Chapter15

TheChromosomalBasisofInheritance
LectureOutline
Overview
TodayweknowthatgenesGregorMendelshereditaryfactorsarelocatedon
chromosomes.

Acenturyago,therelationshipofgenesandchromosomeswasnotsoobvious.

ManybiologistswereskepticalaboutMendelslawsofsegregationandindependent
assortmentuntilevidencemountedthattheyhadaphysicalbasisinthebehaviorof
chromosomes.
A.RelatingMendelianInheritancetotheBehaviorofChromosomes
1.Mendelianinheritancehasitsphysicalbasisinthebehaviorofchromosomesduringsexual
lifecycles.
Around1900,cytologistsandgeneticistsbegantoseeparallelsbetweenthebehaviorof
chromosomesandthebehaviorofMendelsfactors.
Usingimprovedmicroscopytechniques,cytologistsworkedouttheprocessofmitosisin
1875andmeiosisinthe1890s.
Chromosomesandgenesarebothpresentinpairsindiploidcells.
Homologouschromosomesseparateandallelessegregateduringmeiosis.
Fertilizationrestoresthepairedconditionforbothchromosomesandgenes.
Around1902,WalterSutton,TheodorBoveri,andothersnotedtheseparallelsanda
chromosometheoryofinheritancebegantotakeform:
Genesoccupyspecificlocionchromosomes.
Chromosomesundergosegregationduringmeiosis.
Chromosomesundergoindependentassortmentduringmeiosis.
Thebehaviorofhomologouschromosomesduringmeiosiscanaccountforthe
segregationoftheallelesateachgeneticlocustodifferentgametes.
Thebehaviorofnonhomologouschromosomescanaccountfortheindependent
assortmentofallelesfortwoormoregeneslocatedondifferentchromosomes.
2.Morgantracedagenetoaspecificchromosome.
Intheearly20thcentury,ThomasHuntMorganwasthefirstgeneticisttoassociatea
specificgenewithaspecificchromosome.
LikeMendel,Morganmadeaninsightfulchoiceinhisexperimentalanimal.Morgan
workedwithDrosophilamelanogaster,afruitflythateatsfungionfruit.
Fruitfliesareprolificbreedersandhaveagenerationtimeoftwoweeks.
IG Lecture Outline 15-1

Fruitflieshavethreepairsofautosomesandapairofsexchromosomes(XXinfemales,
XYinmales).

Morganspentayearlookingforvariantindividualsamongtheflieshewasbreeding.
Hediscoveredasinglemaleflywithwhiteeyesinsteadoftheusualred.

Thenormalcharacterphenotypeisthewildtype.

Alternativetraitsarecalledmutantphenotypesbecausetheyareduetoallelesthat
originateasmutationsinthewildtypeallele.
WhenMorgancrossedhiswhiteeyedmalewitharedeyedfemale,alltheF 1offspring
hadredeyes,suggestingthattheredallelewasdominanttothewhiteallele.
CrossesbetweentheF1offspringproducedtheclassic3:1phenotypicratiointheF2
offspring.

Surprisingly,thewhiteeyedtraitappearedonlyinF2males.
AlltheF2femalesandhalftheF2maleshadredeyes.

Morganconcludedthataflyseyecolorwaslinkedtoitssex.

MorgandeducedthatthegenewiththewhiteeyedmutationisontheXchromosome,
withnocorrespondingallelepresentontheYchromosome.
Females(XX)mayhavetworedeyedallelesandhaveredeyesormaybeheterozygous
andhaveredeyes.
Males(XY)haveonlyasingleallele.Theywillberedeyediftheyhavearedeyedallele
orwhiteeyediftheyhaveawhiteeyedallele.
3.Linkedgenestendtobeinheritedtogetherbecausetheyarelocatedonthesame
chromosome.

Eachchromosomehashundredsorthousandsofgenes.

Geneslocatedonthesamechromosomethattendtobeinheritedtogetherarecalled
linkedgenes.
Resultsofcrosseswithlinkedgenesdeviatefromthoseexpectedaccordingto
independentassortment.
Morganobservedthislinkageanditsdeviationswhenhefollowedtheinheritanceof
charactersforbodycolorandwingsize.
Thewildtypebodycolorisgray(b+),andthemutantisblack(b).
Thewildtypewingsizeisnormal(vg+),andthemutanthasvestigialwings(vg).

