comparedtheDNAsequencesofthe3A5 genein DNAsamplestakenfrommorethan1,000people
thatplanarianscanperformtheamazingact of regenerationduetothepresenceof,yes, specializedstemcellsintheirbodies. DevelopmentalbiologistAlejandroSnchez AlvaradooftheUniversityofUtahSchool of MedicineinSaltLakeCityusedthegene silencingtechniqueRNAi(seepage28)to identifyplanariangenesessentialforregenera tion.Heandhisteamhopetogureouthow thesegenesallowthespecializedstemcells to traveltoawoundedsiteandturnintoany of the30orsocelltypesneededtorecreatea matureworm.
Althoughhumansareonlydistantlyrelated to planarians,wehavemanyofthesamegenes, sothesendingscouldrevealstrategiesforregen eratinginjuredbodypartsinpeople,too. Scientistshavealsolearnedhowtogenetically reprogramhumanskincells(andothereasily obtainedcells)tomimicthestemcellsofembryos. Intheory,thesesocalledinducedpluripotentstem cellscouldgenerateanytypeofcellandbeused totreatdiseases.Buttorealizethispotential,we needamuchbetterunderstandingoftheproper tiesofthesecellsandhowtoefcientlyproduce cellsthataresafefortherapeuticuses.
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advantageforpeoplelivinginaveryhotclimate, sinceretainingsalthelpswardoffdehydration causedbyintenseheat. However,thereseemstobeacostassociated withthatbenetthe3A5genevariantraises theriskforsometypesofhighbloodpressure. Thatmeansthatinenvironmentsinwhich retainingsaltisnotbenecial,evolutionselects againstthisgenevariant. Anotherscientistwhostudiesinteractions betweengenesandtheenvironmentisSerrine Lau oftheUniversityofArizonainTucson.She studiesaclassofharmfulmoleculescalled polyphenols,presentincigarettesmokeandcar exhaust,thatcausekidneycancerinrats,and perhaps,inpeople. Laudiscoveredthatratsandhumanswho are moresensitivetosomeofthebreakdown productsofpolyphenolshaveanunusualDNA
. ScientistshavediscoveredthatsomeAfricanpopu
lationsneartheequatorhaveahighfrequencyofa geneticvariantthathelpsthebodyconservewater.
sequence ageneticsignaturethatincreases theirriskofdevelopingcancer.Shesuspectsthat thegenethatisaffectedencodesatumorsup pressor:aproteinthatpreventscancerfrom
representingover50populationsworldwide.She wasamazedtondastrikinglinkbetweenthe existenceofthegenevariantandthegeographic localeofthepeoplewhohaveit. DiRienzodiscoveredthatAfricanpopulations livingveryclosetotheequatorweremorelikely thanotherpopulationstohavethesaltsaving versionofthe3A5gene.Shesuggeststhatthisis becausethisgenevariantprovidesahealth
developing.Inpeopleandratswiththegenetic signature,shereasons,thetumorsuppressor doesntworkright,sotumorsgrow. Takingthislogiconestepfurther,itmaybe thatcertainpeoplesgeneticmakeupmakes themunusuallysusceptibletoDNAdamage causedbyexposuretocarcinogens.Ifdoctors couldidentifythoseatrisk,Lausays,suchpeople couldbeforewarnedtoavoidcontactwithspe cicchemicalstoprotecttheirhealth.
However,thinkaboutthisscenario:Who shouldmakethosedecisions?Forexample, would itbeethicalforanemployertorefuseto hiresomebodybecausethepersonhasagenetic signaturethatmakeshimorhermorelikelyto getcancerifexposedtoachemicalusedinthe workplace?Toughquestion.

