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TheNewGenetics
NIHPublicationNo.10 662
RevisedApril2010
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
BeautifulDNA
Copycat
LetsCallItEven
GettingtheMessage
11
NaturesCutandPasteJob
14
AllTogetherNow
16
GeneticsandYou:NurseryGenetics
17
FoundinTranslation
18
RNASurprises
19
AnInterestingDevelopment
20
TheToolsofGenetics:MightyMicroarrays
22
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
24
RNAWorld
25
MolecularEditor
26
HealthyInterference
29
DynamicDNA
30
SecretCode
30
GeneticsandYou:TheGeneticsofAnticipation
32
BattleoftheSexes
33
StartingattheEnd
34
TheOtherHumanGenome
36
TheToolsofGenetics:RecombinantDNAandCloning
38
C H A P TE R 3: LI F E S G E N E TI C TRE E
40
EverythingEvolves
40
SelectiveStudy
42
CluesfromVariation
43
LivingLaboratories
46
TheGenomeZoo
52
GenesMeetEnvironment
53
GeneticsandYou:YouveGotRhythm!
56
AnimalsHelpingPeople
58
MyCollaboratorIsaComputer
58
TheToolsofGenetics:UnlimitedDNA
60
C H A P TE R 4: G E N E S A RE U S
6 2
IndividualizedPrescriptions
64
TheHealingPowerofDNA
65
CauseandEffect
67
Usvs. Them
68
GeneticsandYou:EatLess,LiveLonger?
69
GangWarfare
70
TheToolsofGenetics:MathematicsandMedicine
72
C H A P TE R 5: 2 1 S T C E N TU RY G E N E TI C S
7 4
NoLab?NoProblem!
76
HardQuestions
78
GoodAdvice
80
GeneticsandYou:CrimeFightingDNA
81
Genetics,Business,andtheLaw
82
CareersinGenetics
85
TheToolsofGenetics:InformaticsandDatabases
86
G LO S SA RY
8 8
Foreword
ConsiderjustthreeofEarthsinhabitants:
Andeverylivingthing
doesonethingthesame
a brightyellowdaffodilthatgreetsthe
way:To makemoreof
itself, it first copies its
spring,thesinglecelledcreaturecalled
Thermococcus thatlivesinboilinghot
molecularinstruction
manualitsgenesandthenpassesthisinfor
mationontoitsoffspring.Thiscyclehasbeen
springs,andyou.Evenasciencection
repeatedforthreeandahalf billionyears.
Buthowdidweandourverydistantrela
writerinventingastorysetonadistant
planetcouldhardlyimaginethreemoredif
tivescometolooksodifferentanddevelopso
many different ways of getting along in the
world?Acenturyago,researchersbegantoanswer
ferentformsoflife.Yetyou,Thermococcus
thatquestionwiththehelpofasciencecalled
genetics.Getarefreshercourseonthebasicsin
andthedaffodilarerelated!Indeed,allof
the Earthsbillionsoflivingthingsarekin
Chapter1,HowGenesWork.
Itslikelythatwhenyouthinkofheredity
youthinkrstofDNA,butinthepastfewyears,
to eachother.
researchershavemadesurprisingndingsabout
TheNewGenetics I Foreword 3
anothermolecularactorthatplaysastarringrole.
CanDNAandRNAhelpdoctorspredict
CheckoutthemodernviewofRNAinChapter2,
whetherwellgetdiseaseslikecancer,diabetesor
RNAandDNARevealed:NewRoles,NewRules.
asthma?Whatothermysteriesarelockedwithin
Whengeneticsrststarted,scientistsdidnt
the6feetof DNAinsidenearlyeverycellinour
havethetoolstheyhavetoday.Theycouldonly
bodies?Chapter4,GenesAreUs, explainswhat
lookatonegene,orafewgenes,atatime.Now,
researchersknow,andwhattheyarestilllearning,
researcherscanexamineallofthegenesinaliv
abouttheroleofgenesinhealthanddisease.
ingorganismitsgenomeatonce.Theyare
Finally,inChapter5,21stCentury
doingthisfororganismsoneverybranchofthe
Genetics,seeapreviewofthingstocome.Learn
treeoflifeandndingthatthegenomesofmice,
howmedicineandsciencearechanginginbig
frogs,shandaslewofothercreatureshave
ways,andhowthesechangesinuencesociety.
manygenessimilartoourown.
Sowhydoesntyourbrotherlooklikeyour
dogortheshinyouraquarium?Itsbecauseof
evolution.InChapter3,LifesGeneticTree,
ndouthowevolutionworksandhowitrelates
togeneticsandmedicalresearch.
Frommetabolismtomedicinestoagriculture,
thescienceofgeneticsaffectsuseveryday.Itis
partoflifepartofyour life!
CHAPTER1
How
GenesWork
eoplehaveknownformanyyearsthat
livingthingsinherittraitsfromtheirparents.
Proteinsdomanyotherthings,too.They
providethebodysmainbuildingmaterials,
Thatcommonsenseobservationledtoagricul
formingthecellsarchitectureandstructural
ture,thepurposefulbreedingandcultivationof
components.Butonethingproteinscantdois
animalsandplantsfordesirablecharacteristics.
makecopiesof themselves.Whenacellneeds
Firmingupthedetailstookquitesometime,
moreproteins,itusesthemanufacturinginstruc
though.Researchersdidnotunderstandexactly
tionscodedinDNA.
howtraitswerepassedtothenextgeneration
untilthemiddleof the20thcentury.
Nowitisclearthatgenes arewhatcarryour
TheDNAcodeof agenethe sequenceof

its individualDNAbuildingblocks,labeledA
(adenine),T(thymine),C(cytosine)andG
traitsthroughgenerationsandthatgenesare
(guanine)andcollectivelycallednucleotides
madeof deoxyribonucleicacid(DNA).But
spellsouttheexactorderof aproteinsbuilding
genesthemselvesdontdotheactualwork.
blocks,aminoacids.
Rather,theyserveasinstructionbooksformak
Occasionally,thereisakindof typographical
ingfunctionalmoleculessuchasribonucleic
errorinagenesDNAsequence.Thismistake
acid(RNA) andproteins,whichperformthe
whichcanbeachange,gaporduplicationis
chemicalreactionsin ourbodies.
calledamutation.
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
BeautifulDNA
proteinthatworksincorrectlyorthatdoesnt
Upuntilthe1950s,scientistsknewagooddeal
workatall.Sometimes,theerrormeansthatno
aboutheredity,buttheydidnthaveacluewhat
proteinismade.
DNAlookedlike.Inordertolearnmoreabout
ButnotallDNAchangesareharmful.Some
DNAanditsstructure,somescientistsexperi
mutationshavenoeffect,andothersproduce
mentedwithusingXraysasaformofmolecular
newversionsofproteinsthatmaygiveasurvival
photography.
advantagetotheorganismsthathavethem.Over
RosalindFranklin,aphysicalchemistwork
time,mutationssupplytherawmaterialfrom
ingwithMauriceWilkinsatKingsCollegein
whichnewlifeformsevolve(seeChapter3,
London,wasamongthersttousethismethod
LifesGeneticTree).
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
produced
whatwerereferredtoatthetimeas
COLD SPRING HARBOR LABORATORY ARCHIVES
the mostbeautifulXrayphotographsofany
substanceevertaken.
Otherscientists,includingzoologistJames
WatsonandphysicistFrancisCrick,bothwork
ingatCambridgeUniversityintheUnited
Kingdom,weretryingtodeterminetheshape
of DNAtoo.Ultimately,thislineofresearch
. In1953,WatsonandCrickcreatedtheirhistoric
modeloftheshapeofDNA:thedoublehelix.
revealedoneofthemostprofoundscientic
discoveriesofthe20thcentury:thatDNAexists
handrailswerecomplementarytoeachother,
asa doublehelix.
andthisunlockedthesecretof howgenetic
The1962NobelPrizeinphysiologyormedi
cinewasawardedtoWatson,CrickandWilkins
Ingenetics,complementarymeansthatif
forthiswork.AlthoughFranklindidnotearna
youknowthesequenceofnucleotidebuilding
shareoftheprizeduetoheruntimelydeathatage
blocksononestrand,youknowthesequenceof
38,sheiswidelyrecognizedashavingplayeda
nucleotidebuildingblocksontheotherstrand:
signicantroleinthediscovery.
Thespiralstaircaseshapeddouble
helixhasattainedglobalstatusas
thesymbolforDNA.Butwhat
is sobeautifulaboutthe
OREGON STATE UNIVERSITY LIBRARIES
Longstringsofnucleotidesformgenes,
andgroupsofgenesarepackagedtightlyinto
structurescalledchromosomes.Everycellinyour
ladderstructureisntjust
containsafullsetofchromosomesinitsnucleus.
itsgoodlooks.Rather,the
Ifthechromosomesinoneofyourcellswere
structureof DNAtaught
uncoiledandplacedendtoend,theDNAwould
researchersa fundamental
beabout6feetlong.IfalltheDNAinyourbody
strandswindingtogetherlikeparallel
originalXraydiffraction
photorevealedthephysical
structureofDNA.
toG(seedrawing,page7).
bodyexceptforeggs,spermandredbloodcells
themthatthetwoconnected
. RosalindFranklins
AalwaysmatchesupwithTandCalwayslinks
discoveryof thetwisting
lessonaboutgenetics.Ittaught
SPECIAL COLLECTIONS
informationisstored,transferredandcopied.
wereconnectedinthisway,itwouldstretch
approximately67billionmiles!Thatsnearly
150,000roundtripstotheMoon.
DNAStructure
Thelong,stringyDNAthatmakesupgenesis
spooledwithinchromosomesinsidethenucleus
ofacell.(Notethatagenewouldactuallybeamuch
longerstretchofDNAthanwhatisshownhere.)
Chromosome
Nucleus
GC
Cell
C
A
Bases
G C
DNA
Cytosine
GC
Guanine
A
T
C
Thymine
Gene
A
Sugar
phosphate
backbone
G
C
T
DNAconsistsoftwolong,twistedchainsmadeup
ofnucleotides.Eachnucleotidecontainsonebase,
onephosphatemoleculeandthesugarmolecule
deoxyribose.ThebasesinDNAnucleotidesare
adenine,thymine,cytosineandguanine.
P
Nucleotide
S
C
T
C
Adenine
Copycat
Itsastoundingtothinkthat
yourbodyconsistsoftrillions
ofcells.Butwhatsmost
amazingisthatit allstarts
withonecell.Howdoesthis
massiveexpansiontakeplace?
Asanembryoprogresses
throughdevelopment,itscells
. Humanshave23pairsofchromosomes.MaleDNA(picturedhere)
containsanXandaYchromosome,whereasfemaleDNAcontains
twoXchromosomes.
mustreproduce.Butbefore
a celldividesintotwonew,
CYTOGENETICSLABORATORY,BRIGHAMANDWOMENSHOSPITAL
nearlyidenticalcells,itmust
copyitsDNAsotherewillbea completesetof
thecomplementarynewstrand.Theprocess,
genestopassontoeachofthenewcells.
calledreplication,isastonishinglyfastand
Tomakeacopyofitself,thetwisted,com
accurate,
althoughoccasionalmistakes,suchas
pacteddoublehelixofDNAhastounwindand
deletionsor duplications,occur.Fortunately,a
separateitstwostrands.Eachstrandbecomes
cellularspellcheckercatchesandcorrectsnearly
a pattern,ortemplate,formakinganewstrand,
alloftheseerrors.
sothetwonewDNAmoleculeshaveonenew
strandandoneoldstrand.
Thecopyiscourtesyofacellularprotein
Mistakesthatarenotcorrectedcanleadto
diseasessuchascancerandcertaingeneticdisor
ders.SomeoftheseincludeFanconianemia,early
machinecalledDNApolymerase,whichreads
agingdiseasesandotherconditionsinwhich
thetemplateDNAstrandandstitchestogether
peopleareextremelysensitivetosunlightand
somechemicals.
DNAcopyingisnottheonlytimewhenDNA
damagecanhappen.Prolonged,unprotectedsun
exposurecancauseDNAchangesthatleadto
skincancer,andtoxinsincigarettesmokecan
causelungcancer.
. WhenDNApolymerasemakesanerrorwhilecopyingagenes
DNAsequence,themistakeiscalledamutation.Inthisexample,
thenucleotideGhasbeenchangedtoanA.
CG
AT
CG
Itmayseemironic,then,thatmanydrugs
AT
usedtotreatcancerworkbyattackingDNA.Thats
T A
becausethesechemotherapydrugsdisruptthe
DNAcopyingprocess,whichgoesonmuchfaster
CG
TA
in rapidly dividing cancer cells than in other
GC
cellsofthebody.Thetroubleisthatmostofthese
TA
drugs do affect normal cells that grow and
TA
dividefrequently,suchascellsoftheimmune
systemand haircells.
A
UnderstandingDNAreplicationbettercould
(dimeanstwo,andploidreferstosetsof
T T
GC
AftercopyingitsDNA,acellsnextchallengeis
Mostofyourcellsarecalleddiploid
LetsCallItEven
intoeachofitstwooffspring.
T
A
gettingjusttherightamountofgeneticmaterial
beakeytolimitingadrugsactionto cancer
cellsonly.
Newstrand
GC
AT
GC
AT
GC
A T
GC
AT
chromosomes)becausetheyhavetwosetsof
chromosomes(23pairs).Eggsandspermare
different;theseareknownashaploid cells.Each
haploidcellhasonlyonesetof23chromosomes
sothatatfertilizationthemathwillworkout:
AT
AT
GC
GC
CG
AT
CG
AT
A haploideggcellwillcombinewithahaploid
spermcelltoformadiploidcellwiththeright
AT
numberofchromosomes:46.
AT
Chromosomesarenumbered1to22,
accordingtosize,with1beingthelargest
chromosome.The23rdpair,knownasthesex
chromosomes,arecalledXandY.Inhumans,
abnormalitiesofchromosomenumberusually
occurduringmeiosis,thetimewhenacell
. DuringDNAreplication,eachstrandofthe
originalmoleculeactsasatemplatefor
thesynthesisofanew,complementary
DNAstrand.
10
Meiosis
Chromosomes
fromparents
Duringmeiosis,chromosomes
frombothparentsarecopied
andpairedtoexchangeportions
ofDNA.
Cellnucleus
Chromosomes
replicate
Matching
chromosomes
pairup
Thiscreatesamixofnewgenetic
materialintheoffspringscells.
Nucleusdividesinto
daughternuclei
Daughternuclei
divideagain
Chromosomesswap
sectionsofDNA
Chromosomepairsdivide
Chromosomesdivide;
daughternucleihave
singlechromosomes
andanewmixof
geneticmaterial
reducesitschromosomesfromdiploidtohaploid
increatingeggsorsperm.
Whathappensifaneggoraspermcellgets
Amonhasmademajorprogressinunder
standingthedetailsofmeiosis.Herresearchshows
how,inhealthycells,gluelikeproteincomplexes
the wrongnumberofchromosomes,andhow
calledcohesinsreleasepairsofchromosomesat
oftendoesthishappen?
exactlytherighttime.Thisallowsthechromo
MolecularbiologistAngelikaAmonof
the MassachusettsInstituteof Technologyin
somestoseparateproperly.
Thesendingshaveimportantimplications
CambridgesaysthatmistakesindividingDNA
forunderstandingandtreatinginfertility,birth
betweendaughtercellsduringmeiosisarethe
defectsandcancer.
leadingcauseof humanbirthdefectsandmis
carriages.Currentestimatesarethat10percent
of allembryoshaveanincorrectchromosome
number.Mostof thesedontgotofulltermand
aremiscarried.
Inwomen,thelikelihoodthatchromosomes
GettingtheMessage
So,wevedescribedDNAitsbasicproperties
and howourbodiesmakemoreofit.Buthow
doesDNAserveasthelanguageoflife?Howdo
yougetaproteinfromagene?
wontbeapportionedproperlyincreaseswithage.
Oneofevery18babiesborntowomenover45
hasthreecopiesofchromosome13,18or21
insteadofthenormaltwo,andthisimproper
balancing
cancausetrouble.Forexample,three
copiesofchromosome21leadtoDown
syndrome.
Tomakeherworkeasier,Amonlikemany
otherbasicscientistsstudiesyeastcells,which
separatetheirchromosomesalmostexactlythe
samewayhumancellsdo,exceptthatyeastdoit
muchfaster.AyeastcellcopiesitsDNAand
produces
daughtercellsinabout11/2 hours,
compared
toawholedayforhumancells.
Theyeastcellssheusesarethesamekind
bakeries
usetomakebreadandbreweriesuse
to makebeer!
. Trisomy,thehallmarkofDownsyndrome,results
whenababyisbornwiththreecopiesofchromo
some21insteadoftheusualtwo.
12
Therearetwomajorstepsinmakinga
Youdthinkthatforaprocesssoessentialto
protein.Therstistranscription,wherethe
life,researcherswouldknowalotabouthow
informationcodedinDNAiscopiedintoRNA.
transcription
works.Whileitstruethatthe
TheRNAnucleotidesarecomplementaryto
basicsareclearbiologistshavebeenstudying
thoseontheDNA:aContheRNAstrand
genetranscribingbyRNApolymerasessince
matchesaGontheDNAstrand.
theseproteinswererstdiscoveredin1960
TheonlydifferenceisthatRNApairsa
someof thedetailsareactuallystillmurky.
nucleotidecalleduracil(U),insteadofaT,with
an AontheDNA.
AproteinmachinecalledRNApolymerase
readstheDNAandmakestheRNAcopy.This
copyiscalledmessengerRNA,ormRNA,because
itdeliversthegenesmessagetotheprotein
producing
machinery.
A
C
A
T
T
G
T
A
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.
DNA
. RNApolymerasetranscribesDNAto
makemessengerRNA(mRNA).
Thebiggestobstacletolearningmore
Butourunderstandingisimprovingfast,
has beenalackoftools.Untilfairlyrecently,
thankstospectaculartechnologicaladvances.
researcherswereunabletogetapictureatthe
We havenewXraypicturesthatarefarmore
atomiclevelof thegiantRNApolymerasepro
sophisticatedthanthosethatrevealedthestructure
teinassembliesinsidecellstounderstandhow
ofDNA.RogerKornbergofStanfordUniversityin
themanypiecesofthisamazing,livingmachine
Californiausedsuchmethodstodeterminethe
dowhattheydo,anddoitsowell.
structureofRNApolymerase.Thisworkearned
Threonine
Arginine
Aminoacids
Tyrosine
DNAstrand
Threonine
RNAstrand
. Aminoacidslinkupto
makeaprotein.