Themutantallelesarerecessivetothewildtypealleles.

Neithergeneisonasexchromosome.

MorgancrossedF1heterozygousfemales(b+bvg+vg)withhomozygousrecessivemales
(bbvgvg).

Accordingtoindependentassortment,thisshouldproduce4phenotypesina1:1:1:1ratio.

Surprisingly,Morganobservedalargenumberofwildtype(graynormal)anddouble
mutant(blackvestigial)fliesamongtheoffspring.
Thesephenotypesarethoseoftheparents.
Morganreasonedthatbodycolorandwingshapeareusuallyinheritedtogetherbecause
thegenesforthesecharactersareonthesamechromosome.

IG Lecture Outline 15-2

 Theothertwophenotypes(grayvestigialandblacknormal)werefewerthanexpected
fromindependentassortment(buttotallyunexpectedfromdependentassortment).
Whatledtothisgeneticrecombination,theproductionofoffspringwithnew
combinationsoftraits?
4.Independentassortmentofchromosomesandcrossingoverproducegeneticrecombinants.
Geneticrecombinationcanresultfromindependentassortmentofgeneslocatedon
nonhomologouschromosomesorfromcrossingoverofgeneslocatedonhomologous
chromosomes.
Mendelsdihybridcrossexperimentsproducedoffspringthathadacombinationoftraits
thatdidnotmatcheitherparentinthePgeneration.
IfthePgenerationconsistsofayellowroundseedparent(YYRR)crossedwithagreen
wrinkledseedparent(yyrr),allF1plantshaveyellowroundseeds(YyRr).
AcrossbetweenanF1plantandahomozygousrecessiveplant(atestcross)producesfour
phenotypes.
Halfaretheparentaltypes,withphenotypesthatmatchtheoriginalPparents,with
eitheryellowroundseedsorgreenwrinkledseeds.
Halfarerecombinants,newcombinationsofparentaltraits,withyellowwrinkledor
greenroundseeds.
A50%frequencyofrecombinationisobservedforanytwogeneslocatedondifferent
(nonhomologous)chromosomes.
Thephysicalbasisofrecombinationbetweenunlinkedgenesistherandomorientationof
homologouschromosomesatmetaphaseIofmeiosis,whichleadstotheindependent
assortmentofalleles.
TheF1parent(YyRr)producesgameteswithfourdifferentcombinationsofalleles:YR,
Yr,yR,andyr.
Theorientationofthetetradcontainingtheseedcolorgenehasnobearingonthe
orientationofthetetradwiththeseedshapegene.
Incontrast,linkedgenes,geneslocatedonthesamechromosome,tendtomovetogether
throughmeiosisandfertilization.
UndernormalMendeliangeneticrules,wewouldnotexpectlinkedgenestorecombine
intoassortmentsofallelesnotfoundintheparents.
Iftheseedcolorandseedcoatgeneswerelinked,wewouldexpecttheF 1offspringto
produceonlytwotypesofgametes,YRandyr,whenthetetradsseparate.
OnehomologouschromosomecarriestheYandRallelesonthesamechromosome,and
theotherhomologouschromosomecarriestheyandralleles.
TheresultsofMorganstestcrossforbodycolorandwingshapedidnotconformto
eitherindependentassortmentorcompletelinkage.
Underindependentassortment,thetestcrossshouldproducea1:1:1:1phenotypicratio.
Ifcompletelylinked,weshouldexpecttoseea1:1:0:0ratiowithonlyparental
phenotypesamongoffspring.

Mostoftheoffspringhadparentalphenotypes,suggestinglinkagebetweenthegenes.

However,17%oftheflieswererecombinants,suggestingincompletelinkage.

Morganproposedthatsomemechanismmustoccasionallybreakthephysicalconnection
betweengenesonthesamechromosome.
IG Lecture Outline 15-3

Thisprocess,calledcrossingover,accountsfortherecombinationoflinkedgenes.