Theliverandkidneysare
susceptibletodamagefrom toxinssincethesebody organsprocesschemicals.
Liver
Kidneys
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GENETICS AND YOU:
YouveGotRhythm!
The human body keeps time with a master clock called the suprachiasmatic nucleus or SCN. Situated inside the brain, itsatinysliveroftissueaboutthesizeofa grainofrice,locatedbehindtheeyes.Itsits quiteclosetotheopticnerve,whichcon trolsvision,andthismeansthattheSCN clockcankeeptrackofdayandnight. Givenenoughtime,yourSCNcanreset itselfafteryouyinanairplanefromone timezonetoanother. TheSCNhelpscontrolsleepbycoordi natingtheactionsofbillionsofminiature clocksthroughoutthebody.Thesearent actuallyclocks,butratherareensemblesof genesinsideclustersofcellsthatswitchon andoffinaregular,24hourcycleour physiologicalday. Scientistscallthis24houroscillation acircadian rhythm.(Circadiancomesfrom theLatinwordsmeaningapproximately aday.)Researchershavediscoveredthat alllivingthingsplants,animalsandbac
hatdowaking,sleeping, eating,reproducingand birdsyingsouthforthe
winterhaveincommon?Theseareall examplesofnaturesamazingsenseof
rhythm.Alllivingthingsareequipped withmoleculartimepiecesthatsetthe pulseoflife. Ifyouveevercrossedthecountryor anoceanbyplane,youknowaboutthe importanceoftheseclocks.Youproba blyexperiencedthattravelersmisery calledjetlag,wherethebodyisforced to adaptquicklytoanewtimezone. Butdidyouknowthatcertainforms ofinsomniaandmanicdepressiveillness areassociatedwithbiologicalclocks notworkingproperly?Andbioogical l rhythmsmaybethereasonwhysome medicinesandsurgicaltreatments appeartoworkbestatcertaintimes ofday.
Outputrhythms: physiology behavior
Light
teria havecircadianrhythms.Many researchersworkingwithinsectandother modelsystemshaveidentiedgenesthat arecriticalforkeepingbiologicaltime. Understandingcircadianrhythmswillhelp scientistsbetterunderstandsleepdisorders. Ifwehavetheopportunity,mostofussleep 7 or 8 hours at night, and if we dont get
Suprachiasmatic nucleus(SCN)
enoughrestwemayhaveahardtimegetting things done the next day. Some people,
however,routinelygetbywithonly3to 4hoursofsleep.Researchershavenoted thatthistraitseemstoruninfamilies, suggestingageneticlink. Asitturnsout,fruitiesneedeven moresleepthanpeople.Neuroscientist Chiara Cirelli of the University of WisconsinMadisondidageneticsearch for fruit fly mutants that dont sleep much.Shediscoveredthatieswitha variantofagenecalledshaker sleep only3to4hourspernight.
Althoughtheshaker iesdont appearsleepdeprived,Cirellifoundthat theyhaveadifferentproblem:They dontliveaslongasieswithoutthe mutation.Sheisnowstudyingthisnew connectionbetweensleepandlifespan. Herworkmayalsopavethewayfor improvedsleepaidsandeffective remediesforjetlag.
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AnimalsHelpingPeople
UsingtechnologythatgrewoutoftheHuman Genome Project, scientists have read the sequencesofthegenomesofhundredsoforgan isms:dogs,mice,rats,chickens,honeybees,fruit ies,seaurchins,puffersh,seasquirts,round wormsandmanybacteriaandfungi.Nextin line aredozensofadditionalspecies,including a marmoset,aseaskate,analpaca,ananteater and manyreptiles. Whateffectwillallthisgenesequenceinfor mationhaveonmedicalresearch?Wevealready talkedaboutthefactthatpeoplesharemanyof theirgeneswithotherspecies.Thismeansthat whenscientistsreadthesequenceofanother speciesgenome,theyrelikelytodiscoverthatthe organismhasmanyofthegenesthat,inhumans, causediseaseorraisediseaseriskwhenmutated. Takefruitiesasoneexample.Accordingto biologistEthanBieroftheUniversityofCalifornia, SanDiego,30percentofthecurrentlyidentied humandiseasegenesmostlikelyhavefunctional counterpartsinnoneotherthanDrosophila
melanogaster,afruityspecieswidelyused
ingeneticresearch(seeLivingLaboratories, page49). Currently,Bierandotherscientistsareusing experimentaliestoinvestigateawiderangeof genesinvolvedinconditionssuchasblindness, deafness,mentalretardation,heartdiseaseand the wayinwhichbacterialtoxinscauseillness. ByreadingtheDNAsequencesofmanyother species,researchershopetondmodelsystems thatareevenbetterthanfruitiesforstudying someaspectsofhumandisease. Sometimes,thegenesthatwedonthavein commonwithotherspeciesareasimportantas thegenesweshare.Forexample,considerthefact thathumansandchimpanzeeshaveremarkably differentabilitiesandphysicalfeatures.Butthe chimpanzeegenomeis99percentidenticalto our own. Anddidyouknowthatchimpanzeesdont get malariaorAIDS? Soatinyportionofourgenomedetermines whetherwelookandbehavelikeapersonora chimp,andwhetherwearesusceptibletomalaria orAIDS.
MyCollaboratorIsaComputer
Wevemadethecasethatcomparinggenomes canofferfreshinsightonthebasicgeneticingre dientsforhealthandthecausesofdisease.But whatdoesascientistactuallydowhenheorshe comparesgenesequences?Doesthismeanstaring atthousandsofpagesofgeneticletters,looking forthosethatarethesameordifferent?
Computersare
an essential tool forscientistswho storeandanalyze hugeamountsof genomicdata.Read moreaboutcomput ersandbiologyat http://publications. nigms.nih.gov/ computinglife.
Yesandno.Comparativegenomicsdoes involvelookingforsimilaritiesanddifferences, but itisntsomethingthatscientistsdobyhand. Certainlynotforthousandsofgenesatatime. Rather,thegigantictaskofcomparingthe nucleotidesthatmakeupthegenomesoftwoor morespeciesistheperfectjobforacomputer,a naturalmultitasker.Ifyouconsiderthatthe humangenomecontains3billionnucleotides, you caneasilyseewhythisisworkwellsuitedto a machine(withahumanoperator,ofcourse). Researcherscalledcomputationalbiologists helpanalyzegenomicdata.Thesescientists developsoftwareprogramsthatenablecomputers toperformgenomecomparisons.Amongother
things,theprogramscangureoutwherein the DNAsequencesagenestartsandstops: its boundaries. Otherresearcherswhoworkintheeldof bioinformatics minegenomicinformationhid deninthemassesofdata.Theyarelookingfor scientictreasureintheformofnewbiological knowledge.Theseexperimentscanzeroinonpre viouslyhiddenpatternsandreveallinksbetween differenteldsofresearch. Bioinformaticistsandcomputationalbiolo gistsareinhighdemandbecausetheyplayavery importantrolein21stcenturymedicalscience. Thesescientistsmustbeuentinbothcomputer scienceandbiology.
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TheToolsofGenetics:UnlimitedDNA
Youmightbeamazedtolearnthatamicrobethat livesinaboilinghotspringinYellowstone NationalParkistheessentialingredientforone ofthemostimportantbiologicalresearchtools everinvented. essentialtoalaboratorytechniquecalledthe polymerasechainreaction,or PCR.AndPCR is essentialtolotsofthingsthatlifescientists doandtomanyotherelds,too.PCRsinven tor,KaryMullis,won the1993NobelPrizein chemistry. PCRisaquick,easymethodforgenerating unlimitedcopiesoftinyamountsofDNA.Words
Thermusaquaticus isabacteriumthatmakes
aheatresistantenzyme,whichiswhyit canthrive inhotsprings.Theenzyme,Taqpolymerase,is
. Amicrobethatlivesinhotsprings,likethisonein
YellowstoneNationalPark,ishometotheenzyme thatmakesthepolymerasechainreaction,or PCR,possible.
PCRmachine.
APPLIEDBIOSYSTEMS
GotIt?
Discussreasonswhyresearch
likerevolutionaryand breakthrougharenotan exaggerationofitsimpact. PCRisattheheartof modernDNA sequencing methods.Itisessentialfor pinpointingmutationsingenes,soitisthe basisformuchoftheresearchdiscussedin this booklet.PCRhasdoneforgeneticmaterial whattheinventionof theprintingpressdid forwrittenmaterial.Itmakescopyingeasy, inexpensiveandwidelyavailable. PCRunderliesmanydiagnostictechniques, liketestingindividualsfor genesthatcause breast cancer.Itcanalsohelpdiagnosediseases otherthancancer,suchas infectionsbyHIV and hepatitisC.
PCRisakeyelementof geneticngerprinting,whichhas helpedfreeprisonerswhoreliedonittoprove thattheywereinnocentofthecrimesthat got themlockedup.Conversely,ithaspro videdscienticevidencethathelpedconvict criminals. PCRhasevenrevolutionizedarchaeology byhelpingto analyzebadlydamagedancient DNAsometimesthousandsofyears oldwhichcanrevealnewinformation aboutpastpeopleandcultures. ScientistspredictthatfutureusesofPCR technologywillenhancemedicaltreatment, enablingbetterdiagnosisandmoreaccurate subtypingofdisease.
studieswithidenticaltwins canprovidevaluableinforma tionabouthealthanddisease.
Humansandmiceshareover 80percentofthesame geneticmaterial:forchimps andhumans,it smorethan99 percent.Whyarepeopleand animalssodifferent,iftheir genesaresosimilar?
Youareascientistandyou wanttolearnmoreabouthow humansage.Isthereaway youcanaddressyour researchquestionwithout spendingmanydecades studyingpeople?
Canyouthinkofanexperi mentusingfruitiesthat couldhelpresearchersbetter understandjetlag?
CHAPTER4
GenesAreUs
orscience,thesequencingofthehuman genomewasagroundbreakingachievement,
changescreatewordswithnewmeanings genesthatcodefordifferentproteins.Other spellingchangesappeartohavenoeffect whatsoever,atleastnotonesthattodaysscien tistsknowhowtomeasure. Researchersarebeginningtouseknowledge learnedfromgenomesequencingresearchto gureouthowbeinghealthyandbeingsickare differentatthelevelofmolecules.Anddoctors arestartingtousegeneticinformationtomake treatmentchoices. Forexample,adiagnostictestcansearchfor differencesinthelevelofexpressionofaparticu largeneinbreastcancercellsandpredictwhether apersonwillrespondtoadrugcalledHerceptin. Thecancerouscellsofsomepeoplewhohave breastcancermakeanabundanceofHER2 proteinsthataretargetedbyHerceptin.Forthose people,Herceptinisamiracledrugbecauseit
onethatmadealotofnews.Butwhatdoesit actuallymean?Willanyofthisinformationmake adifferenceinyourlife? Agenomeisallofthegeneticmaterialthatan individual(oraspecies)has.Thehumangenome differsfromthegorillagenome,whichdiffers fromthericegenome,andsoon.Andwhileevery personhasahumangenome,itisnotexactly thesameinallpeople.Sequencevariations
within yourgenesmakesyourDNAdifferent
fromthatofyourmother,yourcousinora completestranger. Thinkofthehumangenomeasalongstory thatcontainsroughly20,000words(thegenes). Withfewexceptions,eachpersonhasthesame numberofwords,butcertainwordshaveslightly differentspellings.Insomecases,thespelling
ReadingtheBookofHumanGenes
InApril2003,researchersacrosstheworldcele bratedamilestoneandananniversary.Almost50 yearstothedayafterJamesWatson,FrancisCrick andMauriceWilkinsunveiledtheirNobelPrize winningdescriptionoftheDNAdoublehelix, scientistscompletedthesequencingofthehuman genome,amomentousachievementinbiology. Thedaywaslongincoming.Inthe1980s, geneticistsrealizedthattheyhadboththeneed andtheabilitytolearnthecompletelayoutofthe humangenome.Theywantedtomapthelocation ofeverygenewithinchromosomesanddecipher thecomplete,letterbylettersequenceofthe genomes3billionnucleotides.
L.BARRYHETHERINGTON
ManyDNAsequencingcentersjoinedeffortsto formtheHumanGenomeProject,completedin 2003.Nowthecenters,likethisoneattheBroad Institute of MIT and Harvard University in Cambridge,Massachusetts,areworkingtobetter understandthehumangenomeandtosequence the genomes of other organisms.
TheNewGenetics I GenesAreUs 63
reducestheriskthattheirbreastcancerwillcome back,anditalsodecreasestheiroddsofdying fromthedisease. Forcancerpatientswhosetumorgenesdo not expressHER2,Herceptinwontdoathing,
though,soitshouldntbeprescribed.Researchis proceedingquicklytodevelopothergenetictests thatmayhelpdiagnoseandtreatawiderangeof healthproblemsbeyondcancer.
With that information in hand, scientists reasoned, it would eventually be possible to learn exactly what job each gene performs as well as how genes contribute to human health and disease. Soon,thousandsofscientistsinlabsallover the worldgotintotheact.Criticaltotheirsuccess werenewtoolsandtechnologiesthatmadethe workgofasterandhelpedtheresearchersman ageandanalyzetheoodofdata. AlthoughtheHumanGenomeProjectisdone, relatedgenomesequencingeffortshavecontin ued.Oneinvolvessequencingthegenomesof manyotherspecies(seepage58).
Another is roughly sequencing the genomes of 2,000 people to produce a detailed haplotype map showing both common and rare patterns of genetic variation. Researchers can link these variations to dis ease risk and healthrelated traits, such as individual reactions to medicines and environmental chemicals.
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IndividualizedPrescriptions
Onewayvariationsinourgenesmakeadiffer enceinourhealthisbyaffectinghowourbodies reacttomedicines.Theunsettlingtruthisthat medicinesworkasexpectedinfewerthanhalfof thepeoplewhotakethem. While environmental and lifestyle factors can explain some of this, a good part of the individualvariabilityinresponsetomedicines canbeattributedtovariantsinthegenesthat makecytochromeP450proteins(seepage53). These proteins process many of the drugs we take.
Becauseeachpersonssetofgenesisalittle different,theproteinsthatthegenesencodeare alsoslightlydifferent.Thesechangescanaffect howthecytochromeP450proteins(andmany othertypesofproteins)workondrugs. Doctors first realized this in the 1950s, whensomepatientshadbadsometimesfatal reactionstoananestheticmedicineusedinsurgery. Experimentsrevealedthatthosewhoreacted poorlyhadageneticvariationintheenzymethat breaksdownanddisposesoftheanestheticafter itsbeeninthebodyforawhile. Peoplewhosegenesencodethevariantenzyme hadnotroubleatalluntiltheyneededsurgerythat requiredgeneralanesthesia.Intheoperatingroom, anormalhumangeneticvariationsuddenlyledto amedicalcrisis! Fortunately,thistypeofseriousreactionto an anestheticisveryrare.Butmanyreactionsto medicinesarentsounusual.Researchersknow thatgeneticvariationscancausesomecommon medicinestohavedangeroussideeffects.For example,somepeoplewhotakethecoloncancer drugCamptosar(alsoknownasirinotecan)can developdiarrheaandalifethreateninginfection iftheyhaveavariantformofthegeneforthe proteinthatmetabolizesCamptosar. Geneticvariationscanalsocausedrugsto havelittleeffectatall.Forexample,insome people,
Didyouknowthatmedicinesworkliketheyre supposedtoinfewerthanhalfofthepeoplewho takethem?Geneticdifferencesamongpeople areonereason.
painmedicinescontainingcodeine,likeTylenol withCodeineElixir,offernoreliefbecausetheir bodiesbreakitdowninanunusualway.
Theuseofgeneticinformationtopredict how peoplewillrespondtomedicinesiscalled pharmacogenetics.Theultimategoalofthiseld ofstudyistocustomizetreatmentsbasedonan individualsgenes. Withthiskindofapproach,everypatient wontbetreatedthesame,becausedoctorswill havethemoleculartoolstoknowaheadoftime whichdrug,andhowmuchofit,toprescribe orwhethertoprescribeitatall.
TheHealingPowerofDNA
Pharmacogeneticsisadvancingquicklysincesci entistshavealotofnewinformationfromthe HumanGenomeProjectandnewcomputertools thathelpthemanalyzetheinformation.Onedis easeforwhichprogresshasbeenrapidiscancer. Considerthefactthatcancerisoftentreated withachemotherapycocktail,acombination of severaldifferentmedicines.Eachofthedrugs inthemixtureinteractswithdifferentproteins thatcontrolhowwellthatparticulardrugworks andhowquicklyitismetabolizedinthebody. Whatsmore,eachdrugmayhaveitsownsetof unpleasantevenpotentiallylifethreatening sideeffects. Forthesereasons,individuallytargeted,gene basedprescriptionsforchemotherapymayoffer a realbenettopeoplewithcancer. Currently,chemotherapycuresabout80per centofthechildrenwhohavebeendiagnosed withacutelymphoblasticleukemia,themost
Pharmacogeneticresearchershavediscovered thatagenetestcanpredictwhichchildrenwith acutelymphoblasticleukemiawillbecuredby chemotherapy.
commonchildhoodcancer.Theremaining20 percentareatriskofthecancercomingback. MaryRelling,aresearchclinicalpharmacist at St.JudeChildrensResearchHospitalin Memphis,Tennessee,discoveredthatvariations in twogenescanpredictwhichpatientswith acutelymphoblasticleukemiaarelikelytobe curedbychemotherapy.Herresearchteamalso identiedmorethan100genesexpressedonlyin cancercellsthatcanbeusedtopredictresistance tochemotherapydrugs. Bytakingpatientandcancercellgeneticpro lesintoaccount,Rellingsays,researcherscan developmoreeffectivetreatmentsforthedisease.
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Geneticvariation produces different i ndividualresponsesto the bloodthinningdrug Coumadin.Agenetic testcouldleadtomore accuratedoses.
Otherpharmaco geneticscientistsare studyingtheeffectsof genevariantsonpatientsresponsestodrugsused totreatAIDS,allergies,infections,asthma,heart disordersandmanyotherconditions. Forexample,researchersrecentlyidentied twodifferentgeneticvariantsthatplayacentral roleindeterminingthebodysresponseto Coumadin(alsoknownaswarfarin),awidely prescribedmedicinegiventopeoplewhoareat riskforbloodclotsorheartattacks.Although 2millionAmericanstakethisbloodthinning drugeveryday,itisverydifculttoadminister, sinceitseffectsvarywidelyindifferentpeople
whoaretakingthesamedose.Givingtheright doseisessential,becausetoomuchCoumadin cancauseexcessivebleeding,whiletoolittlecan allowbloodclotstoform. AllanRettie,amedicinalchemistatthe UniversityofWashingtoninSeattle,discovered thatgeneticvariationamongpeopleinuences theactivityofaproteininthebloodthatis Coumadinsmoleculartarget.Heandothersci entistsarenowtryingtotranslatethesendings intoagenetictestthatcouldhelpdoctorspredict whatdoseofCoumadinisappropriatebasedon eachpatientsDNAprole.
GenesCanDoThat?
Didyouknowthat,inadditionto traitsyoucanseelikehaircolor andphysique,genesalsocon tributetohowwebehave?Itmay comeasasurprisethatmany researchersareansweringbasic questionsaboutthegeneticsof behaviorbystudyinginsects. Forexample,GeneRobinson, anentomologistattheUniversity ofIllinoisatUrbanaChampaign, workswithhoneybees.Robinsonsaysthatifyou lookathoneybeesintheirnaturalhiveenviron ment,youllquicklyseethattheyarevery outgoing.Infact,accordingtoRobinson,honey beescantsurvivewithoutthesocialstructureof theircommunitywithinthehive. Thischaracteristicmakesthemaperfectspecies inwhichtostudythegeneticsofbehavior. Whatsparticularlyinterestingaboutbeesis thatratherthanbeingstuckinaparticularjob, theychangejobsaccordingtothehivesneeds. Robinsonhasidentiedcertaingeneswhose activitychangesduringajobshift,suggesting thattheinsectsenvironmenthelpstoshapetheir geneexpression. Researcherswhoarebeginningtounderstand theseconnectionsareworkinginabrandnew eldofinvestigationnamedbyRobinsonhimself: sociogenomics. Whatdoesallofthismeanforhumans,you wonder?Itunderscoresthefactthat,farfrom beingsetinstone,ourgenomesareinuenced bybothheredityandenvironment,netunedand sculptedbyoursociallifeandthethingswedo everyday.
ZACHARYHUANG,HTTP://CYBERBEE.MSU.EDU
Honeybeesaresocial animalsandtheywork togethertokeeptheir hivehealthy.Theforager bee(ontheleft)isabout amontholdandhunts forfood.The14dayold undertakerbee(onthe right)removesdeadbees from thehive.
CauseandEffect
Whatmoredoweneedtoknowabouthow genesshapewhoweareandwhatwebecome? Alot,saysHarvardsRichardLewontin,who warnedagainstoversimplifyingtheroleofgenes inhealthinhis2001book,TheTripleHelix. Lewontinsmainpointisthatcontextplaysan enormousroleindetermininghoworganisms growanddevelop,andwhatdiseasestheyget. A uniquecombinationofgeneticandenvironmen tal factors,whichinteractinawaythatisveryhard topredict,determineswhateachpersonislike. Veryfew,ifany,scientistswouldarguewith this.Whetherageneisexpressed,andeven whetherthemRNAtranscriptgetstranslated into aprotein,dependsontheenvironment. Few diseasesmostofwhichareveryrare arecausedcompletelybyamutatedgene. Inmostcases,gettingoravoidingadisease dependsnotjustongenesbutonthingswithin yourcontrol,suchasdiet,exerciseandwhether ornotyousmoke. Itwillbemanyyearsbeforescientistsclearly understandthedetailedmeaningofourDNA languageandhowitinteractswiththeenviron mentinwhichwelive.Still,itsagreatideato ndoutasmuchasyoucanaboutyourfamilys healthhistory.Didanyofyourrelativeshave diabetes?Dopeopleinyourfamilytreehave cancerorheartdisease? Keepinmindthatdiseasessuchastheseare relativelycommon,soitsprettylikelythatatleast onerelativewillhaveoneofthem.Butifheart disease,diabetesorparticulartypesofcancer runinyourfamily,especiallyifalotofyour relativesgettheconditionwhentheyarefairly young,youmaywanttotalkwithyourdoctor aboutyourownriskfordevelopingthedisease. In2005,theU.S.SurgeonGeneraldeveloped a Webbasedtoolfororganizingfamilyhealth information.CalledMyFamilyHealthPortrait (seehttp://www.hhs.gov/familyhistory),thistool arrangesinformationintoaprintoutthatyoucan carrytothedoctorsofce.Theinformationcan helpyouandyourdoctordetermineyourrisks forvariousconditions. Ifyoudodiscoverthatyouareathigherthan usualriskforadiseaselikebreastcancerorheart disease,youmaybeabletopreventthedisease,or delayitsonset,byalteringyourdiet,exercising moreormakingotherlifestylechanges.Youmay alsobeabletotakeadvantageofscreeningtests likemammograms(breastXraysthatdetectsigns ofcancer)colonoscopies(imagingtestsforcolon cancer)orbloodsugartestsfordiabetes. Screeningtestscancatchdiseasesearly,when treatmentismostsuccessful.
Knowingaboutdiseases thatruninyourfamilycan helpyouguardagainst illnessinthefuture.
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Resistancetoantimalarial drugslikechloroquineis widespreadthroughout muchofAfricaandother partsof thedeveloping world where malaria transmission is high.
CENTERSFORDISEASECONTROL AND PREVENTION
Countrieswithmalariathat isresistanttochloroquine Countrieswithmalariathat issensitivetochloroquine
Usvs. Them
Manyscientistsfocusonhumangenes,mostof whichhavecounterpartsinthegenomesof modelorganisms.However,inthecaseofinfec tionscausedbymicroorganisms,understanding howthegenomesofbacteria,virusesandpara sitesdifferfromoursisaveryimportantareaof healthresearch. Mostofthemedicineswetaketotreatinfec tionsbybacteriaandviruseshavecomefrom scientistssearchformolecularweakpointsin thesetinyorganisms.AsmentionedinChapter1, forexample,someantibioticskillbacteriaby disarmingtheirproteinmakingribosomes.
Sowhydonttheykillhumancells,too?The answeristhathumanandbacterialribosomesare different.Genomesequencingisapowerfultool foridentifyingdifferencesthatmightbepromis ingtargetsfornewdrugs. Comparinggeneticsequencesinorganisms thatareresistantandnonresistanttodrugscan revealnewapproachestoghtingresistance. Drugresistanceisaworldwideproblemfora numberofdiseases,includingmalaria. Althoughresearchershavedevelopedseveral differenttypesofmedicinestotreatthisdis easecausedbyparasitescarriedbymosquitoes, notbyabacteriumoravirusmalariaisram pant,especiallyinthedevelopingworld.
GENETICS AND YOU:
EatLess,LiveLonger?
thatbyrestrictingthe formationofextraDNA, sirtuinskeeptheyeast young. Notsofast,sayother scientistslikegeneticist StanleyFieldsofthe UniversityofWashington.Hisexperiments haveturnedupother,unrelatedgenes linkedtolifespaninyeast.Hearguesthat whilecalorierestrictionistheonlyinter ventionthathasbeenshowntoextend lifespaninawiderangeoforganisms, includingmammals,theaccumulationof extraDNAdoesnotalwaysappeartoplay aroleinthisprocess. Whatsthenalanswer,youask?Its probablyabitofboth. Moleculeslikesirtuins,whichare involvedincellularmetabolism,maypro tectcellsagainsttheharmfuleffectsof stress,extendinglifespan.Othermole culesthataffectdifferentaspectsofcell healthmaybejustasimportant. Lifespanincomplex,multicellular organismslikepeopleisaffectedbymany differentfactors,mostofwhichweknow verylittleabout.Forsure,understanding moreaboutthesemysterymolecules couldhaveaconsiderablebenet perhapsprovidingyouachancetoadd yearstoyourlifewithoutstarving!
ouldyouconsumeanex tremelylowcaloriedietif it
meantyouwouldlive longer?
Thekindofdietweretalkingabout
isntjustcuttingbackhereandthere.It involvesseverelyreducingcalorieintake toabout60percentofwhatwenor mallyeat,enoughtomakemostpeople ravenouslyhungry. A19thcenturyFrenchdoctor, MauriceGueniot,thoughtthetradeoff wouldbeworthit.Throughouthisadult life,heateverylittle.Hediedattheripe oldageof102! Later,inthe1930s,researchers followeduponthisobservationby showingthatratsonadietcontaining 20percentindigestiblebercalories thatcantbeusedlivedmuchlonger thantheirnormallyfedpeers. Intriguedbythehealthconnection, scientistsarecontinuingtoinvestigate potentiallinksbetweendietandaging, andgeneticstudiesarestartingtoturn upsomeclues. Forexample,geneticistDavidSinclair ofHarvardMedicalSchoolhasfoundthat proteinsknownassirtuinsmaybeableto stallaging.Asyeastcellsage,theyaccu mulateextraDNA,whicheventuallykills them.Sinclairdiscoveredthatsirtuins becomemoreactiveinyeastcellsthat areonalownutrientdiet.Hereasons
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Thisispartly becausenotallpeople haveaccesstotreat ment,ortosimple preventivemeasureslike bednets,whichprotect