A AT
tRNA
C CG
AAT
TUA
G G C
C C G
T U A
AA T
T UA
G
C G
C GC
AT A
Ribosome
AC GU A U CGU A C A
Codon1
Codon2
Codon3
mRNA
. ThemRNAsequence(darkredstrand)iscom
plementarytotheDNAsequence(bluestrand).
. Onribosomes,transferRNA(tRNA)helps
convertmRNAintoprotein.
Codon4
14
himthe2006Nobel
NaturesCutandPasteJob
Prizeinchemistry.In
SeveraltypesofRNAplaykeyrolesinmaking
addition,verypowerful
a protein.Thegenetranscript(themRNA)
microscopesandother
transfers
informationfromDNAinthenucleusto
toolsthatallowusto
theribosomes thatmakeprotein.RibosomalRNA
watch one molecule
formsabout60percentoftheribosomes.Lastly,
at a time provide a
transferRNAcarriesaminoacidstothe ribo
newlookatRNApoly
somes.Asyoucansee,allthreetypesofcellular
merasewhileitsatwork
RNAscometogethertoproducenewproteins.
readingDNAandpro
ducingRNA.
Forexample,Steven
. RNApolymerase(green)andoneendofaDNA
strand(blue)areattachedtoclearbeadspinned
downintwoopticaltraps.AsRNApolymerase
movesalongtheDNA,itcreatesanRNAcopyof
a gene,shownhereasapinkstrand.
STEVENBLOCK
Butthejourneyfromgenetoproteinisnt
quiteassimpleaswevejustmadeitouttobe.
Aftertranscription,severalthingsneedtohap
Block,alsoofStanford,
pentomRNAbeforeaproteincanbemade.For
hasusedaphysicstech
example,thegeneticmaterialofhumansand
niquecalledoptical
othereukaryotes (organismsthathavea
trappingtotrackRNA
nucleus)includesalotofDNAthatdoesnt
polymeraseasitinches
encodeproteins.SomeofthisDNAisstuckright
alongDNA.Blockand
inthemiddleofgenes.
histeamperformed
TodistinguishthetwotypesofDNA,scien
thisworkby designing
tistscallthecodingsequencesofgenesexons and
aspecializedmicroscope
thepiecesinbetweenintrons (forintervening
sensitiveenoughtowatchtherealtimemotionof
asingle polymerase traveling down a gene on
one chromosome.
Theresearchersdiscoveredthatmoleculesof
RNApolymerasebehavelikebatterypowered
spidersastheycrawlalongtheDNAladder,
sequences).
IfRNApolymeraseweretotranscribeDNA
fromthestartofanintroncontaininggeneto
theend,theRNAwouldbecomplementaryto
theintronsaswellastheexons.
TogetanmRNAmoleculethatyieldsawork
addingnucleotidesoneatatimetothegrowing
ingprotein,thecellneedstotrimouttheintron
RNAstrand.Theenzyme worksmuchlikea
sectionsandthenstitchonlytheexonpieces
motor,Blockbelieves,poweredbyenergyreleased
together(seedrawing,page15).Thisprocessis
duringthechemicalsynthesisofRNA.
called RNAsplicing.
RNASplicing
Gene
DNA
Intron1
Exon1
Genesareofteninterrupted
Exon2
Intron2
Exon3
bystretchesofDNA
(introns,blue)thatdonot
containinstructionsfor
makingaprotein.TheDNA
segmentsthatdocontain
proteinmakinginstructions
areknownasexons(green).
Transcription
(RNAsynthesis)
NuclearRNA
Exon1
Intron1
Exon2
Intron2
Exon3
RNAsplicing
Exon1
MessengerRNA
Exon2
Exon3
Translation
(proteinsynthesis)
Protein
Gene
DNA
Exon1
Exon2
Exon3
Exon4
Exon1
Exon2
Exon3
Exon4
Alternativesplicing
Exon1
Exon2
Exon3
Exon1
Exon2
Translation
ProteinA
ProteinB
Exon4
Arrangingexonsindifferent
patterns,calledalternative
splicing,enablescellsto
makedifferentproteins
fromasinglegene.
16
Splicinghastobeextremelyaccurate.An
Bycuttingandpastingtheexonsindifferent
errorinthesplicingprocess,evenonethatresults
patterns,whichscientistscallalternativesplicing,
inthedeletionofjustonenucleotideinanexon
acellcancreatedifferentproteinsfromasingle
ortheadditionofjustonenucleotideinan
gene.Alternative splicing is one of the reasons
intron,willthrowthewholesequenceoutof
why human cells, which have about 20,000
alignment.Theresultisusuallyanabnormal
genes, can make hundreds of thousands of
proteinor
noproteinatall.Oneformof
different proteins.
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).
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
hilemostgeneticresearch
Newbornscreeningisgovernedby
useslaborganisms,test
individualstates.Thismeansthatthe
tubesandpetridishes,
stateinwhichababy
the resultshaverealconsequencesfor
isborndeterminesthe
people.Yourfirstencounterwith
geneticconditionsfor
geneticanalysisprobablyhappened
which heorshewillbe
shortlyafteryouwereborn,whena
screened.Currently,
doctorornursetookadropofblood
statestestforbetween
fromtheheelofyourtinyfoot.
28and54conditions.Allstatestest
Labtestsperformedwiththatsingle
dropofbloodcandiagnosecertainrare
for PKU.
Althoughexpandedscreeningfor
geneticdisordersaswellasmetabolic
geneticdiseasesinnewbornsisadvo
problemslikephenylketonuria(PKU).
catedbysome,othersquestionthe
Screeningnewbornsinthisway
valueofscreeningforconditionsthat
beganinthe1960sinMassachusetts
arecurrentlyuntreatable.Another
withtestingforPKU,adiseaseaffecting
issueisthatsomechildrenwithmild
1in14,000people.PKUiscausedbyan
versionsofcertaingeneticdiseases
enzymethatdoesntworkproperlydue
may betreatedneedlessly.
toageneticmuta
In2006,theAdvisoryCommittee
tion.Thoseborn
on HeritableDisordersinNewborns
withthisdisorder
and Children,whichassiststheSecretary
cannotmetabolize
of theU.S.DepartmentofHealthand
theaminoacid
HumanServices,recommendeda
phenylalanine,
standard,nationalsetofnewborn
whichispresent
tests for29conditions,rangingfrom
in manyfoods.Leftuntreated,PKUcan
relativelycommonhearingproblems
leadtomentalretardationandneurolog
to veryrare metabolicdiseases.
icaldamage,butaspecialdietcan
preventtheseoutcomes.Testingforthis
conditionhasmadeahugedifferencein
manylives.
18
Youngwasabletogureouthowtranscription
methodtoscantheentirehumangenomein
patternsdifferwhentheyeastcellisunderstress
smallsamplesofcellstakenfromthepancreases
(say,inadryenvironment)orthrivinginasugary
andliversofpeoplewithtype2diabetes.He
richnutrientsolution.Doneonegeneatatime,
used theresultstoidentifygenesthatarenttran
usingmethodsconsideredstateoftheartjusta
scribedcorrectlyinpeoplewiththedisease.
fewyearsago,thiskindofanalysiswouldhave
takenhundredsofyears.
Afterdemonstratingthathistechnique
Thisinformationprovidesresearcherswith
an importanttoolforunderstandinghowdia
betesandotherdiseasesareinuencedby
workedinyeast,Youngthentookhisresearch
defectivegenes.Bybuildingmodelstopredict
a stepforward.Heusedavariationoftheyeast
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,
SantaCruz,hasfoundthataribosomeperforms
severalkeyjobswhenittranslatesthegenetic
codeofmRNA.AsthemessengerRNAthreads
GULNARAYUSUPOVA,THOMASEARNESTANDHARRYNOLLER.GRAPHIC
COURTESYOFALBIONBAUCOM,UNIVERSITYOFCALIFORNIA,SANTACRUZ.
throughtheribosomeproteinmachine,the
ribosome
readsthemRNAsequenceandhelps
recognizeandrecruitthecorrectaminoacid
carrying
transferRNAtomatchthemRNAcode.
Theribosomealsolinkseachadditionalamino
acidintoagrowingproteinchain(seedrawing,
page13).
Formanyyears,researchersbelievedthateven
thoughRNAsformedapartoftheribosome,the
proteinportionoftheribosomedidallofthe
work.Nollerthought,instead,thatmaybeRNA,
notproteins,performedtheribosomesjob.His
.Somerstaidointmentscontaintheantibioticneomycin,
whichtreatsinfectionsbyattackingribosomesinbacteria.
ideawasnotpopularatrst,becauseatthattime
itwasthoughtthatRNAcouldnotperformsuch
RNASurprises
complexfunctions.
ButwhichribosomalRNAsaredoingthework?
Sometimelater,however,theconsensus
MostscientistsassumedthatRNAnucleotides
changed.SidneyAltmanofYaleUniversityin
burieddeepwithintheribosomecomplexthe
New Haven,Connecticut,andThomasCech,
onesthathavethesamesequenceineveryspecies
who wasthenattheUniversityofColoradoin
frombacteriatopeopleweretheimportant
Boulder,eachdiscoveredthatRNAcanperform
onesforpiecingthegrowingproteintogether.
workascomplexasthatdonebyproteinenzymes.
However,recentresearchbyRachelGreen,
TheirRNAasanenzymediscoveryturnedthe
who worked with Noller before moving
researchworldonitsheadandearnedCechand
toJohns Hopkins University in Baltimore,
Altmanthe1989NobelPrizeinchemistry.
Maryland,showedthatthisisnotthecase.
Nollerandotherresearchershavecontinued
Green discoveredthatthoseRNAnucleotides
thepainstakingworkofunderstandingribo
arenotneededforassemblingaprotein.Instead,
somes.In1999,heshowedhowdifferentparts
shefound,thenucleotidesdosomethingelse
of a bacterial ribosome interact with one
entirely:Theyhelpthegrowingproteinslipoff
anotherandhowtheribosomeinteractswith
theribosomeonceitsnished.
moleculesinvolvedinproteinsynthesis.
Noller,Greenandhundredsofotherscientists
Thesestudiesprovidednearproof thatthe
workwiththeribosomesofbacteria.Whyshould
fundamentalmechanismof translationis
youcareabouthowbacteriacreateproteinsfrom
performed by RNA, not by the proteins of
theirgenes?
theribosome.
20
Onereasonisthatthisknowledgeisimpor
AnInterestingDevelopment
tantforlearninghowtodisrupttheactionsof
Inthehumanbody,oneofthemostimportant
diseasecausingmicroorganisms.Forexample,
jobsforproteinsistocontrolhowembryos
antibioticslikeerythromycinandneomycinwork
develop.Scientistsdiscoveredahugelyimportant
byattackingtheribosomesofbacteria,whichare
setofproteinsinvolvedindevelopmentbystudy
differentenoughfromhumanribosomesthatour
ingmutationsthatcausebizarremalformations
cellsarenotaffectedbythesedrugs.
infruities.
Asresearchersgainnewinformationabout
Themostfamoussuchabnormalityisafruit
bacterialtranslation,theknowledgemayleadto
ywithaleg,ratherthantheusualantenna,
moreantibioticsforpeople.
growingoutofitshead(seepage21).According
Newantibioticsareurgentlyneededbecause
toThomasC.KaufmanofIndianaUniversity
manybacteriahavedevelopedresistancetothe
inBloomington,thelegisperfectlynormalits
currentarsenal.Thisresistanceissometimesthe
justgrowinginthewrongplace.
resultofchangesinthebacteriasribosomalRNA.
Inthistypeofmutationandmanyothers,
Itcanbedifculttondthosesmall,butcritical,
somethinggoeswrongwiththegeneticprogram
changesthatmayleadtoresistance,soitis
thatdirectssomeofthecellsinanembryoto
importanttondcompletelynewwaystoblock
follow
developmentalpathways,whichare
bacterialtranslation.
a seriesofchemicalreactionsthatoccurina
Greenisworkingonthatproblemtoo.Her
specicorder.Intheantennaintolegproblem,
strategyistomakerandommutationstothe
it is asifthecellsgrowingfromtheyshead,
genesinabacteriumthataffectitsribosomes.
whichnormallywouldbecomeanantenna,
But whatifthemutationdisablestheribosome
mistakenlybelievethattheyareintheys
so muchthatitcantmakeproteins?Thenthe
thorax,andthereforeoughttogrowintoaleg.
bacteriumwontgrow,andGreenwouldntndit.
Andsotheydo.
Usingclevermoleculartricks,Greengured
Thinkingaboutthisoddsituationtaught
outawaytorescuesomeofthebacteriawith
scientistsanimportantlessonthattheproteins
defectiveribosomessotheycouldgrow.While
madebysomegenescanactasswitches.Switch
someoftherescuedbacteriahavechangesin
genesaremastercontrollersthatprovideeach
theirribosomalRNAthatmakethemresistant
bodypartwithakindofidenticationcard.Ifa
to certainantibiotics(andthuswouldnotmake
proteinthatnormallyinstructscellstobecome
goodantibiotictargets)otherRNAchangesthat
an antennaisdisrupted,cellscanreceivenew
dontaffectresistancemaypointtopromising
instructionstobecomealeginstead.
ideasfornewantibiotics.
FLYBASE; R. TURNER
. Normalfruityhead.
. FruityheadshowingtheeffectsoftheAntennapedia
gene.Thisyhaslegswhereitsantennaeshouldbe.
Scientistsdeterminedthatseveraldifferent
genesof differentorganisms,itsagoodclue
genes,eachwithacommonsequence,provide
thatthesegenesdosomethingsoimportantand
theseanatomicalidenticationcardinstructions.
usefulthatevolutionusesthesamesequence
Kaufmanisolatedanddescribedoneofthese
overandoverandpermitsveryfewchangesin
genes,whichbecameknownasAntennapedia,
itsstructureasnewspeciesevolve.
a wordthatmeansantennafeet.
Kaufmanthenbeganlookingalotmore
Researchersquicklydiscoverednearly
identicalversionsofhomeoboxDNAinalmost
closelyatthemolecularstructureofthe
everynonbacterialcelltheyexaminedfrom
Antennapedia gene.Intheearly1980s,heand
yeasttoplants,frogs,worms,beetles,chickens,
otherresearchersmadeadiscoverythathasbeen
miceandpeople.
fundamentaltounderstandingevolutionaswell
asdevelopmentalbiology.
ThescientistsfoundashortsequenceofDNA,
Hundredsofhomeoboxcontaininggenes
havebeenidentied,andtheproteinsthey
maketurnouttobeinvolvedintheearlystages
nowcalledthehomeobox,thatispresentnotonly
ofdevelopmentofmanyspecies.Forexample,
inAntennapediabutintheseveralgenesnextto
researchershavefoundthatabnormalitiesin
itandingenesinmanyotherorganisms.When
thehomeoboxgenescanleadtoextrangersor
geneticistsndverysimilarDNAsequencesinthe
toesinhumans.
22
TheToolsofGenetics:MightyMicroarrays
Wenowhavetheabilitytoattachapieceofevery
but teachersandstudentsareusingthem,too.
geneinagenome (allof anorganismsgenes)to
TheGenomeConsortiumforActiveTeaching
apostagestampsizedglassmicroscopeslide.
program(www.bio.davidson.edu/GCAT)pro
Thisorderedseriesof DNAspotsiscalledaDNA
videsresourcesandinstructionsforhighschool
microarray,agenechip ora DNAchip.
andcollegestudentstodogenechipexperiments
Whichevernameyouprefer,the chipcould
alsobecalledrevolutionary.This technologyhas
inclass.
Microarraysareusedtogetcluesabout
changedthewaymanygeneticistsdotheirwork
which genesareexpressedtocontrolcell,tissue
bymakingitpossibletoobservetheactivityof
ororganfunction.BymeasuringthelevelofRNA
thousandsof genesatonce.
productionforeverygeneatthesametime,
Inrecentyears,microarrayshavebecome
standardequipmentformodernbiologists,
researcherscanlearnthegeneticprogramming
thatmakescelltypesdifferentanddiseasedcells
differentfromhealthyones.
ThechipsconsistoflargenumbersofDNA
fragmentsdistributedinrowsinaverysmall
space.Thearraysarelaidoutbyrobotsthatcan
DNAfragments
DNAfragmentsareattachedto
glassorplastic,thenuorescently
taggedmoleculesarewashedover
thefragments.
ComplementarymRNA
Somemolecules(green)bindtotheir
complementarysequence.Thesemol
eculescanbeidentiedbecausethey
glowunderuorescentlight.
T Theresultingpatternofuorescenceindicates
whichgenesareactive.
GotIt?
Whyaresomeinfectionshard
totreatwithantibiotics?What
aresomethingsresearchers
mightdotosolvethispublic
healthproblem?
positionDNAfragmentssopreciselythat
InDecember2004,theU.S.Foodand
more than20,000ofthemcantononemicro
DrugAdministrationclearedtherst
scopeslide.
gene chipformedicaluse.TheAmplichip
ScientistsisolatemRNAfromcellsgrown
CYP450,madebyRocheMolecularSystems
undertwoconditionsandtagthetwosources
Inc.ofPleasanton,California,analyzesvaria
of RNAwithdifferentcolorsofuorescentmole
tionsintwogenesthatplayamajorrolein
cules.ThetwocolorsofRNAarethenplaced
thebodysprocessingofmanywidelypre
on thechip,wheretheyattachtocomplementary
scribeddrugs.Thisinformationcanhelp
DNAfragmentsanchoredtothechipssurface.
doctorschoosetheproperdoseofcertain
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).
medicinesforanindividualpatient.
HowdoesDNAworkasaform
ofinformationstorage?
Howcan20,000humangenes
providetheinstructionsfor
makinghundredsofthousands
ofdifferentproteins?
Whatnewborntestsdoesyour
areahospitalroutinelydo?
CHAPTER2
RNAandDNARevealed:NewRoles,NewRules
ormanyyears,whenscientiststhought
aboutheredity,DNAwastherstthing
to cometomind.ItstruethatDNAisthebasic
ingredientofourgenesand,assuch,itoften
C
stealsthelimelightfromRNA,theotherform
G
of geneticmaterialinsideourcells.
U
C
But,whiletheyarebothtypesofgenetic
Sugar
phosphate
backbone
material,
RNAandDNAareratherdifferent.
C
G
ThechemicalunitsofRNAarelikethoseof
DNA,exceptthatRNAhasthenucleotideuracil
(U)insteadofthymine(T).Unlikedouble
U
C
strandedDNA,RNAusuallycomesasonlyasingle
G
strand.AndthenucleotidesinRNAcontainribose
G
A
sugarmoleculesinplaceofdeoxyribose.