Crossingoveroccurswhilereplicatedhomologouschromosomesarepairedduring
prophaseofmeiosisI.
Onematernalandonepaternalchromatidbreakatcorrespondingpointsandthenrejoin
witheachother.
Theoccasionalproductionofrecombinantgametesduringmeiosisaccountsforthe
occurrenceofrecombinantphenotypesinMorganstestcross.
Thepercentageofrecombinantoffspring,therecombinationfrequency,isrelatedtothe
distancebetweenlinkedgenes.
5.Geneticistscanuserecombinationdatatomapachromosomesgeneticloci.
OneofMorgansstudents,AlfredSturtevant,usedcrossingoveroflinkedgenesto
developamethodforconstructingageneticmap,anorderedlistofthegeneticlocialonga
particularchromosome.
Sturtevanthypothesizedthatthefrequencyofrecombinantoffspringreflectedthe
distancebetweengenesonachromosome.
Heassumedthatcrossingoverisarandomevent,andthatthechanceofcrossingoveris
approximatelyequalatallpointsonachromosome.
Sturtevantpredictedthatthefartheraparttwogenesare,thehighertheprobabilitythata
crossoverwilloccurbetweenthem,andtherefore,thehighertherecombinationfrequency.
Thegreaterthedistancebetweentwogenes,themorepointstherearebetweenthem
wherecrossingovercanoccur.
Sturtevantusedrecombinationfrequenciesfromfruitflycrossestomaptherelative
positionofgenesalongchromosomes.

Ageneticmapbasedonrecombinationfrequenciesiscalledalinkagemap.

Sturtevantusedthetestcrossdesigntomaptherelativepositionofthreefruitflygenes,
bodycolor(b),wingsize(vg),andeyecolor(cn).
Therecombinationfrequencybetweencnandbis9%.
Therecombinationfrequencybetweencnandvgis9.5%.
Therecombinationfrequencybetweenbandvgis17%.
Theonlypossiblearrangementofthesethreegenesplacestheeyecolorgenebetweenthe
othertwo.
Sturtevantexpressedthedistancebetweengenes,therecombinationfrequency,asmap
units.
Onemapunit(calledacentimorgan)isequivalenttoa1%recombinationfrequency.
Youmaynoticethatthethreerecombinationfrequenciesinourmappingexamplearenot
quiteadditive:9%(bcn)+9.5%(cnvg)>17%(bvg).

Thisresultsfrommultiplecrossingoverevents.
Asecondcrossingovercancelsoutthefirstandreducestheobservednumberof
recombinantoffspring.
Genesfatherapart(forexample,bvg)aremorelikelytoexperiencemultiplecrossing
overevents.

Somegenesonachromosomearesofarapartthatacrossoverbetweenthemisvirtually
certain.
IG Lecture Outline 15-4

 Inthiscase,thefrequencyofrecombinationreachesitsmaximumvalueof50%andthe
genesbehaveasiffoundonseparatechromosomes.
Infact,twogenesstudiedbyMendelforseedcolorandflowercolorarelocatedon
thesamechromosomebutstillassortindependently.
Geneslocatedfarapartonachromosomearemappedbyaddingtherecombination
frequenciesbetweenthedistantgenesandtheinterveninggenes.
Sturtevantandhiscolleagueswereabletomapthelinearpositionsofgenesin
Drosophilaintofourgroups,oneforeachchromosome.

Alinkagemapprovidesanimperfectpictureofachromosome.

Mapunitsindicaterelativedistanceandorder,notpreciselocationsofgenes.
Thefrequencyofcrossingoverisnotactuallyuniformoverthelengthofachromosome.

Alinkagemapdoesportraytheorderofgenesalongachromosome,butdoesnot
accuratelyportraythepreciselocationofthosegenes.
Combinedwithothermethodslikechromosomalbanding,geneticistscandevelop
cytogeneticmapsofchromosomes.
Theseindicatethepositionsofgeneswithrespecttochromosomalfeatures.

RecenttechniquesshowthephysicaldistancesbetweengenelociinDNAnucleotides.

B.SexChromosomes
1.Thechromosomalbasisofsexvarieswiththeorganism.
Althoughtheanatomicalandphysiologicaldifferencesbetweenwomenandmenare
numerous,thechromosomalbasisofsexisrathersimple.

Inhumansandothermammals,therearetwovarietiesofsexchromosomes,XandY.
AnindividualwhoinheritstwoXchromosomesusuallydevelopsasafemale.
AnindividualwhoinheritsanXandaYchromosomeusuallydevelopsasamale.