CDC/JAMESGATHANY
GangWarfare
Didyouknowthatscientistsareusinggeneticsto breakupgangsofmicrobes,thatis?These gangs,knownasbiolms,arelayersofslimethat developnaturallywhenbacteriacongregateon surfaceslikestone,metalandwood.Oronyour teeth:yuck! Biolmsgrowinallsortsofconditions.For example,onebiolmknownasdesertvarnish thrivesonrocks,canyonwallsor,sometimes, entiremountainranges,leavingareddishor othercoloredstain.Itisthoughtthatpetroglyphs leftonbouldersandcavewallsbyearlydesert dwellerswereoftenformedbyscrapingthrough thecoatingofdesertvarnishformationswitha hardobject. Sometimes,biolmsperformhelpfulfunc tions.Oneofthebestexamplesoftheuseof biolmstosolveanimportantproblemisinthe cleaningofwastewater.
sleepingpeoplefrom mosquitobites.But anotherproblemisthe

Mosquitoesspread malariabypickingup parasitesfrombloodand spreadingthemtothe nextpersontheybite. Resistancespreadsthis way,too.
malariaparasiteitself,whichhasrapidlyevolved waystoavoidtheeffectsofantimalarialdrugs. Scientistsaretryingtocounterthisprocessby studyingmicrobialgeneticinformation.Inthe caseofmalaria,geneticistslikeDyannWirthof theHarvardSchoolofPublicHealthcomparethe genomesofdrugresistantparasitesandthose thatcanstillbekilledbyantimalarialmedicines. Wirthsresearchsuggeststhatitshouldbe possibletodevelopasimple,inexpensivegenetic testthatcouldbegiventopeoplewithmalaria, anywhereintheworld.Thistestwouldidentify drugsthatarelikelytobemosteffective andhelpdecreasetherateatwhich parasitesbecomeresistanttotheanti malarialmedicineswealreadyhave.
Biolms,liketheoneshowninthis uorescentmicroscopicphoto,are bacterialcommunities.
P.SINGHANDE.PETERGREENBERG
BonnieBassler(right) usesglowinthedark bacteria to study the geneticsofbiolms.
DENISEAPPLEWHITE
Butbiolmscanbequiteharmful,con tributingtoawiderangeofserioushealth problemsincludingcholera,tuberculosis,cystic brosisandfoodpoisoning.Theyalsounderlie manyconditionsthatarenotlifethreatening but arenonethelesstroublesome,liketooth decay and earinfections. Bacteriaformbiolmsasasurvivalmeasure. Bylivinginbiggroupsratherthaninisolation, theorganismsareabletosharenutrientsand conserveenergy.Howdotheydoit? Abiolmisnotjustalooseclumpofcells itsahighlysophisticatedstructure.Asinany community,theindividualsinbiolmscommu nicatewitheachother. Beyondthat,manyaspectsofbiolmsare poorlyunderstood.BacterialgeneticistBonnie BasslerofPrincetonUniversityinNewJerseyis workingtounderstandbiolmsbetter,withthe
goalofbeingabletousethisknowledgetobreak upbacterialgangmeetings. Basslersresearchsubjectshaveadenite visualappeal.Theyglowinthedark,butonly whentheyarepartofagroup.Thebiolumines cence,astheglowiscalled,arisesfromchemical reactionstakingplacewithinthebiolm.Itpro videsawayforthebacteriatotalktoeachother, estimatethepopulationsizeoftheircommunity anddistinguishthemselvesfromothertypesof microorganisms. Throughherstudies,Basslerhasidentieda setofmoleculesthatbiolmformingmicroor ganismsusetopassmessagestoeachother.By devisinggeneticallybasedmethodstocutoff the chatter,Basslerreasons,shemaybeableto causebacterialcommunitiestofallapart.This approachwouldprovideawholenewwaytotreat healthproblemslinkedtoharmfulbiolms.
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TheToolsofGenetics:MathematicsandMedicine
Whatifpublichealthofcialshadascriptfor whattodointhefaceofaninfectiousdisease outbreakthathadneverbeenseenbefore?One thingthatwouldhelpthemprepareforthissort ofscenarioistheabilitytoknow,aheadoftime, howanepidemicdevelopsandspreads. Towardthisgoal,somescientistsareusing mathematicaltoolstocreatesimulations,or models,ofinfectiousdiseaseoutbreaks.They can thenusethemodelstotesttheeffectsof variousinterventionstrategies.Partofthework involvespluggingingeneticinformationabout howinfectiousorganismsevolveovertime and howfasttheychangeastheyinteractwith humanpopulations. Since2005,theModelsofInfectiousDisease AgentStudy(MIDAS),ateamofbiologists,com puterscientists,statisticians,mathematicians, socialscientistsandothers,hasbeenmodeling a upandemicahuge,globalepidemic. Initially,themodelsfocusedonavian inuenza,atypeofdiseaseoccurringnaturally amongwildbirds.Atthetime,healthexperts worldwideworriedthatthevirusgeneticmate rialcouldmutate,makingitmucheasierforthe socalledbirdutopassbetweenhumans. Tosimulatethepotentialdiseasespread,the scientistswrotecomputerprogramsthatincorpo ratedinformationaboutthebirduvirusand actualcommunities.Includingdetailsabout peoplenotjusttheiragesandgenders,but alsowheretheylive,workorgotoschoollet theresearcherscreateasyntheticpopulationthat couldmirrorhowarealonemightgetsickand spreaddisease. Thescientistsrantheprogramsonlarge computerstoseehowtheucouldspreadwith andwithoutdifferentinterventions.Theresults indicatedthattosuccessfullycontainanepidemic, healthofcialswouldneedtondtherstu casesfastandimplementacombinationofpublic healthmeasuresveryquickly.
Computersimulationsarehelpingscientistsunderstandhowinfectious diseasesspread.
GotIt?
Discusshowmathematics canhelpscientistsaskques tionsabouthumanhealth.
Wouldyoucontributea sampleofyourDNAfor
ThisearlyworkhelpedMIDASscientists developsimilarmodelsofH1N1orswineu, therstactualpandemicustrainsince1968. StartinginApril2009,theygatheredincoming publichealthdatatosimulatethepotential spreadofthisglobalu,identifythegroupsmost likelytogetsickandevaluatetheusefulnessof differentpublichealthmeasures,suchasvaccina tionandquarantine.Theirmodelssuggestedthat vaccinatingschoolchildrenearlyinanoutbreak couldreduceoveralldiseasespreadandthat peopleatriskofseriouscomplicationsshould begivenantiviralmedicationstotakeatthe rstsignsofillness.
Duringboththebirdandswineumodel ingefforts,theMIDASscientistsworked closelywithpublichealthofcialstoaddress specicquestions.TheanswersinformedU.S. pandemicupreparednessplanning. Inuenza,however,isnottheonlyinfec tiousdiseasemakingpeoplesick.MIDAS scientistsarealsomodelingothermajorhealth threats,includingcholera,denguefever, malaria,tuberculosisandmethicillinresistant
geneticresearchoncommon diseaseslikeheartdisease, depressionorcancer evenifyoudidnthaveany of thesehealthproblems? Whyorwhynot?
Drugsworkliketheyre s upposedtoinonlyhalfthe peoplewhotakethem,so scientistsaretryingtomake personalizedmedicinesthat workverywellinanindivid ualbecausetheymatchhis orhergeneticmakeup.Are thereeconomic,socialor otherissuesthatthedevelop mentofsuchmedicines mightraise?
Staphylococcusaureus (MRSA).
CHAPTER5
21stCenturyGenetics
edicinehasevolvedtremendouslysince theearliesthumancivilizations,when
practiceslikeopeningtheveinofasickperson anddrainingoffquartsofpreciousblood! Later,intheRenaissanceperiodofthe15th and16thcenturies,scholarscenteredonanatomy. Oneofthem,theItalianartistinventorLeonardo daVinci,createdbeautifulandaccurate
thediagnosisandtreatmentofdiseasewerefar fromscientic.Medievalmedicine,forexample, reliedheavilyonsupernaturalbeliefs.Limited scienticknowledgeledtoseeminglybizarre
RAREBOOKANDSPECIALCOLLECTIONSDIVISION,LIBRARYOFCONGRESS
Bytheendofthe16th century,anatomywasa commonfocusforscien ticscholars.
TheNewGenetics I 21stCenturyGenetics 75
illustrationsofthehumanbody.Hiswork andthatofotherscientistsofhisday focusedonthepracticeofdissection, providingneverbeforeseendetailsof
19thcenturyscientists discover dthatbacteria e cancausedisease.Bacillus anthracis (left)causesanthrax andVibriocholerae (below) causescholera.