U
RNAisquiteexibleunlikeDNA,whichis
Base
a rigid,spiralstaircasemoleculethatisverystable.
G
C
RNAcantwistitselfintoavarietyofcomplicated,
threedimensionalshapes.RNAisalsounstablein
thatcellsconstantlybreakitdownandmustcon
C
tinuallymakeitfresh,whileDNAisnotbroken
A
downoften.RNAsinstabilityletscellschange
G
C
their patternsofproteinsynthesisveryquickly
A
in responsetowhatsgoingonaroundthem.
ManytextbooksstillportrayRNAasapassive
molecule,simplyamiddlestepinthecells
genereadingactivities.Butthatviewisnolonger
accurate.Eachyear,researchersunlocknew
C
A
U
Ribonucleicacid(RNA)has
thebases adenine(A),
cytosine(C),guanine(G)
anduracil(U).
secretsaboutRNA.Thesediscoveriesrevealthat
itistrulyaremarkablemoleculeandamulti
talentedactorinheredity.
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
becauseofitsabilitytoleadadoublelife:tostore
evolvedontheEarthlongbeforeDNAdid.
informationandtoconductchemicalreactions.
Researchershypothesize obviously,noone
Inotherwords,inthisworld,RNAservedthe
wasaroundtowritethisdown thatRNAwas
functionsof bothDNAandproteins.
amajorparticipantinthechemicalreactions
thatultimatelyspawnedtherstsignsof life
on theplanet.
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
astrategyhecallsdirectedevolution,molecular
engineerRonaldR.Breakerof Yale Universityis
developingwaystocreateentirely newformsof
RNAandDNAthatbothworkasenzymes.
Breakerandothershavealsouncovered
ahiddenworldof RNAsthatplayamajor
roleincontrollinggeneactivity,ajobonce
thoughttobeperformedexclusivelybyproteins.
These RNAs, which the scientists named
riboswitches,arefoundinawidevarietyof
bacteriaandotherorganisms.
inthisprimitiveworld,RNAwasacritical
molecule
26
ThisdiscoveryhasledBreakertospeculate
thatnewkindsofantibioticmedicinescouldbe
developedtotargetbacterialriboswitches.
MolecularEditor
Scientistsarelearningof anotherwaytocus
tomize proteins:byRNAediting.AlthoughDNA
sequencesspelloutinstructionsforproducing
RNAcomesinavarietyof
differentshapes(above
andright).
RNAandproteins,theseinstructionsarent
alwaysfollowedprecisely.Editing
agenesmRNA,evenbyasingle
chemicalletter,canradicallychange
DoublestrandedDNA
theresultingproteinsfunction.
(left)isastaircaselike
molecule.
NaturelikelyevolvedtheRNA
editingfunctionasawaytogetmore
proteinsoutofthesamenumberof
SmallButPowerful
LargerRNA
Dicer
enzyme
MicroRNA
mRNA
Nearperfectcomplementarity
totargetmRNA
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
Notranslation
Noprotein
choppinglargerRNAmoleculesintotiny
Velcrolikepieces.MicroRNAssticktomRNA
moleculesandpreventthemRNAsfrombeing
madeintoproteins.
genes.Forexample,researchershavefoundthat
theRNAsequence,whichinturnchangesthe
themRNAsforcertainproteinsimportantforthe
thatgetsmade.
protein
properfunctioningofthenervoussystemare
BassexperimentsshowthatRNAediting
particularlypronetoediting.Itmaybe thatRNA
occursinavarietyoforganisms,includingpeo
editinggivescertainbraincellsthecapacityto
ple.Anotherinterestingaspectofeditingisthat
reactquicklytoachangingenvironment.
certaindiseasecausingmicroorganisms,suchas
Whichmoleculesserveastheeditorandhow
someformsofparasites,useRNAeditingtogain
doesthishappen?BrendaBassoftheUniversityof
asurvivaledgewhenlivinginahumanhost.
UtahSchoolofMedicineinSaltLakeCitystudies
Understandingthedetailsofthisprocessisan
oneparticularclassofeditorscalledadenosine
importantareaofmedicalresearch.
deaminases.TheseenzymesretypeRNAletters
atvariousplaceswithinanmRNAtranscript.
Theydotheirjobbysearchingforcharacteris
ticRNAshapes.Telltaletwistsandbendsinfolded
RNAmoleculessignaltheseenzymestochange
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
DoublestrandedRNA(dsRNA)ischopped
dsRNA
intoshortinterferingRNAs(siRNAs)bythe
enzymeDicer.
Shortinterfering
RNAs(siRNAs)
RISC
TheRNAinducedsilencing
complex(RISC)enzyme
attachestosiRNA.
ThesiRNARISCcomplex
attachestotargetmRNA
andchopsthemRNAinto
smallpieces.
G
C
mRNA
ChoppedmRNA
(nolongerfunctional)
HealthyInterference
RNAcontrolsgenesinawaythatwasonlydiscov
eredrecently:aprocesscalledRNAinterference,
orRNAi.AlthoughscientistsidentiedRNAiless
than10yearsago,theynowknowthatorganisms
havebeenusingthistrickformillionsofyears.
ResearchersbelievethatRNAiaroseasawayto
of genes that affect cell growth and tissue
reducetheproductionofagenesencodedprotein
formation
inroundworms,usingamolecular
forpurposesofnetuninggrowthorselfdefense.
tool calledantisenseRNA.
Whenvirusesinfectcells,forexample,theycom
Totheirsurprise,MelloandFirefound
mandtheirhosttoproducespecializedRNAs
thattheirantisenseRNAtoolwasntdoing
that allowthevirustosurviveandmakecopies
muchatall.Rather,theydetermined,adouble
of itself.ResearchersbelievethatRNAieliminates
strandedcontaminantproducedduringthe
unwantedviralRNA,andsomespeculatethat
synthesisofthesinglestrandedantisenseRNA
it mayevenplayaroleinhumanimmunity.
interferedwithgeneexpression.Melloand
Oddlyenough,scientistsdiscoveredRNAi
FirenamedtheprocessRNAi,andin2006were
fromafailedexperiment!Researchersinvesti
awardedtheNobelPrizeinphysiologyor
gatinggenesinvolvedinplantgrowthnoticed
medicinefortheirdiscovery.
somethingstrange:Whentheytriedtoturn
Furtherexperimentsrevealedthatthedouble
petuniaowerspurplebyaddinganextra
strandedRNAgetschoppedupinsidethecell
purplegene,theowersbloomedwhiteinstead.
intomuchsmallerpiecesthatsticktomRNAand
Thisresultfascinatedresearchers,whocould
notunderstandhowaddinggeneticmaterial
couldsomehowgetridofaninheritedtrait.The
blockitsaction,muchlikethemicroRNApieces
ofVelcrodiscussedabove(seedrawing,page28).
Today,scientistsaretakingacuefromnature
mysteryremainedunsolveduntil,afewyears
andusingRNAitoexplorebiology.Theyhave
later,twogeneticistsstudyingdevelopmentsaw
learned,forexample,thattheprocessisnotlimited
a similarthinghappeninginlabanimals.
towormsandplants,butoperatesinhumanstoo.
Theresearchers,AndrewZ.Fire,thenofthe
Medicalresearchersarecurrentlytestingnew
CarnegieInstitutionofWashingtoninBaltimore
typesofRNAibaseddrugsfortreatingcondi
andnowatStanfordUniversity,andCraigMello
tionssuchasmaculardegeneration,theleading
oftheUniversityofMassachusettsMedicalSchool
causeofblindness,andvariousinfections,includ
inWorcester,weretryingtoblocktheexpression
ingthosecausedbyHIVandtheherpesvirus.
30
DNA
Histoneproteinslooptogether
withdoublestrandedDNAto
formastructurethatresembles
beadsonastring.
Histones
Chromatin
DynamicDNA
without
changingitssequence.Thesechanges
Agoodpartofwhoweareiswritteninour
makegeneseithermoreorlesslikelytobe
genes,inheritedfromMomandDad.Many
expressed(seedrawing,page31).
traits,likeredorbrownhair,bodyshapeand
Currently,scientistsarefollowinganintrigu
evensomepersonalityquirks,arepassedonfrom
ingcourseofdiscoverytoidentifyepigenetic
parenttooffspring.
factorsthat,alongwithdietandotherenviron
Butgenesarenotthewholestory.Wherewe
live,howmuchweexercise,whatweeat:These
mentalinuences,affectwhoweareandwhat
typeofillnesseswemightget.
andmanyotherenvironmentalfactorscanall
affecthowourgenesgetexpressed.
YouknowthatchangesinDNAandRNAcan
producechangesinproteins.Butadditionalcon
trolhappensatthelevelofDNA,eventhough
thesechangesdonotalterDNAdirectly.Inherited
factorsthatdonotchangetheDNAsequenceof
nucleotidesarecalledepigenetic changes,andthey
toohelpmakeeachofusunique.
Epigeneticmeans,literally,uponorover
genetics.Itdescribesatypeofchemicalreaction
thatcanalterthephysicalpropertiesofDNA
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
Histonetails
genescanbetranscribed.
Theobservationthatacellsgenereading
machinerytracksepigeneticmarkingsled
Histones
C. DavidAllis,whowasthenattheUniversity
of Virginia Health Sciences Center in
Charlottesville and now works at the
Rockefeller University in NewYork City,
Chromosome
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
associated
withseveraltypesofcancer,and
researchersareactivelypursuingthedevelop
mentofmedicinestocorrectsucherrors.
Theepigeneticcodecontrolsgeneactivitywith
chemicaltagsthatmarkDNA(purplediamonds)
andthetailsofh
istoneproteins(purpletriangles).
Thesemarkingshelpdeterminewhethergeneswill
betranscribedbyRNApolymerase.Geneshidden
fromaccesstoRNApolymerasearenotexpressed.
32
GENETICS AND YOU:
TheGeneticsofAnticipation
ccasionally,unusualfactors
inuencewhetherornota
childwillbebornwitha
geneticdisease.
Thenumberoftripletrepeatsseems
toincreaseasthechromosomeis
passeddownthroughseveralgenera
tions.Thus,thegrandsonsofaman
Anexampleisthemolecularerror
withafragileXchromosome,whois
thatcausesFragileXsyndrome,arare
nothimselfaffected,havea40percent
conditionassociatedwithmentalretar
riskofretardationiftheyinheritthe
dation.Themutationleadingtoafragile
repeatcontainingchromosome.The
XchromosomeisnotatypicalDNAtyp
risk forgreatgrandsonsisevenhigher:
ingmistake,inwhichnucleotidesare
50percent.
switchedaroundordropped,oroneof
Intriguedbytheevidencethattriplet
themisswitchedfor
repeatscancausegeneticdisease,scien
anothernucleotide.
tistshavesearchedforotherexamples
Instead,itisakind
of disordersassociatedwiththeDNA
of stutterbytheDNA
expansions.Todate,morethanadozen
polymeraseenzyme
suchdisordershavebeenfound,andall
thatcopiesDNA.This
ofthemaffectthenervoussystem.
stuttercreatesastringofrepeatsofa
Analysisoftherarefamiliesin
DNAsequencethatiscomposedofjust
whichsuchdiseasesarecommonhas
threenucleotides,CGG.
revealedthatexpansionofthetriplet
Somepeoplehaveonlyonerepeat
repeatsislinkedtosomethingcalled
oftheCGGnucleotidetriplet.Thus,they
geneticanticipation,whenadiseases
havetwocopiesoftherepeatinagene,
symptomsappearearlierandmore
andtheextrasequencereadsCGGCGG.
severelyineachsuccessivegeneration.
Othershavemorethanathousand
copiesoftherepeat.Thesepeopleare
themostseverelyaffected.
Igf2isanimprintedgene.A
NormalIgf2genevariant
(expressed)
singlecopyoftheabnormal,
ormutant,formoftheIgf2
gene(red)causesgrowth
defects, but only if the
abnormal gene variant is
inherited from the father.
Paternal
Maternal
MutantIgf2genevariant
(notexpressed)
Normalsizemouse
MutantIgf2genevariant
(expressed)
Paternal
Maternal
Dwarfmouse
NormalIgf2genevariant
(notexpressed)
BattleoftheSexes
fatherscopyofIgf2isexpressed,andthemothers
Aprocesscalledimprinting,whichoccursnatu
copyremainssilent(isnotexpressed)throughout
rallyinourcells,providesanotherexampleof
thelife oftheoffspring.
howepigeneticsaffectsgeneactivity.
Withmostgenes,thetwocopiesworkexactly
Scientistshavediscoveredthatthisselective
silencingofIgf2andmanyotherimprintedgenes
thesameway.Forsomemammaliangenes,how
occursinallplacentalmammals(allexceptthe
ever,onlythemothersorthefatherscopyis
platypus,echidnaandmarsupials)examined
switchedonregardlessofthechildsgender.This
sofar,butnotinbirds.
isbecausethegenesarechemicallymarked,or
Whywouldnaturetolerateaprocessthatputs
imprinted,duringtheprocessthatgenerateseggs
anorganismatriskbecauseonlyoneoftwo
andsperm.
copiesofageneisworking?Thelikelyreason,
Asaresult,theembryothatemergesfromthe
manyresearchersbelieve,isthatmothersand
joiningofeggandspermcantellwhetheragene
fathershavecompetinginterests,andthebattle
copycamefromMomorDad,soitknowswhich
eldisDNA!
copyofthegenetoshutoff.
Oneexampleofanimprintedgeneisinsulin
Thescenariogoeslikethis:Itisinafathers
interestforhisembryostogetbiggerfaster,
likegrowthfactor2(Igf2),agenethathelpsa
becausethatwillimprovehisoffspringschances
mammalianfetusgrow.Inthiscase,onlythe
ofsurvivalafterbirth.Thebetteranindividuals
34
chanceofsurvivinginfancy,thebetteritschance
StartingattheEnd
ofbecominganadult,matingandpassingits
WhenwethinkofDNA,wethinkofgenes.
genesontothenextgeneration.
However,someDNAsequencesaredifferent:
Ofcoursemotherswantstrongbabies,but
unlikefathers,mothersprovidephysicalresources
TheydontencodeRNAsorproteins.Introns,
describedinChapter1,areinthiscategory.
toembryosduringpregnancy.Overherlifetime,
Anotherexampleistelomerestheendsof
afemaleislikelytobepregnantseveraltimes,so
chromosomes.Therearenogenesintelomeres,
sheneedstodivideherresourcesamonganum
but theyserveanessentialfunction.Like
berofembryosindifferentpregnancies.
shoelaceswithouttheirtips,chromosomeswith
Researchershavediscoveredover200imprinted
outtelomeresunravelandfray.Andwithout
genesinmammalssincetherstonewasidentied
telomeres,chromosomessticktoeachotherand
in1991.Wenowknowthatimprintingcontrols
causecellstoundergoharmfulchangeslikedivid
someofthegenesthathaveanimportantrolein
ingabnormally.
regulatingembryonicandfetalgrowthandallocat
Researchersknowagooddealabouttelo
ingmaternalresources.Notsurprisingly,mutations
meres,datingbacktoexperimentsperformed
inthesegenescauseseriousgrowthdisorders.
inthe1970sbyElizabethBlackburn,abasic
MarisaBartolomeioftheUniversityof
PennsylvaniaSchoolofMedicineinPhiladelphia
researcherwhowascuriousaboutsomeofthe
fundamentaleventsthattakeplacewithincells.
istryingtogureouthowIgf2andothergenes
becomeimprintedandstaysilentthroughoutthe
lifeofanindividual.Shehasalreadyidentied
sequenceswithingenesthatareessentialfor
imprinting.Bartolomeiandotherresearchers
haveshownthatthesesequences,calledinsula
tors,serveaslandingsitesforaproteinthat
keepstheimprintedgenefrombeingtranscribed.
HESEDPADILLANASHANDTHOMASRIED
Telomeres,repeatednucleotidesequencesatthe
tipsofchromosomes,appearwhiteinthisphoto.
Atthetime,Blackburn,nowattheUniversity
ofCalifornia,SanFrancisco,wasworkingwith
JosephGallatYaleUniversity.Forherexperi
mentalsystem,shechoseasinglecelled,
CAROLGREIDER
ponddwellingorganismnamedTetrahymena.
Thesetiny,pearshapedcreaturesarecovered
withhairlikeciliathattheyusetopropelthem
selvesthroughthewaterastheydevourbacteria
andfungi.
Tetrahymena wasagoodorganismfor
Molecular biologist Carol Greider discovered the

enzyme telomerase. This license plate, which was
onhercarwhensheworkedatColdSpringHarbor
Laboratory on Long Island, New York, advertises
her research interest!
Blackburnsexperimentsbecauseithasalarge
numberofchromosomeswhichmeansithas
a lotoftelomeres!
Herresearchwasalsoperfectlytimed,because
an enzymethataddedcopiesoftherepeated
methodsforsequencingDNAwerejustbeing
sequencetothetelomeresofsomebutnotall
developed.BlackburnfoundthatTetrahymenas
chromosomes.
telomereshadanunusualnucleotidesequence:
WithherthengraduatestudentCarol
TTGGGG,repeatedabout50timespertelomere.
Greider, now at Johns Hopkins University,
Sincethen,scientistshavediscoveredthatthe
Blackburnhuntedfortheenzyme.Theteam
telomeresofalmostallorganismshaverepeated
founditandGreidernamedittelomerase.
sequencesofDNAwithlotsofTsandGs.In
Blackburn,GreiderandJackSzostakofHarvard
humanandmousetelomeres,forexample,the
MedicalSchoolinBostonsharedthe2009Nobel
repeatedsequenceisTTAGGG.
Prizeinphysiologyormedicinefortheirdiscov
Thenumberoftelomererepeatsvariesenor
mously,notjustfromorganismtoorganismbut
eriesabouttelomeresandtelomerase.
Asitturnsout,thetelomeraseenzymecon
indifferentcellsofthesameorganismandeven
sistsofaproteinandanRNAcomponent,which
withinasinglecellovertime.Blackburnreasoned
theenzymeusesasatemplateforcopyingthe
thattherepeatnumbermightvaryifcellshad
repeatedDNAsequence.
36
Whatisthenaturalfunctionoftelomerase?
TheOtherHumanGenome
Ascellsdivideagainandagain,theirtelomeres
Beforeyouthinkeverythingsbeensaidabout
getshorter.Mostnormalcellsstopdividingwhen
DNA,theresonelittlethingwedidntmention:
theirtelomeresweardowntoacertainpoint,and
SomeoftheDNAineverycellisquitedifferent
eventuallythecellsdie.Telomerasecancounter
fromtheDNAthatwevebeentalkingaboutup
acttheshortening.ByaddingDNAtotelomeres,
to thispoint.ThisspecialDNAisntinchromo
telomeraserebuildsthetelomereandresetsthe
somesitisnteveninsidethecellsnucleus
cellsmolecularclock.
whereallthechromosomesare!