Otheranimalshavedifferentmethodsofsexdetermination.
TheX0systemisfoundinsomeinsects.FemalesareXX,malesareX.
Inbirds,somefishes,andsomeinsects,femalesareZWandmalesareZZ.
Inbeesandants,femalesarediploidandmalesarehaploid.

IntheXYsystem,theYchromosomeismuchsmallerthantheXchromosome.

OnlyrelativelyshortsegmentsateitherendoftheYchromosomearehomologouswith
thecorrespondingregionsoftheXchromosome.
TheXandYrarelycrossover.
Inbothtestes(XY)andovaries(XX),thetwosexchromosomessegregateduring
meiosis,andeachgametereceivesone.
EachovumreceivesanXchromosome.
HalfthespermcellsreceiveanXchromosome,andhalfreceiveaYchromosome.
Becauseofthis,eachconceptionhasaboutafiftyfiftychanceofproducingaparticular
sex.
IfaspermcellbearinganXchromosomefertilizesanovum,theresultingzygoteis
female(XX).
IfaspermcellbearingaYchromosomefertilizesanovum,theresultingzygoteismale
(XY).
IG Lecture Outline 15-5

 Inhumans,theanatomicalsignsofsexfirstappearwhentheembryoisabouttwomonths
old.
In1990,aBritishresearchteamidentifiedageneontheYchromosomerequiredforthe
developmentoftestes.
TheynamedthegeneSRY(sexdeterminingregionoftheYchromosome).

InindividualswiththeSRYgene,thegenericembryonicgonadsdevelopintotestes.
ActivityoftheSRYgenetriggersacascadeofbiochemical,physiological,andanatomical
featuresbecauseitregulatesmanyothergenes.
OthergenesontheYchromosomearenecessaryfortheproductionoffunctionalsperm.
Intheabsenceofthesegenes,anXYindividualismalebutdoesnotproducenormal
sperm.
InindividualslackingtheSRYgene,thegenericembryonicgonadsdevelopintoovaries.

2.Sexlinkedgeneshaveuniquepatternsofinheritance.
Inadditiontotheirroleindeterminingsex,thesexchromosomes,especiallytheX
chromosome,havegenesformanycharactersunrelatedtosex.

Agenelocatedoneithersexchromosomeiscalledasexlinkedgene.

Inhumans,thetermreferstoageneontheXchromosome.

HumansexlinkedgenesfollowthesamepatternofinheritanceasMorganswhiteeye
locusinDrosophila.
Fatherspasssexlinkedallelestoalltheirdaughtersbutnoneoftheirsons.
Motherspasssexlinkedallelestobothsonsanddaughters.
Ifasexlinkedtraitisduetoarecessiveallele,afemalewillexpressthisphenotypeonly
ifsheishomozygous.
Heterozygousfemalesarecarriersfortherecessivetrait.
BecausemaleshaveonlyoneXchromosome(hemizygous),anymalereceivingthe
recessiveallelefromhismotherwillexpresstherecessivetrait.
Thechanceofafemaleinheritingadoubledoseofthemutantalleleismuchlessthanthe
chanceofamaleinheritingasingledose.
Therefore,malesarefarmorelikelytoexhibitsexlinkedrecessivedisordersthanare
females.

Forexample,colorblindnessisamilddisorderinheritedasasexlinkedtrait.
Acolorblinddaughtermaybeborntoacolorblindfatherwhosemateisacarrier.
However,theoddsofthisarefairlylow.

Severalserioushumandisordersaresexlinked.

Duchennemusculardystrophyaffectsonein3,500malesbornintheUnitedStates.
Affectedindividualsrarelylivepasttheirearly20s.
ThisdisorderisduetotheabsenceofanXlinkedgeneforakeymuscleproteincalled
dystrophin.
Thediseaseischaracterizedbyaprogressiveweakeningofthemusclesandalossof
coordination.

Hemophiliaisasexlinkedrecessivedisorderdefinedbytheabsenceofoneormore
proteinsrequiredforbloodclotting.
Theseproteinsnormallyslowandthenstopbleeding.
IG Lecture Outline 15-6

Individualswithhemophiliahaveprolongedbleedingbecauseafirmclotformsslowly.
Bleedinginmusclesandjointscanbepainfulandcanleadtoseriousdamage.