PAUL KEIM (ANTHRAX),
thebodysarchitectureoflimbs,joints, muscles,nervesandvessels. Modernmedicinegotitsrealstart duringthe19thcentury,afterthemicro scopewasinvented.Medicalschoolsubjectslike physiology,pathologyandmicrobiologywere born.Duringthistime,scientistsdiscoveredthat bacterianotevilspiritsorotherimaginary entitiescausedhumandiseaseslikecholera, anthraxandtuberculosis. The birth of modern genetics, which occurredinthe20thcentury,acceleratedthe study of all these areas of science. Now, at the start of the 21st century, opportunities haveneverbeengreaterforturningscientic knowledgeintobetterhealthforall. Weoftentakeforgrantedtheamazing complexityof thehumanbody.Withouteven thinking,wesweattomaintainbodytempera ture,gethungrywhenweneedenergyandfeel tiredwhenweneedtosleep. Theseseeminglysimpleactionsrequirea sophisticatedcoordinationof manydifferent organsandthemillionsof moleculesthatwork togetherinsidethem.Thousandsof networks of interactinggenesunderlietheseactionsin our bodies.Butthesesystemsareprovingto havefarmoreuctuationthanscientists originallysuspected. Oneoftodayschallengesistomapthe actionsandinteractionsofallthesemolecules, a focusoftheneweldcalledsystems biology. Geneticandgenomic researchishelpingscien tiststacklemany questionsinthis area.Bybuilding modelsof cells, tissuesand organsinaction, scientistshopeto learnhowthese complex,dynamic systemswork. Researchersneedtoknow thesebasicsinordertounderstandhowthe systemsfail,whendisease strikes.Anessential toolinthisresearchisthecomputer.
CDC/ WILLIAM A. CLARK (CHOLERA)
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NoLab?NoProblem!
Thosewhoworkattheintersection ofcomputerscienceandbiology oftencombineandanalyzedata frommanydifferentsources,look ingforinformativepatterns. AndreyRzhetskyofthe University of Chicago is one of these people. Through an approach known as knowledge engineering,Rzhetskyandhisteam writecomputerprogramsthatscanthecontents of thousandsof publishedscienticpapers. The knowledgeminingtooltheyuse,called GeneWays,focusesmainlyonresearchliterature aboutchangesingenesandproteins. Theprogramrstscansscienticpapers usingpresetsearchterms,muchlikeaGoogle searchoftheWeb.Next,itevaluatesthesearch resultsandmakessuretheydontoverlap.For example,ifamoleculehas16differentnames indifferentpapers,theprogramsimpliesitto justone.
GreenFluorescentProtein
Heresaninterestingnews ash:Glowinthedark jellysh evolutionizes r geneticresearch! Althoughitmay sound bizarre,theclaim istrue. A jellyshproteinis essentialto modern cell biologyexperiments thattrackthemovements, quantities andinteractions of themillionsof roteins p insidecells. Calledgreenuorescentprotein,orGFP,this naturalproteinisfoundinspecicpartsofthe jellysh.Thosepartsglowbecausetheprotein absorbsenergyfromlightintheenvironment and thenproducesadifferentcoloroflight. Scientistsdontreallyknowhowandwhyjelly shusetheirglow.Theydoknowthatjellysh dontashateachotherinthedark,nordothey glowcontinuously.Andtheglowisrarelyseenin undisturbedanimals. Takenoutofthejellysh,GFPhasplayeda majorroleinadvancingthestudyofgenesand theproteinstheyencode.ThestoryofhowGFP
CATHERINEFERNANDEZANDJERRYCOYNE
.Fruityspermcellsglowbrightgreenwhenthey
expressthegeneforgreenuorescentprotein.
Finally,afterapplyingspecicrules,sortof likebiologicalgrammar,thecomputerprogram identiesassociations,whicharepossiblelinks betweenmolecules.Theinformationthengoesto adatabasethatRzhetskyandotherscientistsuse tobuildlargenetworksofmolecularinteractions. RzhetskyandhisteamusedGeneWaystoiden tifyriskgenesforAlzheimersdisease,acomplex conditionthoughttobecausedbymanyfactors. In analyzingthedata,Rzhetskyfoundimportant nodes,moleculesthatplaykeyrolesinthedis easegenenetworkthatGeneWaysmodeled. Thesepredictedmolecularinteractionswere laterconrmedbyotherresearchersworkingina lab,underscoringthevalueofcomputermodel ingasawaytolearnmoreaboutthemolecular basisofdisease.
. AndreyRzhetskyusesthecomputerprogram
GeneWaystolocateimportanthubsofactivity (largespheres)withinmassivegenenetworks. Thisparticularnetworkrepresentsembryonic developmentalpathwaysinafruity.
ANDREYRZHETSKYANDKEVINP.WHITE
becamearesearchtoolbeganin1992,when MartinChaleofColumbiaUniversityshowed thatthegenethatmakesGFPproducedauores centproteinwhenitwasremovedfromthe jellyshgenomeandtransferredtothecellsof otherorganisms(seepage38).Chale,adevel opmentalbiologist,rstputthegeneinto bacteriaandroundworms,creatingglowing versionsoftheseanimals. Sincethen,researchershavetransferredthe GFPgeneintomanyotherorganisms,including fruities,miceandrabbitsandevenhuman cellsgrowinginalabdish.Recently,scientists
usedtheGFPgenetocreategreenglowing zebrash.Althoughtheshwerecreatedfor the purposeofscienticresearch,theyve also becomeanexoticspeciesforhome aquariums. ThankstoGFPandrelatedtechnologies, scientistscannowviewlivingcellsandtheir constantlymovingcontents.GFPisalsoused in diagnostictestsfordrugs,foods,herbicides andhazardouschemicals. Chaleandtwootherscientistsreceivedthe 2008NobelPrizeinchemistryforthediscovery anddevelopmentof GFP.
MARTINCHALFIE
.Scientistsengineered
thisexperimentalworm toexpressgreenuo rescentproteinintwo of itsnervecells(bright greenspots).
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Anotherlaw,theGeneticInformation NondiscriminationAct,orGINA,prohibits discriminationinhealthcoverageandemploy mentbasedongeneticinformation. Itsimportanttorealizethat,inmostcases, geneticinformationcannotofferdenitiveproof thatadiseasewilloccur.Butifyouhaveavery strongfamilyhistoryofbreastcancer,forexam ple,theremaybeafaultygeneinyourfamilythat
HardQuestions
Whilethetaskofsortingthroughlargevolumes ofgenomicdataremainsacentralchallengein modernbiologyandmedicine,oneoftheknotti estdilemmastoemergefromthisresearchisa socialandethicalone.Thatis,howshouldpeople makeuseofinformationabouttheirowngenes? Becausegeneticinformationisbothpowerful andincrediblypersonal,therearedeepsocietal concernsregardingitsuse.Theseconcerns includethepotentialfordiscriminationonthe basisofapersonsriskofdiseaseorsusceptibility totoxicityfromanenvironmentalchemical. Somelawsarealreadyinplacetoprotect individualsfromthemisuseoftheirgenetic information.Whenyouvisitanewdoctor,nurse practitioner,ordentist,youllbeaskedtoread andsignaformthatoutlinesyourmedical privacyrightsundertheHealthInsurance PortabilityandAccountabilityAct,orHIPAA. Thislawprotectsyourgeneticandotherpersonal healthinformationfrombeingusedorshared withoutyourknowledge.
increasesyourriskofgettingthedisease. Doctorscannowtestfortwoknowngene variantsassociatedwithinheritedformsofbreast cancer,BRCA1andBRCA2.Ifyoucarryeitherof thesegenevariants,yourlifetimeriskofgetting breastcancerissignicantlyhigherthanitwould beforsomeonewithouteithervariant.Butsome peoplewhohaveBRCAgenevariantsneverget breastcancer. Onlyabout5percentofallbreastcancer can betracedtoaknown,inheritedgene variant.Sincesomanybreastcancersarenot linkedtoBRCA1orBRCA2,genetictestingfor thesevariantsisirrelevantforthevastmajority of peoplewhodonothaveafamilyhistoryof breastcancer. Butletssayyoudohavearelativewhotested positiveforBRCA1or2.Shouldyougettested,too? Adifcultquestion,forsure,butconsider this:Knowingaboutthisriskaheadoftime mightsaveyourlife.Forexample,youmight wanttobegingettingmammogramsorother screeningtestsatanearlyage.Ifcancerisfound
veryearly,itisusuallymoretreatable,andthe oddsforacurearemuchhigher. Currently,diagnosticlaboratoriesacrossthe UnitedStatesoffergenetictestsforalmost2,000 disorders.Someofthesetestsdetect problems withentirechromosomes,notjust individual genes.Perhapsthemostwellknownexampleof a chromosomeproblemisDown syndrome,in whichcellshaveanextracopyofchromosome21 (seepage11). Mostgeneticdiseasesarentcausedbya chromosomeabnormality,orevenbyonegene variant.Cysticbrosis,forexample,isduetoa faultygene,butmorethan30differentvariantsof
thisgenecancausethedisease,andthoseare justtheonesresearchersknowabout! Howcantherebe30differentvariantsof one gene?Rememberthatageneisalong DNAsequence,consistingofhundredsof nucleotides.Achangeinoneofthose nucleotidesproducesonevariant,achangein anotherproducesanothervariant,andsoon. Becausetherearesomanypossibilities,its hardtotellwhetherapersonhasavariant formofthecysticbrosisgene.Sothestandard geneticscreeningtestforthisdiseasescansfor allofthemorethan30variantsknowntocause cysticbrosis.
.Scientistsaredevelopinggeneticteststhatwill
helpdoctorsdiagnoseandtreatdiseases.
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Doctorsusuallyorderagenetictestonlyif a personhasastrongfamilyhistoryofadisease. Butevenso,decidingtohavesuchatestisnot a simplechoice.Thinkaboutwhatyouwoulddo withtheinformation. Onethingyoumightconsideriswhetheryou
Asateenoryoungadult,wouldyouwantto knowthatyoudgetaserious,perhapsincurable, diseaselaterinlife? Patientsanddoctorsfacethesetoughissues everyday.Evenyearsfromnow,when researchersknowmoreaboutthemolecular rootsofdisease,genetictestswillrarelyprovide easyanswers.Inmostcases,theywonteven provideyesornoanswers. Rather,muchlikeacholesteroltest,theywill predictwhetherapersonsriskofgettingadisease isrelativelyhigh,loworsomewhereinbetween. Thisisbecausemanyfactorsbesidesgenes,includ inglifestylechoicessuchasdietandexercise,also playaroleindeterminingyourhealth.