Thediscoveryoftelomerasetriggerednew
SowhereisthisspecialDNA?Itsinsidemito
ideasandliterallythousandsof newstudies.
chondria,theorganellesinourcellsthatproduce
Manyresearchersthoughtthattheenzyme
theenergyrichmoleculeadenosinetriphosphate,
mightplayimportantrolesincancerandaging.
orATP.Mendelknewnothingofmitochondria,
Researcherswerehopingtondwaystoturn
sincetheywerentdiscovereduntillateinthe
telomeraseon sothatcellswouldcontinueto
19th century.Anditwasntuntilthe1960sthat
divide(togrowextracellsforburnpatients,
researchersdiscoveredthemitochondrialgenome,
forexample), or off sothatcellswouldstop
whichiscircularlikethegenomesofbacteria.
dividing(tostopcancer, forinstance).
Sofar,theyhavebeenunsuccessful.Although
Inhumancells,mitochondrialDNAmakes
up lessthan1percentofthetotalDNAineach
it isclearthattelomeraseandcellularagingare
of ourcells.Themitochondrialgenomeisvery
related,researchersdonotknowwhethertelo
smallcontainingonlyaboutthreedozengenes.
meraseplaysaroleinthenormalcellularaging
Theseencodeafewoftheproteinsthatareinthe
processorindiseaseslikecancer.
mitochondrion,plusasetofribosomalRNAs
Recently,however,Blackburnandateamof
usedforsynthesizingproteinsfortheorganelle.
otherscientistsdiscoveredthatchronicstressand
Mitochondrianeedmanymoreproteins
theperceptionthatlifeisstressfulaffecttelomere
though,andmostoftheseareencodedbygenes
lengthandtelomeraseactivityinthecellsof
in thenucleus.Thus,theenergyproducingcapa
healthywomen.Blackburnandhercoworkers
bilitiesofhumanmitochondriaavitalpartof
are currentlyconductingalongterm,followup
anycellseverydayhealthdependoncoordi
studytoconrmtheseintriguingresults.
natedteamworkamonghundredsofgenesin
twocellularneighborhoods:thenucleusandthe
mitochondrion.
Mitochondria(labeled
MitochondrialDNAgetstranscribedand
withareddye)are
scatteredthroughout
thecytoplasmofthis
humancancercell.
theRNAistranslatedbyenzymesthatarevery
differentfromthosethatperformthisjobfor
genesinourchromosomes.Mitochondrial
enzymeslookandactmuchmorelikethose
frombacteria,whichisnotsurprisingbecause
mitochondriaarethoughttohavedescended
fromfreelivingbacteriathatwereengulfedby
anothercelloverabillionyearsago.
ScientistshavelinkedmitochondrialDNA
Thecellhasalsobeen
defectswithawiderangeofagerelateddiseases
treatedwithadyethat
colorsthemitochondrial
DNAgreen.
includingneurodegenerativedisorders,some
formsofheartdisease,diabetesandvarious
cancers.
Itisstillunclear,though,whetherdam
agedmitochondriaareasymptomoracauseof
thesehealthconditions.
ScientistshavestudiedmitochondrialDNA
foranotherreason:tounderstandthehistoryof
thehumanrace.UnlikeourchromosomalDNA,
whichweinheritfrombothparents,wegetall
Acomputerizedoverlay
of ourmitochondrialDNAfromourmothers.
ofthesetwoimagesof
thesamecellshowsthat
mitochondriaandits
DNAappeartogether
(yellowregions).
Thus,itispossibletodeducewhoourmater
nalancestorswerebytrackingtheinheritanceof
mutationsinmitochondrialDNA.Forreasons
thatarestillnotwellunderstood,mutations
accumulateinmitochondrialDNAmorequickly
thaninchromosomalDNA.So,itspossibleto
traceyourmaternalancestrywaybackbeyond
waybacktoAfricanEve,theancestorofusall!
ALISONDAVIS
anyrelativesyoumayknowbynameallthe
38
TheToolsofGenetics:RecombinantDNAandCloning
E.coli bacteria,taken
fromhumanintestine
Nucleus
Humancell
Plasmid
E.coli
chromosome
StrandofDNAfromhumancell
Plasmidremoved
fromE.coli
HumanDNAcutintopieces
byrestrictionenzyme
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.
Humaninsulingene
Twopiecessplicedtogether
RecombinantDNA
(hybridplasmid)
Humaninsulingene
Humanplasmid
insertedintoE.coli cell
Bacteriawithhybridplasmidreplicate,creating
clonecapableofproducinghumaninsulin
ROSLININSTITUTE,EDINBURGH
ScientistsinScotlandwerethe
rsttocloneananimal,thissheep
namedDolly.Shelatergavebirth
toBonnie,thelambnexttoher.
Intheearly1970s,scientists
sequence.Mostrestrictionendo
discoveredthattheycould
nucleasesmakeslightlystaggered
changeanorganismsgenetic
incisions,resultinginstickyends,
traitsbyputtinggenetic
outofwhichonestrandprotrudes.
materialfromanotherorgan
Thenextstepinthisexampleis
ismintoitscells.Thisdiscovery,whichcaused
tosplice,orpaste,thehumaninsulingeneinto
quiteastir,pavedthewayformanyextraordinary
acircleofbacterialDNAcalledaplasmid.
accomplishmentsinmedicalresearchthathave
Attachingthecutendstogetherisdonewith
occurredoverthepast35years.
a differentenzyme(obtainedfromavirus),
Howdoscientistsmovegenesfromone
calledDNAligase.Thestickyendsjoinback
organismtoanother?Thecuttingandpasting
togetherkindoflikejigsawpuzzlepieces.The
getsdonewithchemicalscissors:enzymes,tobe
result:acutandpastedmixtureofhuman
specic.Takeinsulin,forexample.Letssayasci
andbacterialDNA.
entistwantstomakelargequantitiesof this
Thelaststepisputtingthenew,recombi
proteintotreatdiabetes.Shedecidestotransfer
nantDNA backintoE.coli andlettingthe
thehumangeneforinsulinintoabacterium,
bacteriareproduceinapetridish.Now,the
Escherichiacoli,orE.coli,whichiscommonly
scientisthasagreattool:aversionof E.coli
usedforgeneticresearch(seeLivingLaboratories,
thatproduceslotsofhumaninsulinthatcan
page46).ThatsbecauseE.coli reproducesreally
beusedfortreatingpeoplewithdiabetes.
fast,soafteronebacteriumgetsthehuman
GotIt?
Besidesthesequenceof
nucleotidesingenes,what
aresomeotherchangesto
DNAandRNAthatcan
affectourhealthandwho
weare?
Canyouimaginetreat
mentsotherthan
vaccinesandcurrent
medicinescraftedfrom
geneticinformationand
newmoleculartools?
So,whatiscloning?Strictlyspeaking,its
insulingene,itdoesnttakemuchtimetogrow
makingmanycopies.However,thetermis
millionsofbacteriathatcontainthegene.
morecommonlyusedtorefertomaking
Howiscloningagene
manycopiesofagene,asintheE.coli
different
fromcloningan
acopied,orcloned,versionofthehumanDNA
exampleabove.Researcherscanalsoclone
animaloraperson?How
usingaspecialbacterialenzymefrombacteria
entireorganisms,likeDollythesheep,which
doresearchersusegene
calledarestrictionendonuclease.(Thenormalrole
containedtheidenticalgeneticmaterialof
cloningtostudyhealth
oftheseenzymesinbacteria
istochewupthe
anothersheep.
anddisease?
Therststepistocuttheinsulingeneoutof
DNAofvirusesandotherinvaders.)Eachrestric
tionenzymerecognizesandcutsatadifferent
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.
Time
Becauseofbiologicalevolution,earlyhumans
gainedtheabilitytowalkontwofeet.Becauseof
evolution,airbreathingwhalescanliveinthe
oceandespitebeingmammalslikeus.Becauseof
evolution,somebacteriacanliveinscaldingwater,
otherscansurviveinsolidiceandstillotherscan
livedeepintheEartheatingonlyrocks!
Evolutionhappenseveryday,anditaffects
everyspeciesincludingus.Itchangesentire
populations,notindividuals.Andithasabig
impactonmedicalresearch.
EverythingEvolves
Tounderstandevolution,letsgobackintime a
centuryandahalfto1854,when theBritish
naturalistCharles DarwinpublishedThe Origin
Firstlivingspecies
TheNewGenetics I LifesGeneticTree 41
CharlesDarwindescribed
evolutioninhisclassictext,
TheOriginofSpecies.
ofSpecies,abookthat
proposedanexplanationfor
howevolutionworks.
Themainconceptinevolutionisthatall
livingthingsshareacommonancestor.Thevery
earliestancestorofalllifeformsonEarthlived
about4billionyearsago.Fromthatearlyorgan
withinagivengenerationwillsurvivelong
ism,millionsoftypesofcreaturessomeliving
enoughtoreproduce.
andsomenowextincthaveevolved.
Evolutionrequiresdiversity.Youcantellthat
Asanexample,considerhouseies,eachof
whichlaysthousandsofeggseveryyear.Why
livingthingsarediversejustbywalkingdownthe
haventtheytakenovertheworld?Because
streetandlookingaroundyou.Individualpeople
almostallofthebabyhouseiesdie.Theiesthat
areverydifferentfromoneanother.Chihuahuas
survivearetheonesthatcanndsomethingto
aredifferentfromGreatDanes,andSiamesecats
eatanddrinktheonesthatavoidbeingeaten,
aredifferentfromtabbies.
steppedonorswattedandtheonesthatdont
Evolutionalsodependsoninheritance.Many
ofouruniquecharacteristicsareinheritedthey
freeze,drownorlandonabugzapper.
Theiesthatsurviveallthesewaystodiehave
arepassedfromparenttooffspring.Thisiseasy
whatittakestooutlivemostoftheirbrothersand
tosee:DalmatianpuppieslooklikeDalmatians,
sisters.Theseinheritedtraitsgiveanorganisma
notChihuahuas.Petuniasgrowdifferentlyfrom
survivaledge.Thosewhosurvivewillmatewith
pansies.Evolutionworksonly ontraitsthatare
eachotherandwillpassontothenextgeneration
inherited.
someoftheirDNAthatencodedtheseadvanta
Finally,asyouprobablyalreadyknow,
evolutionfavorsthettest.Throughaprocess
callednaturalselection,onlysomeoffspring
geoustraits.
Ofcourse,notallaspectsofsurvivalare
determined
bygenes.Whetheraygetsswatted
42
dependsongenesthataffectitsreexeswhether
discoveredararegeneticvariant thatprotects
itsfastenoughtoavoidtheswatter butalso
peoplefromgettingAIDS.Ageneticvariantisa
on theenvironment.Iftheresnohumanaround
differentversionofagene,onethathasaslightly
waving
theswatter,theyisquitelikelytosur
differentsequenceofnucleotides.
vive,regardlessofitsreexes.
Evolutionoftentakesalongtimetomakea
Scientiststhinkthattherarevariantofagene
calledCCR5originallymayhavebeenselected
difference.Butitcanalsohappenveryquickly,
duringevolutionbecauseitmadepeopleresistant
especiallyinorganismswithshortlifespans.For
toanorganismunrelatedtoHIV.
example,asyoureadearlier,somebacteriahave
molecularfeaturesthatletthemsurviveinthe
presenceofantibiotics.Whenyoutakean
antibiotic
medicine,antibioticresistantbacteria
ourishwhileantibioticsensitivebacteriadie.
Becauseantibioticresistanceisagrowing
publichealththreat,itsimportanttotakethe
wholecourseofantibioticmedicine,notstop
whenyoufeelbetter.Andyoushouldtakeantibi
oticsonlywhentheyreneeded,notforcolds
or otherviralinfections,whichantibiotics
cant treat.
MontgomerySlatkinoftheUniversityof
California,Berkeley,hasusedmathematical
techniquestoshowthatnaturalselec
modeling
tionovertimecouldexplainthefrequencyofthe
CCR5variantinhumanpopulations.Thework
indicatesthattheCCR5genevariantsabilityto
protectagainstAIDSmaycontributetokeepingit
inthehumangenepool.
So,throughevolution,livingthingschange.
Sometimes,thatsgoodforus,aswhenhumans
understandHIVresistanceinhopesofpreventing
AIDS.Butsometimesthechangesarentsogreat
SelectiveStudy
fromahumanperspective,anywayaswhen
Scientistsdoingmedicalresearchareveryinter
bacteriabecomeresistanttoantibiotics.
estedingeneticvariantsthathavebeenselected
byevolution.Forexample,researchershave
Differentnucleotides
(inthisexample,Aor
G)canappearinthe
DNAsequenceofthe
samechromosome
fromtwodifferent
individuals,creating
asinglenucleotide
polymorphism(SNP).
Whethertheconsequencesofevolutionary
changearegoodorbad,understandingthe
TCG A TAA TG CA TG CA TA
OnepersonsDNA
TCG A TA G TG CA TG CA TA
AnotherpersonsDNA
Haplotypesarecombina
Originalhaplotype
onchromosome
TAT
CAT
10,000nucleotides
Haplotype1
C
AT
CAT
TAT
CA A
TAT
C CA
CG
CAT
Haplotype2
Haplotype3
Haplotype4
T
process canhelpusdevelopnewstrategiesfor
polymorphisms(abbreviatedSNPsandpro
ghtingdisease.
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
different
versionsofthatgene.Scientistscallthe
different
geneversionsalleles.
Iftwogenessitrightnexttoeachotherona
chromosome,theSNPsinthosegenestendtobe
inheritedtogether.ThissetofneighboringSNPs
is calledahaplotype (seedrawingabove).
Mostchromosomeregionshaveonlyafew,
commonhaplotypesamongallhumans.Asit
turnsout,thesefewhaplotypesindifferent
combinationsineachpersonappeartoaccount
formostofthevariationfrompersontoperson
in apopulation.
tionsofgenevariants,or
SNPs,thatarelikelytobe
inheritedtogetherwithin
thesamechromosomal
region.Inthisexample,an
originalhaplotype(top)
evolvedovertimetocreate
threenewerhaplotypes
thateachdifferbyafew
nucleotides(red).
44
Scientistscanusehaplotypeinformation
to comparethegenesofpeopleaffectedbya
disease
withthoseofunaffectedpeople.For
example,thisapproachrevealedageneticvaria
tionthatsubstantiallyincreasestheriskof
agerelatedmaculardegeneration,theleading
causeofseverevisionlossintheelderly.Scientists
discoveredthatasingleSNPonenucleotidein
the3billionnucleotidehumangenomemakes
somepeoplemorelikelytogetthiseyedisease.
Thediscoverypavesthewayforbetterdiagnostic
testsandtreatments.
Whataboutotherdiseases?In2007,an
internationalscienticteamcompletedacatalog
environments.Hesalsocuriousaboutwhether
ofcommonhumanhaplotypes.Sincethen,
it cancreateproblemsforsomeindividuals.
researchershavebeenusingthecatalogtoidentify
Youmightbesurprisedtolearnthat
genesassociatedwithsusceptibilitytomanycom
Riesebergsprincipalresearchsubjectisthesun
mondiseases,includingasthma,diabetes,cancer
ower.Althoughmanyplantsproduceonlyone
andheartdisease.
generationayear,plantslikesunowerscanbe
ButnotallSNPsareingenes.Scientistsstudy
veryusefultoolsforresearchersaskingfunda
inggeneticvariationhavealsofoundSNPsin
mentalquestionsaboutgenetics.Becausetheir
DNAthatdoesntencodeproteins.Nonetheless,
geneticmaterialismoremalleablethanthatof
someoftheseSNPsappeartoaffectgeneactivity.
manyanimals,plantsareexcellentmodelsfor
Someresearcherssuspectthatthecryptic
(hidden)variationassociatedwithSNPsin
studyinghowevolutionworks.
WildsunowersappealedtoRieseberg
noncodingDNAplaysanimportantrolein
becausethereareseveralspeciesthatlivein
determiningthephysicalcharacteristicsand
differenthabitats.Twoancientspeciesofwild
behaviorsofanorganism.
sunowersgrowinmoderateclimatesandare
LorenRiesebergofIndianaUniversityin
Bloomingtonisonescientistwhowouldlove
to takethemysteryoutofcrypticvariation.He
broadlydistributedthroughoutthecentraland
westernUnitedStates.
Threerecentlyevolvedsunowerspecieslive
wantstoknowhowthisnoncodinggenetic
inmorespecializedenvironments:Oneofthe
variation
canhelporganismsadapttonew
newspeciesgrowsonsanddunes,anothergrows
indrydesertsoilandthethirdspeciesgrowsin
a saltmarsh.
Toseehowquicklynewplantspeciescould
ButwhenRieseberglookedatthegenomes
of hishybridsunowers,hewassurprisedto
nd thattheywerejustcutandpastedversions
evolve,Riesebergforcedthetwoancientsunow
of theancientsunowerspeciesgenomes:
erstointerbreedwitheachother,something
largechunkshadbeen
plantsbutnototherorganismscando.Among
movedratherthanmany
thehybridprogenyweresunowersthatwerejust
newSNPscreated.
likethethreerecentlyevolvedspecies!Whatthat
Riesebergreasons
meansisthatRieseberghadstimulatedevolution
thatplantsstashaway
inhislab,similartowhatactuallyhappenedin
unusedgeneticmaterial,
naturesome60,000to200,000yearsago,when
givingthemareadysupplyof
thenewerspeciesrstarose.
ingredientstheycanusetoadapt
ThatRiesebergcoulddothisisprettyamaz
quicklyto anewenvironment.Itmaybethat
ing,butthereallyinterestingpartishowit
humangenomescanrecycleunusedgenetic
happened.Scientistsgenerallyassumethat,fora
toconfrontnewchallenges,aswell.
material
newspecieswithverydifferentcharacteristicsto
evolve,alotofnewmutationshavetooccur.
Plantslikethesesunowers
makegreatmodelsforstudy
inghowevolutionworks.
ALISONDAVIS
46
Living
Laboratories
Likemostpeople,youprobablythinkoffruities
REX L. CHISHOLM
Belowisasamplingofthewidevarietyof
askitchennuisances.Butdidyouknowthatsci
living
laboratoriesthatscientistsareusingto
entistsusetheseorganismsformedicalresearch?
advancehumanhealth.
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.