could dosomethingwithwhatyoulearnfrom
a genetictest. Youvealreadyreadaboutwhatyoucould do ifyoudiscoveredthatyouwereathighrisk for developingbreastcancer.Butwhatabouta conditionthatshowsupinmiddleagedorolder peopleoroneforwhichthereiscurrently no cure?
GoodAdvice
Since the story of genes and health is so complicatedandislikelytostaythatway forawhile,itis veryimportanttoconsider geneticinformationincontext.Healthcare professionalsknownasgeneticcounselors canbeabig helptopeoplewhoarethinking about gettingagenetictest. Asaprofession,geneticcounselinghas beenaroundsincethemid1900s.However, onlyafewspecialtyclinicsofferedcounseling atthattime.Now,geneticcounselingismuch morewidely available.
GENETICS AND YOU:
CrimeFightingDNA
bloodorskincells),DNAforensictech nologycanidentifyvictimsinanatural disaster,suchastheDecember2004 tsunamithatravagedIndonesiaand otherAsian ountries.DNAngerprint c ingcan alsomatchatransplantpatient toanorgandonororestablishpaternity andotherfamilyrelationships. Geneticngerprintingisnotlimited topeople.Itcanndsmallbutpoten tiallydeadlytracesofdiseasecausing bacteriainfoodorwater,determine whetheranexpensivehorsewassired byaKentuckyDerbywinnerorgure outwhetherapuppysparentswere rstcousins. DNAngerprintingtechniqueswork bylookingfordifferencesamonggene sequencesthatareknowntovary betweenpeople(orbetweenindividuals fromanyspecies).Scientistsreadthe sequenceinadozenorsoplacesto createamolecularprole.Thechances of amolecularngerprintbeingthe sameintwopeopleortwoorganisms are vanishinglysmall.
ikeyourthumbprint,yourgenes areunique,unlessyouhavean identicaltwin.Assuch,DNA
ngerprintinghasbecomeapowerful crimeghtingtool.DNAforensicsis a fastgrowingspecialtythathasappli cationsbeyondputtingcriminals behind bars. Inadditiontoidentifyingsuspects wholeavetracesatthesceneofacrime (forexample,strandsofhair,dropsof
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Todaysgeneticcounselorshavegonethrough arigoroustrainingprocessinwhichtheyearn a mastersdegreeandlearngenetics,medicine, laboratoryprocedures,counseling,socialwork andethics.Geneticcounselorsdotheirwork in manydifferentsettings,includinghospitals, privateclinics,governmentagenciesanduni versity laboratories. Aninterestingaspectofthejobisthatgenetic counselorsaddresstheneedsofentirefamilies, ratherthanjustindividualpatients.Toevaluate geneticriskanditspotentialconsequences,these professionalsgatherafamilymedicalhistory coveringgenerations.
Genetics,Business,andtheLaw
Canascientistclaimrightstoagenethathedis coveredinwormsandthathasanearlyidentical counterpartinhumans? Isapersonwhogaveabloodortissuesample entitledtoprotsfromacompanythatdevelops adrugbasedongeneticinformationinhersam ple,ortoalifetimesupplyofthedrug? Canabloodortissuesamplethatwasdonated foronepurposebeusedforanentirelydifferent studyseveralyearslater,withoutaskingthedonor ifthatsOK? These and other issues are hotly debated in ethics and legal circles. Many of the most
FieldStudy
Thewordmostoftenusedtoreferto applicationsofgeneticresearch,espe ciallythoseleadingtoproductsfor humanuse,isbiotechnology.It involvestechniquesthatuseliving organismsorsubstancesderived fromthoseorganismsforvarious practicalpurposes,suchasmakinga biologicalproduct. Onemajorapplicationofbiotech nologyisinagriculture.Actually,thisis hardlynew:Humanityhasengagedin agriculturalbiotechnologyfor10,000 yearsormore.Manytraditionalfarming practices,fromplantbreedingtoanimal husbandry,arereallyformsofbiotech nology. Butintodaysagriculturalindustry, biotechnologygenerallymeanstheuse ofmolecularbiology,recombinantDNA technology,cloningandotherrecent scienticapproachestoproduceplants andanimalswithnewtraits. Thisusuallyinvolvestransferringgeneticmate rialfromonekindoforganismintoanother.Using thesametechniquesthatweredevelopedforput tinggenesintoanimalsforresearchpurposes, scientistscancreatecropplantswithdesirable traits,suchasimprovedavororbetterresistance toinsectpests.Transferringspecicgenesis fasterandmoreefcientthantraditionalbreeding approaches. TheUnitedStatesishometofarmoregeneti callymodiedcropsthananywhereelseinthe world.In2009,85percentofthecountryscorn, 88 percentofitscottonand91percentofitssoy beanswerecultivatedfromseedsgenetically modiedtoresistplantpestsandcertainherbi cidesusedtocontrolweeds. Manybelievethatagriculturalbiotechnologyis animportantdriverforimprovingworldhealth. Theysaythatgeneticmodicationsmaybethe onlyhopeforpestravagedcrops,suchas bananas,thatareessentialtotheeconomiesof poorcountries.Thecreationofedibleplantsthat containmedicine,serveasaformofvaccination
controversialtopicshavetodowiththeideaof patentinglifeforms. Traditionally,whenaninventorcomesup with anewideaandwantstosellitwhether its aradiocontrolledtoyboatoracustomized laboratorychemicalheorshesubmitsanappli cationtotheU.S.PatentandTrademarkOfce. Byissuingpatents,theFederalGovernment givesaninventorownershipofhisorhercre ation.Patentsgiveinventorstimetooptimize theirproductsandcontrolhowtheirinventions areused,allowingthemtomakemoneyfrom theircreativity.
ordeliverextranutrientssuchastherecently developedricethatmakesvitaminAcouldalso contributein majorwaystoglobalhealth. Butoppositionfromfarmersandconsumers withinandoutsidetheUnitedStateshasclouded agriculturalbiotechnologysfuture.Someobject tothedevelopmentofplantsthatarenaturally resistanttoherbicides,partlyoutofconcernthat thetraitmightjumptoweeds,makingthem impossibletodestroy. Environmentaladvocacygroupsworrythat geneticallymodiedplantsmayimpactthefuture biodiversityofourplanetbyharmingbenecial insectsandpossiblyotherorganisms.However, theU.S.EnvironmentalProtectionAgencyhas statedthatthereisnoevidencetodatethat indicatesthatbiotechcropshaveanyadverse effectsonnontargetedwildlife,plantsor benecialinsects. Ofcourse,carefuleldtestsofnewlycreated, geneticallymodiedplantsandanimalsare essentialtobesurethattheycausenoharmto otherorganismsortotheenvironment.
.Biotechnologyhelpsagriculturalscientistscreate
cropswithdesiredtraits.Themajorityofcotton andsoybeansintheUnitedStatesaregrownwith geneticallymodiedseedsthatresistvirusesand otherplantpests.
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However,nobodyinventedagene,anaturally occurringchemicaloraprotein,sowhyshould a personoracompanybeabletoownitand controlitsdestinyinthemarketplace? PatentlawsintheUnitedStatesandEurope prohibitanyonefrompatentingageneasitexists inthehumanbody.Butpatentshavebeenissued forspecicmedicalusesofgeneticinformation.
Patentscanbegreatforbusiness,andtheycan helpmaketheresultsofresearchwidelyavailable throughcommercialventures,buttheyalsohave thepotentialtoslowresearchbecausepatent holderscontrolhowinformationrelatedtothe patentisused.Forexample,researcherswhowish tousepatentedgeneticinformationmayneedto acquirealicenserst.Thiscanbetimeconsuming andexpensive. Concernedaboutpossiblenegativeeffects of patentinggenes,theU.S.NationalInstitutes of HealthhasworkedwiththeU.S.Patentand TrademarkOfcetoestablishguidelinesforwhat kindofgeneticinformationcanbepatented.Since thisareaofmedicalresearchisanevermoving target,governmentscientists,policymakersand thecourtscontinuetoclarify patentandlicensing issuesinthehopeof keepingdatathatis valuable forresearchinthepublicdomain.
CareersinGenetics
Opportunities to be part of genetic and genomicresearchhaveneverbeengreateror moreexciting.Inadditiontostudyinghuman genes, scientists are gathering information about the genes of many other living things, from microbes that cause disease to model organisms likemiceandDrosophila,livestock and crop plants. Althoughcomputersdosomeofthework, thisavalancheofinformationhastobeanalyzed bythousandsandthousandsofhumanbrains. In additiontoidentifyinggenes,scientistsmust gureoutwhatthegenesdoandevenmore complicatedhowtheydoit. Weneedlaboratoryscientists,doctorstodo clinicalresearchandtreatpatients,geneticcoun selorstohelppeopleunderstandtheinformation intheirgenes,andlawyersandethicalspecialists whocanaddresslegalandpolicyconcernsabout theuseofgeneticinformation. Inespeciallyhighdemandarepeoplewith expertiseinmathematics,engineering,computer scienceandphysics.Theeldofbioinformatics, whichdevelopshardwareandsoftwaretostore andanalyzethehugeamountsofdatabeing generatedbylifescientists,isespeciallyshort of qualiedworkers.Asaresult,bioinformatics scientistsareinhighdemand. Manycareersingeneticsandgenomics requireadvanceddegreessuchasaPh.D.orM.D. Butpeoplewithmastersorbachelorsdegreesare alsoneededtollthousandsofrewardingjobsas geneticcounselors,researchassistantsandlab technicians. Formorecareerinformation,see http://www.ornl.gov/sci/techresources/ Human_genome/education/careers.shtmlor http://science.education.nih.gov/LifeWorks.
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TheToolsofGenetics:InformaticsandDatabases
Formostof itshistory,biologymanagedto amassitsdatamostlywiththehelpofplainold arithmetic.GregorMendeldidgeneticanalysis bysimplycountingthedifferentkindsofoff springproducedbyhispeas.Bycontrast,todays geneticresearchcreatestoomuchdataforone person,orevenascienticteam,tounderstand. Newtechnologiesareneededtomanagethis hugeamountof data. Considerthis:Genesequencingmachines canreadhundredsof thousandsofnucleotidesa day.Genechipsareevenfaster.Theinformation inGenBank,awidelyuseddatabaseof all knownDNAsequences,nowdoublesinjust 3 years.Asinglelaboratory doingcuttingedgegenetic researchcangeneratehun dredsof gigabytesof data a day,everyday.Forcompar ison,100gigabytescould holdanentireoor of jour nalsinanacademiclibrary. Howcananyonemake sense of all this information? The only way is to enlistthe aidof computersandsoftware thatcanstorethedataand makeitpos iblefor researchers s to organize, searchandanalyze it.Infact,manyof todayschallengesin
IMAGEONCOMPUTERSCREENCOURTESYOFTOMSLEZAK,
This isnotsurprisingwhenyourememberthat DNAisitselfaformofinformationstorage. Wherearegeneticandgenomicdatastored? Oneoftherstbiologicaldatabaseswascreated tostorethehugevolumeofdatafromexperi mentswiththefruityDrosophilamelanogaster. CalledFlyBase,ithasgrownintoahuge, comprehensive,internationalelectronicreposi toryforinformationonDrosophila geneticsand molecularbiology,runbyscientistsforscientists. Theinformationspansacenturysworthof publishedscienticliteratureonDrosophila
melanogaster anditsrelatives,includingtheir
completegenomesequences.
biology,fromgeneanalysistodrugdiscovery, are reallychallengesininformationtechnology.
LAWRENCELIVERMORENATIONALLABORATORY
http://www.dictybase.org/
http://www.yeastgenome.org/
http://www.wormbase.org/
http://flybase.org/
GotIt?
Doyouthinkmodernresearch toolsderivedfromgenomicsand bioinformaticswillchangethe practiceofmedicine?How?
Ifagenetictestrevealedthatyou hada1in100chanceofdevelop ingadiseaseliketype2diabetes, whichcanbepreventedwith
DatabaseslikeFlyBasearealsousefultosci entistsworkingwithotherorganisms,likemice orhumans.Aresearcherwhodiscoversanew mammaliangenemayconsultFlyBasetoseeif fruitieshaveasimilargeneandifthedatabase containshintsaboutwhatthegenedoes.Since thefunctionsofmanygenesareretainedduring evolution,knowingwhatagenedoesinone organismoftenprovidesvaluablecluesabout whatitdoesinanotherorganism,evenif the two speciesareonlydistantlyrelated. Severalothercommunitiesof researchers havecreatedtheirowndatabases,includingthose dedicatedtotheinvestigationoftheroundworm
manylaboratorystudies(Saccharomyces GenomeDatabase). Akeygoalistomakesurethatallofthese databasescantalktoeachother.Thatway, similardiscoveriesindifferentorganisms theimportant,commonthreadsofall biologycanbeidentiedquicklyand analyzedfurther. Forthisdatabasecommunicationto work,researchersindifferenteldsmust use thesametermstodescribebiological processes.Thedevelopmentanduseof such auniversalontologyacommon languageishelpingscientistsanalyzethe complexnetworkofbiologythatunderlies ourhealth.
lifestylechangeslikeeatinga healthierdietandexercisingmore, wouldyouchangeyourbehavior? Whatiftheriskwere1in10?
Howisgeneticengineeringsimilar totraditionalfarming?Howisit different?
Abiotechnologycompanyuses geneticinformationfromapatient volunteeranddevelopsaneffec tive,protablemedicine.Should thepatientknowthatheorshe waspartofthisprocess?Whyor whynot?Whatiftheresearchdid notleadtoanymedicaladvance?
Caenorhabditiselegans (WormBase),thesoil
dwellingamoebaDictyosteliumdiscoideum (DictyBase)andthestrainofyeastusedfor
88
Glossary
Aminoacid |Abuildingblockofproteins. Thereare20aminoacids,eachofwhichis coded forbythreeadjacentnucleotidesina DNA sequence. Anticipation |Thediseaseprocessinwhich symptomsshowupearlierandareincreasingly severeineachgeneration. Biolm |Aslimelayerthatdevelopsnaturally whenbacteriacongregateonsurfaces. Bioinformatics |Theeldofbiologyspecializ ingindevelopinghardwareandsoftwaretostore andanalyzethehugeamountsofdatabeing generatedbylifescientists. Biotechnology |Theindustrialuseofliving organismsorbiologicalmethodsderivedthrough basicresearch;examplesrangefromgeneticengi neeringtomakingcheeseorbread. Chromatin |Theorganizationanddensepack agingofDNAinthenucleusofcells. Chromosome |Acellularstructurecontaining genes.ChromosomesarecomposedofDNAand proteins.Humanshave23pairsofchromosomes ineachbodycell,oneofeachpairfromthe motherandtheotherfromthefather. Circadian |Pertainingtoaperiodofabout 24 hours;appliedespeciallytorhythmicbiologi calrepetitionlikethesleepwakecycle. Gene |AsegmentofaDNAmoleculethat Clone |Ingenetics,theprocessofmakingmany copiesofageneorawholeorganism.Theterm alsoreferstotheisolationandmanipulationof a gene. containsinformationformakingaproteinor, sometimes,anRNAmolecule. ComparativeGenomics |The study ofhumangeneticsbycomparisonswiththe genetics ofotherorganisms. Diploid |Havingtwocopiesofeach chromosome. DNA |Abbreviationfordeoxyribonucleicacid, themoleculethatcontainsthegeneticcodeforall lifeformsexceptforafewviruses.Itconsistsof twolong,twistedchainsmadeupof nucleotides. Eachnucleotidecontainsonebase,onephosphate molecule and the sugar molecule deoxyribose. The bases in DNA nucleotides are adenine, thymine, guanine and cytosine. DNAchip |Seemicroarray. DNApolymerase |Anenzymethatcopies DNA. Enzyme |Asubstance(oftenaprotein)that speedsup,orcatalyzes,achemicalreactionwith outbeingpermanentlyalteredorconsumed. Epigenetics |Thestudyofheritablechangesin genefunctionthatoccurwithoutachangeinthe DNAsequence. Eukaryote |Anorganismwhosecellshave a membraneboundnucleus. Exon |ADNAsequenceinagenethatcodes for ageneproduct.
TheNewGenetics I Glossary 89
Genechip |Seemicroarray. Geneexpression |Theprocessbywhich genesarerstconvertedtomessengerRNAand thento proteins. Genetics |Thescienticstudyofgenesand heredity ofhowparticularqualitiesortraits are transmittedfromparentstooffspring. Genome |Allofanorganismsgeneticmaterial. Genomics |Ascaledupversionofgenetic researchinwhichscientistscanlookatlarge numbersorallofthegenesinanorganismat the sametime.
Meiosis |Thetypeofcelldivisionthatcreates eggandspermcells. Microarray |Sometimescalledagenechipor a DNAchip.Microarraysconsistoflargenum bersofmolecules(often,butnotalways,DNA) distributedinrowsinaverysmallspace. Microarrayspermitscientiststostudygene expressionby providingasnapshotofallthe genesthatareactiveinacellataparticulartime. MicroRNA |Ashortpieceofsinglestranded RNAthatdoesnotencodeaproteinandcontrols theexpressionofgenes. Mitochondrion |Thecellspowerplant,
Haploid |Havingonecopyofeachchromo some,asinaspermoregg. Haplotype |Asetofcloselylinkedgenesor DNApolymorphismsinheritedasaunit. Histone |Atypeofproteinfoundinchromo somes;histonesattachedtoDNAresemble beads onastring. Homeobox |ADNAsequencefoundingenes involvedintheregulationofthedevelopment of animals,fungiandplants. Imprinting |Thephenomenoninwhichagene maybeexpresseddifferentlyinanoffspring dependingonwhetheritwasinheritedfrom the fatherorthemother. Intron |ADNAsequence,ortheRNAsequence transcribedfromit,thatinterruptsthesequences codingforageneproduct(exon).
supplyingtheenergytocarryoutallofthecells jobs.Eachcellcontainsupto1,000mitochon dria.Thestructurescontaintheirownsmall genomes,calledmitochondrialDNA. Mutation |AchangeinaDNAsequence. Nucleotide |AbuildingblockofDNAor RNA.Itincludesonebase,onephosphatemole culeandonesugarmolecule(deoxyribosein DNA,riboseinRNA). Nucleus |Thestructureintheeukaryoticcell containingmostofitsgeneticmaterial. Pharmacogenetics |Thestudyofhowpeo ples geneticmakeupaffectstheirresponses to medicines. Protein |Amoleculeconsistingofsubunits calledaminoacids.Proteinsarethecellsmain buildingmaterialsand domostofacellswork.
90
RecombinantDNA |HybridDNAproduced in thelaboratorybyjoiningpiecesofDNAfrom differentsources. Replication |TheprocessbywhichDNA copiesitselfinordertomakeanewgenometo passontoadaughtercell. Ribosome |Thecellstructureinwhichpro teinsaremanufactured.Mostcellscontain thousandsof ribosomes. RNA |Abbreviationforribonucleicacid,the moleculethatcarriesoutDNAsinstructionsfor makingproteins.Itconsistsofonelongchain madeupofnucleotides.Eachnucleotidecontains onebase,onephosphatemoleculeandthesugar moleculeribose.ThebasesinRNAnucleotides are adenine,uracil,guanineandcytosine. RNAinterference(RNAi) |Agenesilencing processinwhichdoublestrandedRNAstrigger thedestructionofspecicRNAs. RNApolymerase |Anenzymethattranscribes aDNAsequence,creatingmRNA. RNAsplicing |Theprocessbywhichintrons areremovedandexonsarejoinedtogether from anRNAtranscripttoproduceanmRNA molecule.
Sequencing |SometimescalledDNAsequenc ingorgenesequencing.Discoveringtheexact orderofthebuildingblocks(seenucleotides)of a particularpieceofDNA. StemCell |Acellthatcandevelopintomany differentcelltypesinthebody. Systemsbiology |Aeldthatseekstostudy therelationshipsandinteractionsbetweenvari ouspartsofabiologicalsystem(metabolic pathways,organelles,cellsandorganisms)and to integratethisinformationtounderstandhow biological systemsfunction. Telomere |ArepeatedDNAsequencethatcaps theendsofchromosomes. Transcription |Therstmajorstepingene expression,inwhichtheinformationcodedin DNAiscopiedintoamoleculeofRNA. Translation |Thesecondmajorstepingene expression,inwhichtheinstructionsencodedin RNAarecarriedoutbymakingaproteinorstart ingorstoppingproteinsynthesis. Variant |Adifferentversionofagene,onethat hasaslightlydifferentsequenceofnucleotides.
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The New Genetics