1 Escherichiacoli:Bacterium
Onceweunderstandthebiologyof Escherichia
coli, wewillunderstandthebiologyofanele
phant. SosaidJacquesMonod,aFrenchscientist
whowonthe1965NobelPrizeinphysiologyor
medicineforhisworkongeneregulation.Monod
wasanearlyproponentofthevalueofexperi
mentingwithsimpleorganismslikebacteria.Are
allbacteriabad?IfallyouveeverheardaboutE.
coli isitsnotoriouslinktotaintedhamburger
meat,youmaynotrealizethatnondiseasecausing
strainsofthebacteriumliveintheintestinaltracts
ofhumansandotheranimals,helpingthemina
varietyofways.Foronething,thesebacteriaare
a mainsourceofvitaminKandBcomplex
vitamins.Theyalsoaiddigestionandprotect
againstinfectionbyharmfulbacteria.
NAMBOORI B. RAJU
Scientistsallovertheworldhavebanded
Dicty normallygrowsasseparate,independent
togethertosequencedifferentversionsofthe
cells.However,whenfoodislimited,neighboring
E.coli genome.Amongotherthings,thesestudies
cellspileontopofeachothertocreatealarge,
willhelpdistinguishthegeneticdifferences
multicelledstructurecontainingupto100,000
betweenbacteriainahealthyhumangutand
cells.Thisblobamblesalonglikeaslug,leaving
thosethatcausefoodpoisoning.
a trailofslimebehind.Aftermigratingtoamore
suitableenvironment,theblobrmsupintoa
2 Dictyosteliumdiscoideum: Amoeba
Thismicroscopicamoeba100,000ofthem
form amoundasbigasagrainofsandisan
importanttoolforhealthstudies.Scientistshave
determinedthatDictyosteliumdiscoideum(Dicty)
hassomewherebetween8,000and10,000genes,
towerlikestructurethatdispersesspores,each
capableofgeneratinganewamoeba.Becauseof
itsunusualpropertiesandabilityto livealoneor
inagroup,Dicty intriguesresearcherswhostudy
celldivision,movementandvariousaspectsof
organandtissuedevelopment.
manyofwhichareclosecopiesofthoseinpeople
andanimalsbutaremissinginanothersingle
3 Neurosporacrassa:BreadMold
celledorganism,yeast.Dicty wasrstdiscovered
Chancesareyoudontthinkofamoldybread
in the1930sinaNorthCarolinaforestandhas
crustasapotentialscienceexperiment,but
sincebeenfoundinmanysimilarhabitatsaround
thousandsofresearchersaroundtheworlddo!
theworld.
Neurosporacrassa(Neurospora),whichis
a speciesofmoldthatthriveson bread,isawidely
usedmodelorganismforgeneticresearch.
48
GARY DITTA
ALAN WHEALS
BiologistsliketouseNeurospora because
likeyeastbecauseitgrowsfast,ischeaptofeed
itissimpleto growandhasfeaturesthatmake
andsafetohandle,anditsgenesareeasytowork
itverysuitableforansweringquestionsabout
with.Weknowalotaboutmammaliangenes
howspeciesariseandadapt, aswellashowcells
becausescientistscaneasilyinsertthemintoyeast
and tissues change their shape in different
andthenstudyhowtheyworkandwhathappens
environments.SinceNeurospora producesspores
whentheydontwork.
ona24hourcycle,theorganismisalsouseful
for studying the biological clocks that govern
sleep, wakefulness and other rhythms of life.
5 Arabidopsisthaliana:MustardPlant
Researcherswhostudyplantgrowthoftenuse
Arabidopsisthaliana(Arabidopsis),asmall,
4 Saccharomycescerevisiae:Yeast
owering
plantrelatedtocabbageandmustard.
Therearehundredsofdifferentkindsofyeast,but
This organismisappealingtobiologistsbecause
Saccharomycescerevisiae,theonescientistsstudy
Arabidopsis hasalmostallofthesamegenesas
mostoften,isanimportantpartofhumanlife
otheroweringplantsandhasrelativelylittle
outsidethelab,too.Itistheyeastthatbakersuse
DNA thatdoesnotencodeproteins,simplifying
tomakebreadandbrewersuseforbeer.
thestudyofitsgenes.Likepeopleandyeast,
LikeNeurospora,yeastis actuallyafungus
plantsare alsoeukaryotes.Arabidopsis grows
nota plant,notananimal,butrelatedtoboth.
quickly,goingfromseedtomatureplantinonly
It isalsoaeukaryote(asisNeurospora)a
6weeksanotherplusforresearcherswhostudy
higherorganismwithanorganized,protective
howgenesaffectbiology.
nucleusthatholdsitschromosomes.Researchers
7
Whatdoyouhaveincommonwithamustard
hasalotofgenesmorethan19,000(humans
plant?Plantcells,andpartsofplantcells,com
haveabout20,000).DecodingtheC.elegans
municatewitheachotherinmuchthesameway
genomewasahugemilestoneforbiology,since
thathumancellsdo.Forthatreason,plantsare
it wastherstanimalgenometobesequenced
goodmodelsforgeneticdiseasesthataffect
completely.Scientistsquicklylearnedthatavast
cell communication.
numberofgenesinC.elegans arevery similar

to genesinotherorganisms,includingpeople.
6 Caenorhabditiselegans:Roundworm
Caenorhabditiselegans(C.elegans) isacreature
7 Drosophilamelanogaster: FruitFly
thatisalotsmallerthanitsname!Severalof
Thefruityspeciesmostcommonlyusedfor
theseharmlessroundwormswouldtonthe
researchisnamedDrosophilamelanogaster
headofapin,althoughtheirusualhabitatis
(Drosophila).Ageneticistsfruityispretty
dirt.Inthelab,theyliveinpetridishesandeat
muchthesameastheonesthatyaroundyour
bacteria.C.eleganscontainsjust959cells,
overripebananas.Inthelab,though,someof
almostathirdofthemformingitsnervous
theiesareexposedtodamagingchemicalsor
system.Researchersknowthe fateofeveryone
radiation,whichchangesthesequenceoftheir
ofthesecells!
DNA.Researchersallowtheiestomate,then
Thiswormisparticularlyprizedbybiologists
searchamongtheoffspringforieswith
becauseitistransparent,sowhatgoesoninits
abnormalities.Themutantiesarethenmated
tinybodyisinplainviewunderamicroscope.
toproducemoreoffspringwiththeabnormality,
But forsuchasmall,simpleanimal,C.elegans
enablingresearcherstocloseinonthedefective
genesinvolved.
50
MONTE WESTERFIELD
Fruitieshavebeenafavoriteexperimental
Manyresearchersaredrawntozebrash
organismamonggeneticistssinceearlyinthe
becausetheireggsandembryosaretransparent,
20thcentury.Hundredsofthemcanliveina
makingitpossibletowatchdevelopmentunfold.
pintsizedmilkbottleorevenasmallvial,and
Inaspanof2to4days,zebrashcellssplitand
theyreproducesoquicklythatkeepingtrack
formdifferentpartsofthebabyshsbody:eyes,
ofaparticulargeneasitpassesthroughacouple
heart,liver,stomachandsoon.Sometimes,
ofDrosophila generationstakesonlyabouta
researcherswillmoveacelltoanotherspottosee
month.Itsalsorelativelyeasytocreateieswith
ifitwillstillgoontoformthesamepartofthe
mutationsinmanygenes,enablingscientiststo
bodyorifitwilldosomethingdifferent.This
studyhowthegenesworktogether.
researchhastaughtscientistsaboutarangeof
healthrelatedmattersinpeople,includingbirth
8 Daniorerio:Zebrash
Zebrashwereoriginallyfoundinslowstreams,
defectsandtheproperdevelopmentofblood,the
heartandtheinnerear.
ricepaddiesandtheGangesRiverinEastIndia
andBurma.Theycanalsobefoundinmostpet
9 Musmusculus:Mouse
storesandareahomeaquariumfavorite.
Thebranchesoflifesgenetictreethatledeventu
Althoughtheshhavebeenusedbysome
allytomiceandtohumanbeingssplitofffrom
geneticistsforresearchsincetheearly1970s,in
eachother75millionyearsago,backinthe
recentyearstheyhavebecomeanespecially
dinosaurage.Butwearebothmammals,andwe
popularmodelorganism.
share85percentofourgenes.Becausesome
mousediseasesareverysimilarsometimes
10
identicaltohumandiseases,miceare
exceptionallyvaluableforresearch.
Sincethelate1980s,researchershavebeen
Althoughratsaremammalsjustlikemice,
theydifferinimportantways.Ratsaremuch
biggerthanmice,makingiteasierforscientists
abletoengineermicewithmissinggenes.
todoexperimentsthatinvolvethebrain.For
Scientistsmaketheseknockoutmicetolearn
example,ratshavetaughtscientistsalotabout
whatgoeswrongwhena particulargeneis
substanceabuseandaddiction,learning,memory
removed.Thisgivesthemvaluablecluesabout
andcertainneurologicaldiseases.Ratsarealso
thegenesnormalfunction.Identifyingthese
muchbettermodelsthanmiceforstudying
genesinhumanshashelpeddenethemolecular
asthmaandlunginjury.Andsince,inpeople,the
basisformanyillnesses.
diseasearthritisismorecommoninwomen,
studyingratsmakesmoresensebecausefemale
10 Rattusnorvegicus:Rat
TheNorwayrat,orlabrat,wastherstanimal
ratsappeartobemoresusceptibletoarthritis
thanmalerats.Theoppositeistruewithmice.
domesticatedforuseinscienticresearch.
Currently,theymakeupaboutonefourthofall
researchanimalsintheUnitedStates.Labratshave
beenusedformanydecadesfortestingdrugs,and
muchofwhatweknowaboutcancercausing
moleculeswaslearnedinbasicresearchwithrats.
ThisLivingLaboratories sectionis
availableasaposter.Toorderafreecopy,
visithttp://publications.nigms.nih.gov/order.
52
TheGenomeZoo
longeragothantheancestorof humansand
Scientistsoftenuseanimageofatreetodepict
chimpanzees,yetwestillsharehundredsofgenes
howallorganisms,livingandextinct,arerelated
withbacteria.
to acommonancestor.Inthistreeoflife,each
Scientistsusethetermcomparativegenomics
branchrepresentsaspecies,andtheforksbetween
todescribewhattheyredoingwhentheycom
branchesshowwhenthespeciesrepresentedby
parethegenomesofdifferentspeciestoseehow
thosebranchesbecamedifferentfromoneanother.
similar(orhowdifferent!)thespeciesDNA
Forexample,researchersestimatethatthe com
sequencesare.Sequencesthatthespecieshavein
monancestorofhumansandchimpanzeeslived
commonarethemolecularfootprintsofan
about6millionyearsago.
ancestorofthosespecies.
Whileitisobviousjustbylookingthatpeople
WhyareoldDNAsequencesstillinour
havealotincommonwithourclosestlivingrela
genomes?Itturnsoutthatnatureisquiteeco
tives,chimpanzees,whataboutmoredistant
nomical,soDNAsequencesthatareresponsible
species?Ifyoulookatanevolutionarytree,youll
forsomethingascomplicatedandimportantas
seethathumansarerelatedtomice,wormsand
controllinggeneactivitymaystayintactfor
evenbacteria.Theancestralspeciesthatgaverise
millions
ofyears.
tobothhumansandbacteriawasalivealot
Comparativegenomicstudiesalsohavemed
icalimplications.Whatwouldyoudoifyou
wantedtodevelopnewmethodsofpreventing,
diagnosingortreatingahumandiseasethat
animals
dontget?
PHILLIPNEWMARK
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
Ifpeoplehaveagenethatinuencestheirrisk
cytochromeP450family,abbreviated3A4and
foradisease,andmicehavethegenetoo,you
3A5,encodeproteinsthatprocessmorethanhalf
couldstudysomeaspectofthediseaseinmice,
ofallofthemedicinesthataresoldtoday.
eventhoughtheydonteverhavethesymptoms
Sincethechemicalstowhichpeopleare
of thedisease.Youcouldevenstudythedisease
exposedvarysowidely,ascientistmightpre
in yeast,ifithasthegene,aswell.
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
populations.Usingcomparativegenomics,
researcherssuchasAnnaDi Rienzoofthe
UniversityofChicagohave shownthatthisis
indeedthecase.DiRienzohasfoundmany
sequencedifferenceswithinthesegenesinpeople
livingthroughoutthe world.
Itturnsoutthatonevariantofthegenethat
encodesthecytochromeP4503A5proteinmakes
thisenzymeveryefcientatbreakingdown
cortisol,
ahormonethatraisessaltlevelsinthe
kidneysandhelpsthebodyretainwater.DiRienzo
comparedtheDNAsequencesofthe3A5 genein
DNAsamplestakenfrommorethan1,000people
medicines. In fact, just two genes within the
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.
54
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
developing.Inpeopleandratswiththegenetic
wasamazedtondastrikinglinkbetweenthe
signature,shereasons,thetumorsuppressor
existenceofthegenevariantandthegeographic
doesntworkright,sotumorsgrow.
localeofthepeoplewhohaveit.
DiRienzodiscoveredthatAfricanpopulations
Takingthislogiconestepfurther,itmaybe
thatcertainpeoplesgeneticmakeupmakes
livingveryclosetotheequatorweremorelikely
themunusuallysusceptibletoDNAdamage
thanotherpopulationstohavethesaltsaving
causedbyexposuretocarcinogens.Ifdoctors
version
ofthe3A5gene.Shesuggeststhatthisis
couldidentifythoseatrisk,Lausays,suchpeople
becausethisgenevariantprovidesahealth
couldbeforewarnedtoavoidcontactwithspe
cicchemicalstoprotecttheirhealth.
However,thinkaboutthisscenario:Who
shouldmakethosedecisions?Forexample,
would itbeethicalforanemployertorefuseto
hiresomebodybecausethepersonhasagenetic
Theliverandkidneysare
signaturethatmakeshimorhermorelikelyto
susceptibletodamagefrom
toxinssincethesebody
organsprocesschemicals.
getcancerifexposedtoachemicalusedinthe
workplace?Toughquestion.
Liver
Kidneys
56
GENETICS AND YOU:
YouveGotRhythm!
hatdowaking,sleeping,
The human body keeps time with
eating,reproducingand
a master clock called the suprachiasmatic
birdsyingsouthforthe
nucleus or SCN. Situated inside the brain,
winterhaveincommon?Theseareall
itsatinysliveroftissueaboutthesizeofa
examplesofnaturesamazingsenseof
grainofrice,locatedbehindtheeyes.Itsits
rhythm.Alllivingthingsareequipped
quiteclosetotheopticnerve,whichcon
withmoleculartimepiecesthatsetthe
trolsvision,andthismeansthattheSCN
pulseoflife.
clockcankeeptrackofdayandnight.
Ifyouveevercrossedthecountryor
Givenenoughtime,yourSCNcanreset
anoceanbyplane,youknowaboutthe
itselfafteryouyinanairplanefromone
importanceoftheseclocks.Youproba
timezonetoanother.
blyexperiencedthattravelersmisery
TheSCNhelpscontrolsleepbycoordi
calledjetlag,wherethebodyisforced
natingtheactionsofbillionsofminiature
to adaptquicklytoanewtimezone.
clocksthroughoutthebody.Thesearent
Butdidyouknowthatcertainforms
actuallyclocks,butratherareensemblesof
ofinsomniaandmanicdepressiveillness
genesinsideclustersofcellsthatswitchon
areassociatedwithbiologicalclocks
andoffinaregular,24hourcycleour
notworkingproperly?Andbiological
physiologicalday.
rhythmsmaybethereasonwhysome
Scientistscallthis24houroscillation
medicinesandsurgicaltreatments
acircadian rhythm.(Circadiancomesfrom
appeartoworkbestatcertaintimes
theLatinwordsmeaningapproximately
ofday.
aday.)Researchershavediscoveredthat
alllivingthingsplants,animalsandbac
Light
Outputrhythms:
physiology
behavior
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
Althoughtheshaker iesdont
4hoursofsleep.Researchershavenoted
appearsleepdeprived,Cirellifoundthat
thatthistraitseemstoruninfamilies,
theyhaveadifferentproblem:They
suggestingageneticlink.
dontliveaslongasieswithoutthe
Asitturnsout,fruitiesneedeven
mutation.Sheisnowstudyingthisnew
moresleepthanpeople.Neuroscientist
connectionbetweensleepandlifespan.
Chiara Cirelli of the University of
Herworkmayalsopavethewayfor
WisconsinMadisondidageneticsearch
improvedsleepaidsandeffective
for fruit fly mutants that dont sleep
remediesforjetlag.
much.Shediscoveredthatieswitha
variantofagenecalledshaker sleep
only3to4hourspernight.
58
AnimalsHelpingPeople
melanogaster,afruityspecieswidelyused
UsingtechnologythatgrewoutoftheHuman
ingeneticresearch(seeLivingLaboratories,
Genome Project, scientists have read the
page49).
sequencesofthegenomesofhundredsoforgan
Currently,Bierandotherscientistsareusing
isms:dogs,mice,rats,chickens,honeybees,fruit
experimentaliestoinvestigateawiderangeof
ies,seaurchins,puffersh,seasquirts,round
genesinvolvedinconditionssuchasblindness,
wormsandmanybacteriaandfungi.Nextin
deafness,mentalretardation,heartdiseaseand
line aredozensofadditionalspecies,including
the wayinwhichbacterialtoxinscauseillness.
a marmoset,aseaskate,analpaca,ananteater
and manyreptiles.
Whateffectwillallthisgenesequenceinfor
mationhaveonmedicalresearch?Wevealready
talkedaboutthefactthatpeoplesharemanyof
ByreadingtheDNAsequencesofmanyother
species,researchershopetondmodelsystems
thatareevenbetterthanfruitiesforstudying
someaspectsofhumandisease.
Sometimes,thegenesthatwedonthavein
theirgeneswithotherspecies.Thismeansthat
commonwithotherspeciesareasimportantas
whenscientistsreadthesequenceofanother
thegenesweshare.Forexample,considerthefact
speciesgenome,theyrelikelytodiscoverthatthe
thathumansandchimpanzeeshaveremarkably
organismhasmanyofthegenesthat,inhumans,
differentabilitiesandphysicalfeatures.Butthe
causediseaseorraisediseaseriskwhenmutated.
chimpanzeegenomeis99percentidenticalto
Takefruitiesasoneexample.Accordingto
biologistEthanBieroftheUniversityofCalifornia,
SanDiego,30percentofthecurrentlyidentied
humandiseasegenesmostlikelyhavefunctional
counterpartsinnoneotherthanDrosophila
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
things,theprogramscangureoutwherein
involvelookingforsimilaritiesanddifferences,
the DNAsequencesagenestartsandstops:
but itisntsomethingthatscientistsdobyhand.
its boundaries.