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The New Genetics

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TheNewGenetics

U.S.DEPARTMENTOF HEALTHANDHUMANSERVICES NationalInstitutesofHealth NationalInstituteofGeneralMedicalSciences

WHAT IS NIGM S? TheNationalInstituteofGeneralMedical

ProducedbytheOfceofCommunicationsandPublicLiaison NationalInstituteofGeneralMedicalSciences NationalInstitutesofHealth U.S.DepartmentofHealthandHumanServices

NIHPublicationNo.10 662 RevisedApril2010 http://www.nigms.nih.gov

BeautifulDNA Copycat LetsCallItEven GettingtheMessage NaturesCutandPasteJob AllTogetherNow

RNAWorld MolecularEditor HealthyInterference DynamicDNA SecretCode

EverythingEvolves SelectiveStudy CluesfromVariation

IndividualizedPrescriptions TheHealingPowerofDNA CauseandEffect Usvs. Them

NoLab?NoProblem! HardQuestions GoodAdvice

National Institute of General Medical Sciences

Gene Sugar phosphate backbone A G C T

DNAconsistsoftwolong,twistedchainsmadeup ofnucleotides.Eachnucleotidecontainsonebase, onephosphatemoleculeandthesugarmolecule deoxyribose.ThebasesinDNAnucleotidesare adenine,thymine,cytosineandguanine.

National Institute of General Medical Sciences

UnderstandingDNAreplication bettercould beakeytolimitingadrugsactionto cancer cellsonly.

numberofchromosomes:46. Chromosomesarenumbered1to22, accordingtosize,with1beingthelargest chromosome.The23rdpair,knownasthesex chromosomes,arecalledXandY.Inhumans, abnormalitiesofchromosomenumberusually occurduringmeiosis,thetimewhenacell

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Matching chromosomes pairup

Chromosomesdivide; daughternucleihave singlechromosomes andanewmixof geneticmaterial

National Institute of General Medical Sciences

Youdthinkthatforaprocesssoessentialto life,researcherswouldknowalotabouthow transcriptionworks.Whileitstruethatthe basicsareclearbiologistshavebeenstudying genetranscribingbyRNApolymerasessince these proteinswererstdiscoveredin1960 someof thedetailsareactuallystillmurky.

Thebiggestobstacletolearningmore has beenalackoftools.Untilfairlyrecently, researcherswereunabletogetapictureatthe atomiclevelof thegiantRNApolymerasepro teinassembliesinsidecellstounderstandhow themanypiecesofthisamazing,livingmachine dowhattheydo,anddoitsowell.

Butourunderstandingisimprovingfast, thankstospectaculartechnologicaladvances. We havenewXraypicturesthatarefarmore sophisticatedthanthosethatrevealedthestructure ofDNA.RogerKornbergofStanfordUniversityin Californiausedsuchmethodstodeterminethe structureofRNApolymerase.Thisworkearned

Aminoacids DNAstrand RNAstrand Tyrosine Threonine

AC GU A U CGU A C A Codon1 Codon2 Codon3 Codon4

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polymeraseasitinches alongDNA.Blockand histeamperformed thisworkby designing aspecializedmicroscope

Exon3 Translation (proteinsynthesis)

Translation ProteinA ProteinB

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GENETICS AND YOU:

hilemostgeneticresearch useslaborganisms,test tubesandpetridishes,

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SantaCruz,hasfoundthataribosomeperforms severalkeyjobswhenittranslatesthegenetic codeofmRNA.AsthemessengerRNAthreads throughtheribosomeproteinmachine,the

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Scientistsdeterminedthatseveraldifferent genes,eachwithacommonsequence,provide theseanatomicalidenticationcardinstructions. Kaufmanisolatedanddescribedoneofthese genes,whichbecameknownasAntennapedia, a wordthatmeansantennafeet. Kaufmanthenbeganlookingalotmore closelyatthemolecularstructureofthe

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Whyaresomeinfectionshard totreatwithantibiotics?What aresomethingsresearchers mightdotosolvethispublic healthproblem?

Howcan20,000humangenes providetheinstructionsfor makinghundredsofthousands ofdifferentproteins?

to cometomind.ItstruethatDNAisthebasic ingredientofourgenesand,assuch,itoften stealsthelimelightfromRNA,theotherform

Sugar phosphate backbone

downoften.RNAsinstabilityletscellschange their patternsofproteinsynthesisveryquickly

becauseofitsabilitytoleadadoublelife:tostore informationandtoconductchemicalreactions. Inotherwords,inthisworld,RNAservedthe functionsof bothDNAandproteins. Whatdoesanyofthishavetodowithhuman health?Plenty,itturnsout. Todaysresearchersareharnessingsomeof RNAsexibilityandpower.Forexample,through

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ThisdiscoveryhasledBreakertospeculate thatnewkindsofantibioticmedicinescouldbe developedtotargetbacterialriboswitches.

sequencesspelloutinstructionsforproducing RNAandproteins,theseinstructionsarent alwaysfollowedprecisely.Editing agenesmRNA,evenbyasingle chemicalletter,canradicallychange

theresultingproteinsfunction. NaturelikelyevolvedtheRNA editingfunctionasawaytogetmore proteinsoutofthesamenumberof

mRNA Nearperfectcomplementarity totargetmRNA Notranslation Noprotein

WormswithamutatedformofthemicroRNAlet7 (right)haveseveregrowthproblems,rupturingas theydevelop.

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RISC TheRNAinducedsilencing complex(RISC)enzyme attachestosiRNA.

ThesiRNARISCcomplex attachestotargetmRNA andchopsthemRNAinto smallpieces.

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withoutchangingitssequence.Thesechanges makegeneseithermoreorlesslikelytobe expressed(seedrawing,page31). Currently,scientistsarefollowinganintrigu ingcourseofdiscoverytoidentifyepigenetic factorsthat,alongwithdietandotherenviron mentalinuences,affectwhoweareandwhat typeof illnesseswemightget.

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GENETICS AND YOU:

ccasionally,unusualfactors inuencewhetherornota childwillbebornwitha

NormalIgf2genevariant (expressed) Paternal

Maternal MutantIgf2genevariant (notexpressed)

MutantIgf2genevariant (expressed) Paternal

Maternal NormalIgf2genevariant (notexpressed) Dwarfmouse

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National Institute of General Medical Sciences