Certainlynotforthousandsofgenesatatime.
Rather,thegigantictaskofcomparingthe
Otherresearcherswhoworkintheeldof
bioinformatics minegenomicinformationhid
nucleotidesthatmakeupthegenomesoftwoor
deninthemassesofdata.Theyarelookingfor
morespeciesistheperfectjobforacomputer,a
scientictreasureintheformofnewbiological
naturalmultitasker.Ifyouconsiderthatthe
knowledge.Theseexperimentscanzeroinonpre
humangenomecontains3billionnucleotides,
viouslyhiddenpatternsandreveallinksbetween
you caneasilyseewhythisisworkwellsuitedto
differenteldsofresearch.
a machine(withahumanoperator,ofcourse).
Researcherscalledcomputationalbiologists
Bioinformaticistsandcomputationalbiolo
gistsareinhighdemandbecausetheyplayavery
helpanalyzegenomicdata.Thesescientists
importantrolein21stcenturymedicalscience.
developsoftwareprogramsthatenablecomputers
Thesescientistsmustbeuentinbothcomputer
toperformgenomecomparisons.Amongother
scienceandbiology.
60
TheToolsofGenetics:UnlimitedDNA
Youmightbeamazedtolearnthatamicrobethat
essentialtoalaboratorytechniquecalledthe
livesinaboilinghotspringinYellowstone
polymerase
chainreaction,or PCR.AndPCR
NationalParkistheessentialingredientforone
is essentialtolotsofthingsthatlifescientists
ofthemostimportantbiologicalresearchtools
doandtomanyotherelds,too.PCRsinven
everinvented.
tor,KaryMullis,won the1993NobelPrizein
Thermusaquaticus isabacteriumthatmakes
aheatresistantenzyme,whichiswhyit canthrive
inhotsprings.Theenzyme,Taqpolymerase,is
chemistry.
PCRisaquick,easymethodforgenerating
unlimitedcopiesoftinyamountsofDNA.Words
. Amicrobethatlivesinhotsprings,likethisonein
YellowstoneNationalPark,ishometotheenzyme
thatmakesthepolymerasechainreaction,or
PCR,possible.
PCRmachine.
APPLIEDBIOSYSTEMS
GotIt?
Discussreasonswhyresearch
likerevolutionaryand
breakthrougharenotan
exaggerationofitsimpact.
PCRisattheheartof modernDNA
PCRisakeyelementof
geneticngerprinting,whichhas
helpedfreeprisonerswhoreliedonittoprove
got themlockedup.Conversely,ithaspro
pinpointingmutationsingenes,
soitisthe
videdscienticevidencethathelpedconvict
basisformuchoftheresearchdiscussedin
criminals.
PCRhasevenrevolutionizedarchaeology
whattheinventionof theprintingpressdid
byhelpingtoanalyzebadlydamagedancient
forwrittenmaterial.Itmakescopyingeasy,
DNAsometimesthousandsofyears
inexpensiveandwidelyavailable.
oldwhichcanrevealnewinformation
PCRunderliesmanydiagnostictechniques,
liketestingindividualsfor genesthatcause
canprovidevaluableinforma
tionabouthealthanddisease.
thattheywereinnocentofthecrimesthat
sequencing methods.Itisessentialfor
this booklet.PCRhasdoneforgeneticmaterial
studieswithidenticaltwins
aboutpastpeopleandcultures.
Humansandmiceshareover
80percentofthesame
geneticmaterial:forchimps
andhumans,it smorethan99
percent.Whyarepeopleand
animalssodifferent,iftheir
genesaresosimilar?
ScientistspredictthatfutureusesofPCR
breast cancer.Itcanalsohelpdiagnosediseases
technologywillenhancemedicaltreatment,
otherthancancer,suchas infectionsbyHIV
enablingbetterdiagnosisandmoreaccurate
and hepatitisC.
subtypingofdisease.
Youareascientistandyou
wanttolearnmoreabouthow
humansage.Isthereaway
youcanaddressyour
researchquestionwithout
spendingmanydecades
studyingpeople?
Canyouthinkofanexperi
mentusingfruitiesthat
couldhelpresearchersbetter
understandjetlag?
CHAPTER4
GenesAreUs
orscience,thesequencingofthehuman
changescreatewordswithnewmeanings
genomewasagroundbreakingachievement,
genesthatcodefordifferentproteins.Other
onethatmadealotofnews.Butwhatdoesit
spellingchangesappeartohavenoeffect
actuallymean?Willanyofthisinformationmake
whatsoever,atleastnotonesthattodaysscien
adifferenceinyourlife?
tistsknowhowtomeasure.
Agenomeisallofthegeneticmaterialthatan
Researchersarebeginningtouseknowledge
individual(oraspecies)has.Thehumangenome
learnedfromgenomesequencingresearchto
differsfromthegorillagenome,whichdiffers
gureouthowbeinghealthyandbeingsickare
fromthericegenome,andsoon.Andwhileevery
differentatthelevelofmolecules.Anddoctors
personhasahumangenome,itisnotexactly
arestartingtousegeneticinformationtomake
thesameinallpeople.Sequencevariations
treatmentchoices.
within yourgenesmakesyourDNAdifferent
Forexample,adiagnostictestcansearchfor
fromthatofyourmother,yourcousinora
differencesinthelevelofexpressionofaparticu
completestranger.
largeneinbreastcancercellsandpredictwhether
Thinkofthehumangenomeasalongstory
apersonwillrespondtoadrugcalledHerceptin.
thatcontainsroughly20,000words(thegenes).
Thecancerouscellsofsomepeoplewhohave
Withfewexceptions,eachpersonhasthesame
breastcancermakeanabundanceofHER2
numberofwords,butcertainwordshaveslightly
proteinsthataretargetedbyHerceptin.Forthose
differentspellings.Insomecases,thespelling
people,Herceptinisamiracledrugbecauseit
L.BARRYHETHERINGTON
ReadingtheBookofHumanGenes
ManyDNAsequencingcentersjoinedeffortsto
formtheHumanGenomeProject,completedin
2003.Nowthecenters,likethisoneattheBroad
Institute of MIT and Harvard University in
Cambridge,Massachusetts,areworkingtobetter
understandthehumangenomeandtosequence
the genomes of other organisms.
InApril2003,researchersacrosstheworldcele
bratedamilestoneandananniversary.Almost50
yearstothedayafterJamesWatson,FrancisCrick
andMauriceWilkinsunveiledtheirNobelPrize
winningdescriptionoftheDNAdoublehelix,
scientistscompletedthesequencingofthehuman
genome,amomentousachievementinbiology.
Thedaywaslongincoming.Inthe1980s,
geneticistsrealizedthattheyhadboththeneed
andtheabilitytolearnthecompletelayoutofthe
humangenome.Theywantedtomapthelocation
ofeverygenewithinchromosomesanddecipher
thecomplete,letterbylettersequenceofthe
genomes3billionnucleotides.
TheNewGenetics I GenesAreUs 63
reducestheriskthattheirbreastcancerwillcome
though,soitshouldntbeprescribed.Researchis
back,anditalsodecreasestheiroddsofdying
proceedingquicklytodevelopothergenetictests
fromthedisease.
thatmayhelpdiagnoseandtreatawiderangeof
Forcancerpatientswhosetumorgenesdo
healthproblemsbeyondcancer.
not expressHER2,Herceptinwontdoathing,
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.
64
IndividualizedPrescriptions
Becauseeachpersonssetofgenesisalittle
Onewayvariationsinourgenesmakeadiffer
different,theproteinsthatthegenesencodeare
enceinourhealthisbyaffectinghowourbodies
alsoslightlydifferent.Thesechangescanaffect
reacttomedicines.Theunsettlingtruthisthat
howthecytochromeP450proteins(andmany
medicinesworkasexpectedinfewerthanhalfof
othertypesofproteins)workondrugs.
thepeoplewhotakethem.
While environmental and lifestyle factors
Doctors first realized this in the 1950s,

whensomepatientshadbadsometimesfatal
can explain some of this, a good part of the
reactionstoananestheticmedicineusedinsurgery.
individualvariabilityinresponsetomedicines
Experimentsrevealedthatthosewhoreacted
canbeattributedtovariantsinthegenesthat
poorlyhadageneticvariationintheenzymethat
makecytochromeP450proteins(seepage53).
breaksdownanddisposesoftheanestheticafter
These proteins process many of the drugs
itsbeeninthebodyforawhile.
we take.
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,insomepeople,
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
Pharmacogeneticresearchershavediscovered
thatagenetestcanpredictwhichchildrenwith
acutelymphoblasticleukemiawillbecuredby
chemotherapy.
HumanGenomeProjectandnewcomputertools
thathelpthemanalyzetheinformation.Onedis
easeforwhichprogresshasbeenrapidiscancer.
Considerthefactthatcancerisoftentreated
withachemotherapycocktail,acombination
commonchildhoodcancer.Theremaining20
of severaldifferentmedicines.Eachofthedrugs
percentareatriskofthecancercomingback.
inthemixtureinteractswithdifferentproteins
MaryRelling,aresearchclinicalpharmacist
thatcontrolhowwellthatparticulardrugworks
at St.JudeChildrensResearchHospitalin
andhowquicklyitismetabolizedinthebody.
Memphis,Tennessee,discoveredthatvariations
Whatsmore,eachdrugmayhaveitsownsetof
in twogenescanpredictwhichpatientswith
unpleasantevenpotentiallylifethreatening
acutelymphoblasticleukemiaarelikelytobe
sideeffects.
curedbychemotherapy.Herresearchteamalso
Forthesereasons,individuallytargeted,gene
identiedmorethan100genesexpressedonlyin
basedprescriptionsforchemotherapymayoffer
cancercellsthatcanbeusedtopredictresistance
a realbenettopeoplewithcancer.
tochemotherapydrugs.
Currently,chemotherapycuresabout80per
Bytakingpatientandcancercellgeneticpro
centofthechildrenwhohavebeendiagnosed
lesintoaccount,Rellingsays,researcherscan
withacutelymphoblasticleukemia,themost
developmoreeffectivetreatmentsforthedisease.
66
Geneticvariation
produces different
individualresponsesto
the bloodthinningdrug
Coumadin.Agenetic
testcouldleadtomore
accuratedoses.
Otherpharmaco
geneticscientistsare
studyingtheeffectsof
genevariantsonpatientsresponsestodrugsused
totreatAIDS,allergies,infections,asthma,heart
disordersandmanyotherconditions.
Forexample,researchersrecentlyidentied
whoaretakingthesamedose.Givingtheright
doseisessential,becausetoomuchCoumadin
cancauseexcessivebleeding,whiletoolittlecan
allowbloodclotstoform.
AllanRettie,amedicinalchemistatthe
UniversityofWashingtoninSeattle,discovered
thatgeneticvariationamongpeopleinuences
twodifferentgeneticvariantsthatplayacentral
theactivityofaproteininthebloodthatis
roleindeterminingthebodysresponseto
Coumadinsmoleculartarget.Heandothersci
Coumadin(alsoknownaswarfarin),awidely
entistsarenowtryingtotranslatethesendings
prescribedmedicinegiventopeoplewhoareat
intoagenetictestthatcouldhelpdoctorspredict
riskforbloodclotsorheartattacks.Although
whatdoseofCoumadinisappropriatebasedon
2millionAmericanstakethisbloodthinning
eachpatientsDNAprole.
drugeveryday,itisverydifculttoadminister,
sinceitseffectsvarywidelyindifferentpeople
ZACHARYHUANG,HTTP://CYBERBEE.MSU.EDU
GenesCanDoThat?
Honeybeesaresocial
animalsandtheywork
togethertokeeptheir
hivehealthy.Theforager
bee(ontheleft)isabout
amontholdandhunts
forfood.The14dayold
undertakerbee(onthe
right)removesdeadbees
from thehive.
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.
CauseandEffect
Whatmoredoweneedtoknowabouthow
genesshapewhoweareandwhatwebecome?
Alot,saysHarvardsRichardLewontin,who
warnedagainstoversimplifyingtheroleofgenes
inhealthinhis2001book,TheTripleHelix.
Lewontinsmainpointisthatcontextplaysan
enormousroleindetermininghoworganisms
growanddevelop,andwhatdiseasestheyget.
A uniquecombinationofgeneticandenvironmen
disease,diabetesorparticulartypesofcancer
tal factors,whichinteractinawaythatisveryhard
runinyourfamily,especiallyifalotofyour
topredict,determineswhateachpersonislike.
relatives
gettheconditionwhentheyarefairly
Veryfew,ifany,scientistswouldarguewith
this.Whetherageneisexpressed,andeven
whetherthemRNAtranscriptgetstranslated
young,youmaywanttotalkwithyourdoctor
aboutyourownriskfordevelopingthedisease.
In2005,theU.S.SurgeonGeneraldeveloped
into aprotein,dependsontheenvironment.
a Webbasedtoolfororganizingfamilyhealth
Few diseasesmostofwhichareveryrare
information.CalledMyFamilyHealthPortrait
arecausedcompletelybyamutatedgene.
(seehttp://www.hhs.gov/familyhistory),thistool
Inmostcases,gettingoravoidingadisease
arrangesinformationintoaprintoutthatyoucan
dependsnotjustongenesbutonthingswithin
carrytothedoctorsofce.Theinformationcan
yourcontrol,suchasdiet,exerciseandwhether
helpyouandyourdoctordetermineyourrisks
ornotyousmoke.
forvariousconditions.
Itwillbemanyyearsbeforescientistsclearly
Ifyoudodiscoverthatyouareathigherthan
understandthedetailedmeaningofourDNA
usualriskforadiseaselikebreastcancerorheart
languageandhowitinteractswiththeenviron
disease,youmaybeabletopreventthedisease,or
mentinwhichwelive.Still,itsagreatideato
delayitsonset,byalteringyourdiet,exercising
ndoutasmuchasyoucanaboutyourfamilys
moreormakingotherlifestylechanges.Youmay
healthhistory.Didanyofyourrelativeshave
alsobeabletotakeadvantageofscreeningtests
diabetes?Dopeopleinyourfamilytreehave
likemammograms(breastXraysthatdetectsigns
cancerorheartdisease?
ofcancer)colonoscopies(imagingtestsforcolon
Keepinmindthatdiseasessuchastheseare
cancer)orbloodsugartestsfordiabetes.
relativelycommon,soitsprettylikelythatatleast
Screeningtestscancatchdiseasesearly,when
onerelativewillhaveoneofthem.Butifheart
treatmentismostsuccessful.
Knowingaboutdiseases
thatruninyourfamilycan
helpyouguardagainst
illnessinthefuture.
68
Resistancetoantimalarial
drugslikechloroquineis
widespreadthroughout
muchofAfricaandother
partsof thedeveloping
world where malaria
transmission is high.
Countrieswithmalariathat
isresistanttochloroquine
CENTERSFORDISEASECONTROL
Countrieswithmalariathat
issensitivetochloroquine
AND PREVENTION
Usvs. Them
Sowhydonttheykillhumancells,too?The
Manyscientistsfocusonhumangenes,mostof
answeristhathumanandbacterialribosomesare
whichhavecounterpartsinthegenomesof
different.Genomesequencingisapowerfultool
modelorganisms.However,inthecaseofinfec
foridentifyingdifferencesthatmightbepromis
tionscausedbymicroorganisms,understanding
ingtargetsfornewdrugs.
howthegenomesofbacteria,virusesandpara
Comparinggeneticsequencesinorganisms
sitesdifferfromoursisaveryimportantareaof
thatareresistantandnonresistanttodrugscan
healthresearch.
revealnewapproachestoghtingresistance.
Mostofthemedicineswetaketotreatinfec
tionsbybacteriaandviruseshavecomefrom
scientistssearchformolecularweakpointsin
Drugresistanceisaworldwideproblemfora
numberofdiseases,includingmalaria.
Althoughresearchershavedevelopedseveral
thesetinyorganisms.AsmentionedinChapter1,
differenttypesofmedicinestotreatthisdis
forexample,someantibioticskillbacteriaby
easecausedbyparasitescarriedbymosquitoes,
disarming
theirproteinmakingribosomes.
notbyabacteriumoravirusmalariaisram
pant,especiallyinthedevelopingworld.
GENETICS AND YOU:
EatLess,LiveLonger?
ouldyouconsumeanex
thatbyrestrictingthe
tremelylowcaloriedietif it
formationofextraDNA,
meantyouwouldlive longer?
Thekindofdietweretalkingabout
isntjustcuttingbackhereandthere.It
sirtuinskeeptheyeast
young.
Notsofast,sayother
involvesseverelyreducingcalorieintake
scientistslikegeneticist
toabout60percentofwhatwenor
StanleyFieldsofthe
mallyeat,enoughtomakemostpeople
UniversityofWashington.Hisexperiments
ravenouslyhungry.
haveturnedupother,unrelatedgenes
A19thcenturyFrenchdoctor,
linkedtolifespaninyeast.Hearguesthat
MauriceGueniot,thoughtthetradeoff
whilecalorierestrictionistheonlyinter
wouldbeworthit.Throughouthisadult
ventionthathasbeenshowntoextend
life,heateverylittle.Hediedattheripe
lifespaninawiderangeoforganisms,
oldageof102!
includingmammals,theaccumulationof
Later,inthe1930s,researchers
followeduponthisobservationby
showingthatratsonadietcontaining
20percentindigestiblebercalories
thatcantbeusedlivedmuchlonger
thantheirnormallyfedpeers.
extraDNAdoesnotalwaysappeartoplay
aroleinthisprocess.
Whatsthenalanswer,youask?Its
probablyabitofboth.
Moleculeslikesirtuins,whichare
involvedincellularmetabolism,maypro
Intriguedbythehealthconnection,
tectcellsagainsttheharmfuleffectsof
scientistsarecontinuingtoinvestigate
stress,extendinglifespan.Othermole
potentiallinksbetweendietandaging,
culesthataffectdifferentaspectsofcell
andgeneticstudiesarestartingtoturn
healthmaybejustasimportant.
upsomeclues.
Forexample,geneticistDavidSinclair
Lifespanincomplex,multicellular
organismslikepeopleisaffectedbymany
ofHarvardMedicalSchoolhasfoundthat
differentfactors,mostofwhichweknow
proteinsknownassirtuinsmaybeableto
verylittleabout.Forsure,understanding
stallaging.Asyeastcellsage,theyaccu
moreaboutthesem
ysterymolecules
mulateextraDNA,whicheventuallykills
couldhaveaconsiderablebenet
them.Sinclairdiscoveredthatsirtuins
erhapsprovidingyouachancetoadd
p
becomemoreactiveinyeastcellsthat
yearstoyourlifewithoutstarving!
areonalownutrientdiet.Hereasons
70
CDC/JAMESGATHANY
Thisispartly
becausenotallpeople
Didyouknowthatscientistsareusinggeneticsto
haveaccesstotreat
breakupgangsofmicrobes,thatis?These
ment,ortosimple
gangs,knownasbiolms,arelayersofslimethat
preventivemeasureslike
developnaturallywhenbacteriacongregateon
bednets,whichprotect
surfaceslikestone,metalandwood.Oronyour
sleepingpeoplefrom
teeth:yuck!
mosquitobites.But
anotherproblemisthe
Mosquitoesspread
malariabypickingup
parasitesfrombloodand
spreadingthemtothe
nextpersontheybite.
Resistancespreadsthis
way,too.
GangWarfare
Biolmsgrowinallsortsofconditions.For
example,onebiolmknownasdesertvarnish
malariaparasiteitself,whichhasrapidlyevolved
thrivesonrocks,canyonwallsor,sometimes,
waystoavoidtheeffectsofantimalarialdrugs.
entiremountainranges,leavingareddishor
Scientistsaretryingtocounterthisprocessby
othercoloredstain.Itisthoughtthatpetroglyphs
studyingmicrobialgeneticinformation.Inthe
leftonbouldersandcavewallsbyearlydesert
caseofmalaria,geneticistslikeDyannWirthof
dwellerswereoftenformedbyscrapingthrough
theHarvardSchoolofPublicHealthcomparethe
thecoatingofdesertvarnishformationswitha
genomesofdrugresistantparasitesandthose
hardobject.
thatcanstillbekilledbyantimalarialmedicines.
Wirthsresearchsuggeststhatitshouldbe
Sometimes,biolmsperformhelpfulfunc
tions.Oneofthebestexamplesoftheuseof
possibletodevelopasimple,inexpensivegenetic
biolmstosolveanimportantproblemisinthe
testthatcouldbegiventopeoplewithmalaria,
cleaningofwastewater.
anywhereintheworld.Thistestwouldidentify
drugsthatarelikelytobemosteffective
andhelpdecreasetherateatwhich
parasitesbecomeresistanttotheanti
malarialmedicineswealreadyhave.
P.SINGHANDE.PETERGREENBERG
Biolms,liketheoneshowninthis
uorescentmicroscopicphoto,are
bacterialcommunities.
BonnieBassler(right)
usesglowinthedark
bacteria to study
the geneticsofbiolms.
DENISEAPPLEWHITE
Butbiolmscanbequiteharmful,con
tributingtoawiderangeofserioushealth
problemsincludingcholera,tuberculosis,cystic
goalofbeingabletousethisknowledgetobreak
upbacterialgangmeetings.
Basslersresearchsubjectshaveadenite
brosisandfoodpoisoning.Theyalsounderlie
visualappeal.Theyglowinthedark,butonly
manyconditionsthatarenotlifethreatening
whentheyarepartofagroup.Thebiolumines
but arenonethelesstroublesome,liketooth
cence,astheglowiscalled,arisesfromchemical
decay and earinfections.
reactionstakingplacewithinthebiolm.Itpro
Bacteriaformbiolmsasasurvivalmeasure.
videsawayforthebacteriatotalktoeachother,
Bylivinginbiggroupsratherthaninisolation,
estimatethepopulationsizeoftheircommunity
theorganismsareabletosharenutrientsand
anddistinguishthemselvesfromothertypesof
conserveenergy.Howdotheydoit?
microorganisms.
Abiolmisnotjustalooseclumpofcells
Throughherstudies,Basslerhasidentieda
itsahighlysophisticatedstructure.Asinany
setofmoleculesthatbiolmformingmicroor
community,theindividualsinbiolmscommu
ganismsusetopassmessagestoeachother.By
nicatewitheachother.
devisinggeneticallybasedmethodstocutoff
Beyondthat,manyaspectsofbiolmsare
the chatter,Basslerreasons,shemaybeableto
poorlyunderstood.BacterialgeneticistBonnie
causebacterialcommunitiestofallapart.This
BasslerofPrincetonUniversityinNewJerseyis
approachwouldprovideawholenewwaytotreat
workingtounderstandbiolmsbetter,withthe
healthproblemslinkedtoharmfulbiolms.
72
TheToolsofGenetics:MathematicsandMedicine
Whatifpublichealthofcialshadascriptfor
Since2005,theModelsofInfectiousDisease
whattodointhefaceofaninfectiousdisease
AgentStudy(MIDAS),ateamofbiologists,com
outbreakthathadneverbeenseenbefore?One
puterscientists,statisticians,mathematicians,
thingthatwouldhelpthemprepareforthissort
socialscientistsandothers,hasbeenmodeling
ofscenarioistheabilitytoknow,aheadoftime,
a upandemicahuge,globalepidemic.
howanepidemicdevelopsandspreads.
Towardthisgoal,somescientistsareusing
Initially,themodelsfocusedonavian
inuenza,atypeofdiseaseoccurringnaturally
mathematicaltoolstocreatesimulations,or
amongwildbirds.Atthetime,healthexperts
models,ofinfectiousdiseaseoutbreaks.They
worldwideworriedthatthevirusgeneticmate
can thenusethemodelstotesttheeffectsof
rialcouldmutate,makingitmucheasierforthe
variousinterventionstrategies.Partofthework
socalledbirdutopassbetweenhumans.
involvespluggingingeneticinformationabout
Tosimulatethepotentialdiseasespread,the
howinfectiousorganismsevolveovertime
scientistswrotecomputerprogramsthatincorpo
and howfasttheychangeastheyinteractwith
ratedinformationaboutthebirduvirusand
humanpopulations.
actualcommunities.Includingdetailsabout
peoplenotjusttheiragesandgenders,but
alsowheretheylive,workorgotoschoollet
theresearcherscreateasyntheticpopulationthat
couldmirrorhowarealonemightgetsickand
spreaddisease.
Thescientistsrantheprogramsonlarge
computerstoseehowtheucouldspreadwith
andwithoutdifferentinterventions.Theresults
indicatedthattosuccessfullycontainanepidemic,
healthofcialswouldneedtondtherstu
casesfastandimplementacombinationofpublic
healthmeasuresveryquickly.
Computersimulationsarehelpingscientistsunderstandhowinfectious
diseasesspread.
GotIt?
Discusshowmathematics
canhelpscientistsaskques
tionsabouthumanhealth.
Wouldyoucontributea
pleofyourDNAfor
sam
ThisearlyworkhelpedMIDASscientists
Duringboththebirdandswineumodel
developsimilarmodelsofH1N1orswineu,
ingefforts,theMIDASscientistsworked
therstactualpandemicustrainsince1968.
closelywithpublichealthofcialstoaddress
StartinginApril2009,theygatheredincoming
specicquestions.TheanswersinformedU.S.
publichealthdatatosimulatethepotential
pandemicupreparednessplanning.
spreadofthisglobalu,identifythegroupsmost
Inuenza,however,isnottheonlyinfec
likelytogetsickandevaluatetheusefulnessof
tiousdiseasemakingpeoplesick.MIDAS
differentpublichealthmeasures,suchasvaccina
scientistsarealsomodelingothermajorhealth
tionandquarantine.Theirmodelssuggestedthat
threats,includingcholera,denguefever,
vaccinatingschoolchildrenearlyinanoutbreak
malaria,tuberculosisandmethicillinresistant
couldreduceoveralldiseasespreadandthat
Staphylococcusaureus (MRSA).
peopleatriskofseriouscomplicationsshould
begivenantiviralmedicationstotakeatthe
rstsignsofillness.
geneticresearchoncommon
diseaseslikeheartdisease,
depressionorcancer
evenifyoudidnthaveany
of thesehealthproblems?
Whyorwhynot?
Drugsworkliketheyre
supposedtoinonlyhalfthe
peoplewhotakethem,so
scientistsaretryingtomake
personalizedmedicinesthat
workverywellinanindivid
ualbecausetheymatchhis
orhergeneticmakeup.Are
thereeconomic,socialor
otherissuesthatthedevelop
mentofsuchmedicines
mightraise?
CHAPTER5
21stCenturyGenetics
practiceslikeopeningtheveinofasickperson
theearliesthumancivilizations,when
anddrainingoffquartsofpreciousblood!
thediagnosisandtreatmentofdiseasewerefar
Later,intheRenaissanceperiodofthe15th
fromscientic.Medievalmedicine,forexample,
and16thcenturies,scholarscenteredonanatomy.
reliedheavilyonsupernaturalbeliefs.Limited
Oneofthem,theItalianartistinventorLeonardo
scienticknowledgeledtoseeminglybizarre
daVinci,createdbeautifulandaccurate
RAREBOOKANDSPECIALCOLLECTIONSDIVISION,LIBRARYOFCONGRESS
Bytheendofthe16th
century,anatomywasa
commonfocusforscien
ticscholars.
edicinehasevolvedtremendouslysince
TheNewGenetics I 21stCenturyGenetics 75
19thcenturyscientists
discovere
dthatbacteria
cancausedisease.Bacillus
anthracis (left)causesanthrax
andVibriocholerae (below)
causescholera.
illustrationsofthehumanbody.Hiswork
andthatofotherscientistsofhisday
focusedonthepracticeofdissection,
providingneverbeforeseendetailsof
PAUL KEIM (ANTHRAX),
thebodysarchitectureoflimbs,joints,
CDC/ WILLIAM A. CLARK (CHOLERA)
muscles,nervesandvessels.
Modernmedicinegotitsrealstart
duringthe19thcentury,afterthemicro
scopewasinvented.Medicalschoolsubjectslike
physiology,pathologyandmicrobiologywere
born.Duringthistime,scientistsdiscoveredthat
bacterianotevilspiritsorotherimaginary
Oneoftodayschallengesistomapthe
entitiescausedhumandiseaseslikecholera,
actionsandinteractionsofallthesemolecules,
anthraxandtuberculosis.
a focusoftheneweldcalledsystems
The birth of modern genetics, which
biology. Geneticandgenomic
occurredinthe20thcentury,acceleratedthe
researchishelpingscien
study of all these areas of science. Now, at
tiststacklemany
the start of the 21st century, opportunities
questionsinthis
haveneverbeengreaterforturningscientic
area.Bybuilding
knowledgeintobetterhealthforall.
modelsof cells,
Weoftentakeforgrantedtheamazing
tissuesand
complexityof
thehumanbody.Withouteven
organsinaction,
thinking,wesweattomaintainbodytempera
scientistshopeto
ture,gethungrywhenweneedenergyandfeel
learnhowthese
tiredwhenweneedtosleep.
complex,dynamic
Theseseeminglysimpleactionsrequirea
sophisticatedcoordinationof manydifferent
systemswork.
Researchersneedtoknow
organsandthemillionsof moleculesthatwork
thesebasicsinordertounderstandhowthe
togetherinsidethem.Thousandsof networks
whendisease strikes.Anessential
systemsfail,
of interactinggenesunderlietheseactionsin
toolinthisresearchisthecomputer.
our bodies.Butthesesystemsareprovingto
havefarmoreuctuationthanscientists
originallysuspected.
76
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
Theprogramrstscansscienticpapers
of thousandsof publishedscienticpapers.
usingpresetsearchterms,muchlikeaGoogle
The knowledgeminingtooltheyuse,called
searchoftheWeb.Next,itevaluatesthesearch
GeneWays,focusesmainlyonresearchliterature
resultsandmakessuretheydontoverlap.For
aboutchangesingenesandproteins.
example,ifamoleculehas16differentnames
indifferentpapers,theprogramsimpliesitto
justone.
CATHERINEFERNANDEZANDJERRYCOYNE
GreenFluorescentProtein
.Fruityspermcellsglowbrightgreenwhenthey
expressthegeneforgreenuorescentprotein.
Heresaninterestingnews
ash:Glowinthedark
jellyshrevolutionizes
geneticresearch!
Althoughitmay sound
bizarre,theclaim istrue.
A jellyshproteinis
essentialto modern
cell biologyexperiments
thattrackthemovements,
quantities andinteractions
of themillionsofproteins
insidecells.
Calledgreenuorescentprotein,orGFP,this
naturalproteinisfoundinspecicpartsofthe
jellysh.Thosepartsglowbecausetheprotein
absorbsenergyfromlightintheenvironment
and thenproducesadifferentcoloroflight.
Scientistsdontreallyknowhowandwhyjelly
shusetheirglow.Theydoknowthatjellysh
dontashateachotherinthedark,nordothey
glowcontinuously.Andtheglowisrarelyseenin
undisturbedanimals.
Takenoutofthejellysh,GFPhasplayeda
majorroleinadvancingthestudyofgenesand
theproteinstheyencode.ThestoryofhowGFP
Finally,afterapplyingspecicrules,sortof
likebiologicalgrammar,thecomputerprogram
identiesassociations,whicharepossiblelinks
betweenmolecules.Theinformationthengoesto
adatabasethatRzhetskyandotherscientistsuse
tobuildlargenetworksofmolecularinteractions.
RzhetskyandhisteamusedGeneWaystoiden
tifyriskgenesforAlzheimersdisease,acomplex
conditionthoughttobecausedbymanyfactors.
In analyzingthedata,Rzhetskyfoundimportant
nodes,moleculesthatplaykeyrolesinthedis
easegenenetworkthatGeneWaysmodeled.
ANDREYRZHETSKYANDKEVINP.WHITE
Thesepredictedmolecularinteractionswere
laterconrmedbyotherresearchersworkingina
lab,underscoringthevalueofcomputermodel
ingasawaytolearnmoreaboutthemolecular
basisofdisease.
. AndreyRzhetskyusesthecomputerprogram
GeneWaystolocateimportanthubsofactivity
(largespheres)withinmassivegenenetworks.
Thisparticularnetworkrepresentsembryonic
developmentalpathwaysinafruity.
usedtheGFPgenetocreategreenglowing
zebrash.Althoughtheshwerecreatedfor
the purposeofscienticresearch,theyve
also becomeanexoticspeciesforhome
aquariums.
ThankstoGFPandrelatedtechnologies,
scientists
cannowviewlivingcellsandtheir
constantlymovingcontents.GFPisalsoused
in diagnostictestsfordrugs,foods,herbicides
andhazardouschemicals.
Chaleandtwootherscientistsreceivedthe
2008NobelPrizeinchemistryforthediscovery
anddevelopmentof GFP.
MARTINCHALFIE
becamearesearchtoolbeganin1992,when
MartinChaleofColumbiaUniversityshowed
thatthegenethatmakesGFPproducedauores
centproteinwhenitwasremovedfromthe
jellyshgenomeandtransferredtothecellsof
otherorganisms(seepage38).Chale,adevel
opmentalbiologist,rstputthegeneinto
bacteriaandroundworms,creatingglowing
versionsoftheseanimals.
Sincethen,researchershavetransferredthe
GFPgeneintomanyotherorganisms,including
fruities,miceandrabbitsandevenhuman
cellsgrowinginalabdish.Recently,scientists
.Scientistsengineered
thisexperimentalworm
toexpressgreenuo
rescentproteinintwo
of itsnervecells(bright
greenspots).
78
Anotherlaw,theGeneticInformation
NondiscriminationAct,orGINA,prohibits
discriminationinhealthcoverageandemploy
mentbasedongeneticinformation.
Itsimportanttorealizethat,inmostcases,
geneticinformationcannotofferdenitiveproof
thatadiseasewilloccur.Butifyouhaveavery
strongfamilyhistoryofbreastcancer,forexam
ple,theremaybeafaultygeneinyourfamilythat
HardQuestions
increasesyourriskofgettingthedisease.
Whilethetaskofsortingthroughlargevolumes
Doctorscannowtestfortwoknowngene
ofgenomicdataremainsacentralchallengein
variantsassociatedwithinheritedformsofbreast
modernbiologyandmedicine,oneoftheknotti
cancer,BRCA1andBRCA2.Ifyoucarryeitherof
estdilemmastoemergefromthisresearchisa
thesegenevariants,yourlifetimeriskofgetting
socialandethicalone.Thatis,howshouldpeople
breastcancerissignicantlyhigherthanitwould
makeuseofinformationabouttheirowngenes?
beforsomeonewithouteithervariant.Butsome
Becausegeneticinformationisbothpowerful
andincrediblypersonal,therearedeepsocietal
concernsregardingitsuse.Theseconcerns
peoplewhohaveBRCAgenevariantsneverget
breastcancer.
Onlyabout5percentofallbreastcancer
includethepotentialfordiscriminationonthe
can betracedtoaknown,inheritedgene
basisofapersonsriskofdiseaseorsusceptibility
variant.Sincesomanybreastcancersarenot
totoxicityfromanenvironmentalchemical.
linkedtoBRCA1orBRCA2,genetictestingfor
Somelawsarealreadyinplacetoprotect
thesevariantsisirrelevantforthevastmajority
individualsfromthemisuseoftheirgenetic
of peoplewhodonothaveafamilyhistoryof
information.Whenyouvisitanewdoctor,nurse
breastcancer.
practitioner,ordentist,youllbeaskedtoread
Butletssayyoudohavearelativewhotested
andsignaformthatoutlinesyourmedical
positiveforBRCA1or2.Shouldyougettested,too?
privacyrightsundertheHealthInsurance
Adifcultquestion,forsure,butconsider
PortabilityandAccountabilityAct,orHIPAA.
this:Knowingaboutthisriskaheadoftime
Thislawprotectsyourgeneticandotherpersonal
mightsaveyourlife.Forexample,youmight
healthinformationfrombeingusedorshared
wanttobegingettingmammogramsorother
withoutyourknowledge.
screeningtestsatanearlyage.Ifcancerisfound
veryearly,itisusuallymoretreatable,andthe
thisgenecancausethedisease,andthoseare
oddsforacurearemuchhigher.
justtheonesresearchersknowabout!
Currently,diagnosticlaboratoriesacrossthe
Howcantherebe30differentvariantsof
UnitedStatesoffergenetictestsforalmost2,000
one gene?Rememberthatageneisalong
disorders.Someofthesetestsdetectproblems
DNAsequence,consistingofhundredsof
withentirechromosomes,notjustindividual
nucleotides.Achangeinoneofthose
genes.Perhapsthemostwellknownexampleof
nucleotidesproducesonevariant,achangein
a chromosomeproblemisDownsyndrome,in
anotherproducesanothervariant,andsoon.
whichcellshaveanextracopyofchromosome21
(seepage11).
Becausetherearesomanypossibilities,its
hardtotellwhetherapersonhasavariant
Mostgeneticdiseasesarentcausedbya
formofthecysticbrosisgene.Sothestandard
chromosome
abnormality,orevenbyonegene
geneticscreeningtestforthisdiseasescansfor
variant.Cysticbrosis,forexample,isduetoa
allofthemorethan30variantsknowntocause
faultygene,butmorethan30differentvariantsof
cysticbrosis.
.Scientistsaredevelopinggeneticteststhatwill
helpdoctorsdiagnoseandtreatdiseases.
80
Doctorsusuallyorderagenetictestonlyif
Asateenoryoungadult,wouldyouwantto
a personhasastrongfamilyhistoryofadisease.
knowthatyoudgetaserious,perhapsincurable,
Butevenso,decidingtohavesuchatestisnot
diseaselaterinlife?
a simplechoice.Thinkaboutwhatyouwoulddo
withtheinformation.
Onethingyoumightconsideriswhetheryou
Patientsanddoctorsfacethesetoughissues
everyday.Evenyearsfromnow,when
researchersknowmoreaboutthemolecular
could dosomethingwithwhatyoulearnfrom
rootsofdisease,genetictestswillrarelyprovide
a genetictest.
easyanswers.Inmostcases,theywonteven
Youvealreadyreadaboutwhatyoucould
do ifyoudiscoveredthatyouwereathighrisk
provideyesornoanswers.
Rather,muchlikeacholesteroltest,theywill
for developingbreastcancer.Butwhatabouta
predictwhetherapersonsriskofgettingadisease
conditionthatshowsupinmiddleagedorolder
isrelativelyhigh,loworsomewhereinbetween.
peopleoroneforwhichthereiscurrently
Thisisbecausemanyfactorsbesidesgenes,includ
no cure?
inglifestylechoicessuchasdietandexercise,also
playaroleindeterminingyourhealth.
GoodAdvice
Since the story of genes and health is so
complicatedandislikelytostaythatway
forawhile,itis veryimportanttoconsider
geneticinformationincontext.Healthcare
professionalsknownasgeneticcounselors
canbeabig helptopeoplewhoarethinking
aboutgettingagenetictest.
Asaprofession,geneticcounselinghas
beenaroundsincethemid1900s.However,
onlyafewspecialtyclinicsofferedcounseling
atthattime.Now,geneticcounselingismuch
morewidely available.
GENETICS AND YOU:
CrimeFightingDNA
ikeyourthumbprint,yourgenes
bloodorskincells),DNAforensictech
areunique,unlessyouhavean
nologycanidentifyvictimsinanatural
identicaltwin.Assuch,DNA
disaster,suchastheDecember2004
ngerprintinghasbecomeapowerful
tsunamithatravagedIndonesiaand
crimeghtingtool.DNAforensicsis
otherAsiancountries.DNAngerprint
a fastgrowingspecialtythathasappli
ingcan alsomatchatransplantpatient
cationsbeyondputtingcriminals
toanorgandonororestablishpaternity
behind bars.
andotherfamilyrelationships.
Inadditiontoidentifyingsuspects
Geneticngerprintingisnotlimited
wholeavetracesatthesceneofacrime
topeople.Itcanndsmallbutpoten
(forexample,strandsofhair,dropsof
tiallydeadlytracesofdiseasecausing
bacteriainfoodorwater,determine
whetheranexpensivehorsewassired
byaKentuckyDerbywinnerorgure
outwhetherapuppysparentswere
rstcousins.
DNAngerprintingtechniqueswork
bylookingfordifferencesamonggene
sequencesthatareknowntovary
betweenpeople(orbetweenindividuals
fromanyspecies).Scientistsreadthe
sequenceinadozenorsoplacesto
createamolecularprole.Thechances
of amolecularngerprintbeingthe
sameintwopeopleortwoorganisms
are vanishinglysmall.
82
Todaysgeneticcounselorshavegonethrough
Genetics,Business,andtheLaw
arigoroustrainingprocessinwhichtheyearn
Canascientistclaimrightstoagenethathedis
a mastersdegreeandlearngenetics,medicine,
coveredinwormsandthathasanearlyidentical
laboratoryprocedures,counseling,socialwork
counterpartinhumans?
andethics.Geneticcounselorsdotheirwork
Isapersonwhogaveabloodortissuesample
in manydifferentsettings,includinghospitals,
entitledtoprotsfromacompanythatdevelops
privateclinics,governmentagenciesanduni
adrugbasedongeneticinformationinhersam
versitylaboratories.
ple,ortoalifetimesupplyofthedrug?
Aninterestingaspectofthejobisthatgenetic
Canabloodortissuesamplethatwasdonated
counselorsaddresstheneedsofentirefamilies,
foronepurposebeusedforanentirelydifferent
ratherthanjustindividualpatients.Toevaluate
studyseveralyearslater,withoutaskingthedonor
geneticriskanditspotentialconsequences,these
ifthatsOK?
professionalsgatherafamilymedicalhistory
covering
generations.
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
indicates
thatbiotechcropshaveanyadverse
effectsonnontargetedwildlife,plantsor
benecialinsects.
Ofcourse,carefuleldtestsofnewlycreated,
geneticallymodiedplantsandanimalsare
essentialtobesurethattheycausenoharmto
otherorganismsortotheenvironment.
.Biotechnologyhelpsagriculturalscientistscreate
cropswithdesiredtraits.Themajorityofcotton
andsoybeansintheUnitedStatesaregrownwith
geneticallymodiedseedsthatresistvirusesand
otherplantpests.
84
However,nobodyinventedagene,anaturally
Patentscanbegreatforbusiness,andtheycan
occurringchemicaloraprotein,sowhyshould
helpmaketheresultsofresearchwidelyavailable
a personoracompanybeabletoownitand
throughcommercialventures,buttheyalsohave
controlitsdestinyinthemarketplace?
thepotentialtoslowresearchbecausepatent
PatentlawsintheUnitedStatesandEurope
holderscontrolhowinformationrelatedtothe
prohibitanyonefrompatentingageneasitexists
patentisused.Forexample,researcherswhowish
inthehumanbody.Butpatentshavebeenissued
tousepatentedgeneticinformationmayneedto
forspecicmedicalusesofgeneticinformation.
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
generated
bylifescientists,isespeciallyshort
gureoutwhatthegenesdoandevenmore
of qualiedworkers.Asaresult,bioinformatics
complicatedhowtheydoit.
scientists
areinhighdemand.
Weneedlaboratoryscientists,doctorstodo
Manycareersingeneticsandgenomics
clinicalresearchandtreatpatients,geneticcoun
requireadvanceddegreessuchasaPh.D.orM.D.
selorstohelppeopleunderstandtheinformation
Butpeoplewithmastersorbachelorsdegreesare
intheirgenes,andlawyersandethicalspecialists
alsoneededtollthousandsofrewardingjobsas
whocanaddresslegalandpolicyconcernsabout
geneticcounselors,researchassistantsandlab
theuseofgeneticinformation.
technicians.
Inespeciallyhighdemandarepeoplewith
Formorecareerinformation,see
expertiseinmathematics,engineering,computer
http://www.ornl.gov/sci/techresources/
scienceandphysics.Theeldofbioinformatics,
Human_genome/education/careers.shtmlor
whichdevelopshardwareandsoftwaretostore
http://science.education.nih.gov/LifeWorks.
andanalyzethehugeamountsofdatabeing
86
TheToolsofGenetics:InformaticsandDatabases
Formostof itshistory,biologymanagedto
This isnotsurprisingwhenyourememberthat
amassitsdatamostlywiththehelpofplainold
DNAisitselfaformofinformationstorage.
arithmetic.GregorMendeldidgeneticanalysis
Wherearegeneticandgenomicdatastored?
bysimplycountingthedifferentkindsofoff
Oneoftherstbiologicaldatabaseswascreated
springproducedbyhispeas.Bycontrast,todays
tostorethehugevolumeofdatafromexperi
geneticresearchcreatestoomuchdataforone
mentswiththefruityDrosophilamelanogaster.
person,orevenascienticteam,tounderstand.
CalledFlyBase,ithasgrownintoahuge,
Newtechnologiesareneededtomanagethis
comprehensive,internationalelectronicreposi
hugeamountof data.
toryforinformationonDrosophila geneticsand
Considerthis:Genesequencingmachines
molecularbiology,runbyscientistsforscientists.
canreadhundredsof thousandsofnucleotidesa
Theinformationspansacenturysworthof
day.Genechipsareevenfaster.Theinformation
publishedscienticliteratureonDrosophila
inGenBank,awidelyuseddatabaseof all
melanogaster anditsrelatives,includingtheir
knownDNAsequences,nowdoublesinjust
completegenomesequences.
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
makeitpossiblefor researchers
to organize, searchandanalyze
it.Infact,manyof todayschallengesin
IMAGEONCOMPUTERSCREENCOURTESYOFTOMSLEZAK,
biology,fromgeneanalysistodrugdiscovery,
are reallychallengesininformationtechnology.
LAWRENCELIVERMORENATIONALLABORATORY
http://www.dictybase.org/
http://www.yeastgenome.org/
http://www.wormbase.org/
GotIt?
http://flybase.org/
Doyouthinkmodernresearch
toolsderivedfromgenomicsand
bioinformaticswillchangethe
practiceofmedicine?How?
Ifagenetictestrevealedthatyou
hada1in100chanceofdevelop
ingadiseaseliketype2diabetes,
whichcanbepreventedwith
DatabaseslikeFlyBasearealsousefultosci
entistsworkingwithotherorganisms,likemice
orhumans.Aresearcherwhodiscoversanew
manylaboratorystudies(Saccharomyces
GenomeDatabase).
Akeygoalistomakesurethatallofthese
mammaliangenemayconsultFlyBasetoseeif
databasescantalktoeachother.Thatway,
fruitieshaveasimilargeneandifthedatabase
similardiscoveriesindifferentorganisms
containshintsaboutwhatthegenedoes.Since
theimportant,commonthreadsofall
thefunctionsofmanygenesareretainedduring
biologycanbeidentiedquicklyand
evolution,knowingwhatagenedoesinone
analyzedfurther.
organismoftenprovidesvaluablecluesabout
lifestylechangeslikeeatinga
healthierdietandexercisingmore,
wouldyouchangeyourbehavior?
Whatiftheriskwere1in10?
Howisgeneticengineeringsimilar
totraditionalfarming?Howisit
different?
Forthisdatabasecommunicationto
whatitdoesinanotherorganism,evenif the
work,researchersindifferenteldsmust
two speciesareonlydistantlyrelated.
use thesametermstodescribebiological
Abiotechnologycompanyuses
processes.Thedevelopmentanduseof
geneticinformationfromapatient
havecreatedtheirowndatabases,includingthose
such auniversalontologyacommon
volunteeranddevelopsaneffec
dedicatedtotheinvestigationoftheroundworm
languageishelpingscientistsanalyzethe
tive,protablemedicine.Should
Caenorhabditiselegans (WormBase),thesoil
complexnetworkofbiologythatunderlies
thepatientknowthatheorshe
dwellingamoebaDictyosteliumdiscoideum
ourhealth.
waspartofthisprocess?Whyor
Severalothercommunitiesof researchers
(DictyBase)andthestrainofyeastusedfor
whynot?Whatiftheresearchdid
notleadtoanymedicaladvance?
88
Glossary
Aminoacid |Abuildingblockofproteins.
ComparativeGenomics |The study
Thereare20aminoacids,eachofwhichis
ofhumangeneticsbycomparisonswiththe
coded forbythreeadjacentnucleotidesina
genetics ofotherorganisms.
DNA sequence.
Anticipation |Thediseaseprocessinwhich
symptomsshowupearlierandareincreasingly
severeineachgeneration.
Diploid |Havingtwocopiesofeach
chromosome.
DNA |Abbreviationfordeoxyribonucleicacid,
themoleculethatcontainsthegeneticcodeforall
Biolm |Aslimelayerthatdevelopsnaturally
lifeformsexceptforafewviruses.Itconsistsof
whenbacteriacongregateonsurfaces.
twolong,twistedchainsmadeupof nucleotides.
Bioinformatics |Theeldofbiologyspecializ
ingindevelopinghardwareandsoftwaretostore
andanalyzethehugeamountsofdatabeing
generatedbylifescientists.
Biotechnology |Theindustrialuseofliving
Eachnucleotidecontainsonebase,onephosphate
molecule and the sugar molecule deoxyribose.
The bases in DNA nucleotides are adenine,
thymine, guanine and cytosine.
DNAchip |Seemicroarray.
organismsorbiologicalmethodsderivedthrough
DNApolymerase |Anenzymethatcopies
basicresearch;examplesrangefromgeneticengi
DNA.
neeringtomakingcheeseorbread.
Enzyme |Asubstance(oftenaprotein)that
Chromatin |Theorganizationanddensepack
speedsup,orcatalyzes,achemicalreactionwith
agingofDNAinthenucleusofcells.
outbeingpermanentlyalteredorconsumed.
Chromosome |Acellularstructurecontaining
Epigenetics |Thestudyofheritablechangesin
genes.ChromosomesarecomposedofDNAand
genefunctionthatoccurwithoutachangeinthe
proteins.Humanshave23pairsofchromosomes
DNAsequence.
ineachbodycell,oneofeachpairfromthe
motherandtheotherfromthefather.
Circadian |Pertainingtoaperiodofabout
24 hours;appliedespeciallytorhythmicbiologi
Eukaryote |Anorganismwhosecellshave
a membraneboundnucleus.
Exon |ADNAsequenceinagenethatcodes
for ageneproduct.
calrepetitionlikethesleepwakecycle.
Gene |AsegmentofaDNAmoleculethat
Clone |Ingenetics,theprocessofmakingmany
copiesofageneorawholeorganism.Theterm
alsoreferstotheisolationandmanipulationof
a gene.
containsinformationformakingaproteinor,
sometimes,anRNAmolecule.
TheNewGenetics I Glossary 89
Genechip |Seemicroarray.
Geneexpression |Theprocessbywhich
Meiosis |Thetypeofcelldivisionthatcreates
eggandspermcells.
genesarerstconvertedtomessengerRNAand
Microarray |Sometimescalledagenechipor
thento proteins.
a DNAchip.Microarraysconsistoflargenum
Genetics |Thescienticstudyofgenesand
heredity ofhowparticularqualitiesortraits
are transmittedfromparentstooffspring.
bersofmolecules(often,butnotalways,DNA)
distributedinrowsinaverysmallspace.
Microarrayspermitscientiststostudygene
expressionbyprovidingasnapshotofallthe
Genome |Allofanorganismsgeneticmaterial.
Genomics |Ascaledupversionofgenetic
researchinwhichscientistscanlookatlarge
numbersorallofthegenesinanorganismat
genesthatareactiveinacellataparticulartime.
MicroRNA |Ashortpieceofsinglestranded
RNAthatdoesnotencodeaproteinandcontrols
theexpressionofgenes.
the sametime.
Mitochondrion |Thecellspowerplant,
Haploid |Havingonecopyofeachchromo
some,asinaspermoregg.
supplyingtheenergytocarryoutallofthecells
jobs.Eachcellcontainsupto1,000mitochon
Haplotype |Asetofcloselylinkedgenesor
dria.Thestructurescontaintheirownsmall
DNApolymorphismsinheritedasaunit.
genomes,calledmitochondrialDNA.
Histone |Atypeofproteinfoundinchromo
Mutation |AchangeinaDNAsequence.
somes;histonesattachedtoDNAresemble
beads onastring.
Nucleotide |AbuildingblockofDNAor
RNA.Itincludesonebase,onephosphatemole
Homeobox |ADNAsequencefoundingenes
culeandonesugarmolecule(deoxyribosein
involvedintheregulationofthedevelopment
DNA,riboseinRNA).
of animals,fungiandplants.
Imprinting |Thephenomenoninwhichagene
maybeexpresseddifferentlyinanoffspring
dependingonwhetheritwasinheritedfrom
the fatherorthemother.
Intron |ADNAsequence,ortheRNAsequence
transcribedfromit,thatinterruptsthesequences
codingforageneproduct(exon).
Nucleus |Thestructureintheeukaryoticcell
containingmostofitsgeneticmaterial.
Pharmacogenetics |Thestudyofhowpeo
ples geneticmakeupaffectstheirresponses
to medicines.
Protein |Amoleculeconsistingofsubunits
calledaminoacids.Proteinsarethecellsmain
buildingmaterialsand domostofacellswork.
90
RecombinantDNA |HybridDNAproduced
Sequencing |SometimescalledDNAsequenc
in thelaboratorybyjoiningpiecesofDNAfrom
ingorgenesequencing.Discoveringtheexact
differentsources.
orderofthebuildingblocks(seenucleotides)of
Replication |TheprocessbywhichDNA
a particularpieceofDNA.
copiesitselfinordertomakeanewgenometo
StemCell |Acellthatcandevelopintomany
passontoadaughtercell.
differentcelltypesinthebody.
Ribosome |Thecellstructureinwhichpro
Systemsbiology |Aeldthatseekstostudy
teinsaremanufactured.Mostcellscontain
therelationshipsandinteractionsbetweenvari
thousandsof ribosomes.
ouspartsofabiologicalsystem(metabolic
RNA |Abbreviationforribonucleicacid,the
moleculethatcarriesoutDNAsinstructionsfor
makingproteins.Itconsistsofonelongchain
pathways,organelles,cellsandorganisms)and
to integratethisinformationtounderstandhow
biologicalsystemsfunction.
madeupofnucleotides.Eachnucleotidecontains
Telomere |ArepeatedDNAsequencethatcaps
onebase,onephosphatemoleculeandthesugar
theendsofchromosomes.
moleculeribose.ThebasesinRNAnucleotides
are adenine,uracil,guanineandcytosine.
RNAinterference(RNAi) |Agenesilencing
processinwhichdoublestrandedRNAstrigger
thedestructionofspecicRNAs.
Transcription |Therstmajorstepingene
expression,inwhichtheinformationcodedin
DNAiscopiedintoamoleculeofRNA.
Translation |Thesecondmajorstepingene
expression,inwhichtheinstructionsencodedin
RNApolymerase |Anenzymethattranscribes
RNAarecarriedoutbymakingaproteinorstart
aDNAsequence,creatingmRNA.
ingorstoppingproteinsynthesis.
RNAsplicing |Theprocessbywhichintrons
Variant |Adifferentversionofagene,onethat
areremovedandexonsarejoinedtogether
hasaslightlydifferentsequenceofnucleotides.
from anRNAtranscripttoproduceanmRNA
molecule.
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