Today,peoplewithhemophiliacanbetreatedwithintravenousinjectionsofthemissing
protein.
AlthoughfemalemammalsinherittwoXchromosomes,onlyoneXchromosomeis
active.
Therefore,malesandfemaleshavethesameeffectivedose(onecopy)ofgenesontheX
chromosome.
Duringfemaledevelopment,oneXchromosomepercellcondensesintoacompactobject
calledaBarrbody.
MostofthegenesontheBarrbodychromosomearenotexpressed.

ThecondensedBarrbodychromosomeisreactivatedinovariancellsthatproduceova.

MaryLyon,aBritishgeneticist,demonstratedthatselectionofwhichXchromosomewill
formtheBarrbodyoccursrandomlyandindependentlyinembryoniccellsatthetimeofX
inactivation.
Asaconsequence,femalesconsistofamosaicoftwotypesofcells,somewithanactive
paternalXchromosome,otherswithanactivematernalXchromosome.
AfteranXchromosomeisinactivatedinaparticularcell,allmitoticdescendantsofthat
cellwillhavethesameinactiveX.
Ifafemaleisheterozygousforasexlinkedtrait,approximatelyhalfhercellswillexpress
oneallele,andtheotherhalfwillexpresstheotherallele.
Inhumans,thismosaicpatternisevidentinwomenwhoareheterozygousforanX
linkedmutationthatpreventsthedevelopmentofsweatglands.
Aheterozygouswomanwillhavepatchesofnormalskinandskinpatcheslackingsweat
glands.
Similarly,theorangeandblackpatternontortoiseshellcatsisduetopatchesofcells
expressinganorangeallelewhileotherpatcheshaveanonorangeallele.
XinactivationinvolvesmodificationoftheDNAbyattachmentofmethyl(CH 3)
groupstocytosinenucleotidesontheXchromosomethatwillbecometheBarrbody.

ResearchershavediscoveredagenecalledXIST(Xinactivespecifictranscript).
ThisgeneisactiveonlyontheBarrbodychromosomeandproducesmultiplecopiesof
anRNAmoleculethatattachtotheXchromosomeonwhichtheyweremade.
ThisinitiatesXinactivation.
ThemechanismthatconnectsXISTRNAandDNAmethylationisunknown.

WhatdetermineswhichofthetwoXchromosomeshasanactiveXISTgeneisalso
unknown.
C.ErrorsandExceptionsinChromosomalInheritance

Physicalandchemicaldisturbancescandamagechromosomesinmajorways.

Errorsduringmeiosiscanalterchromosomenumberinacell.

Plantstolerategeneticdefectstoagreaterextentthatdoanimals.

1.Alterationsofchromosomenumbercausesomegeneticdisorders.

IG Lecture Outline 15-7

 Nondisjunctionoccurswhenproblemswiththemeioticspindlecauseerrorsindaughter
cells.
ThismayoccuriftetradchromosomesdonotseparateproperlyduringmeiosisI.
Alternatively,sisterchromatidsmayfailtoseparateduringmeiosisII.
Asaconsequenceofnondisjunction,onegametereceivestwoofthesametypeof
chromosome,andanothergametereceivesnocopy.
Offspringresultingfromfertilizationofanormalgametewithoneproducedby
nondisjunctionwillhaveanabnormalchromosomenumber,aconditionknownas
aneuploidy.
Trisomiccellshavethreecopiesofaparticularchromosometypeandhave2n+1total
chromosomes.
Monosomiccellshaveonlyonecopyofaparticularchromosometypeandhave2n1
chromosomes.

Iftheorganismsurvives,aneuploidytypicallyleadstoadistinctphenotype.

Aneuploidycanalsooccurduringfailuresofthemitoticspindle.

Ifthishappensearlyindevelopment,theaneuploidconditionwillbepassedalongby
mitosistoalargenumberofcells.
Thisislikelytohaveasubstantialeffectontheorganism.

Organismswithmorethantwocompletesetsofchromosomesarepolyploid.

Thismayoccurwhenanormalgametefertilizesanothergameteinwhichtherehasbeen
nondisjunctionofallitschromosomes.
Theresultingzygotewouldbetriploid(3n).
Alternatively,ifa2nzygotefailedtodivideafterreplicatingitschromosomes,a
tetraploid(4n)embryowouldresultfromsubsequentsuccessfulcyclesofmitosis.
Polyploidyisrelativelycommonamongplantsandmuchlesscommonamonganimals,
althoughitisknowntooccurinfishesandamphibians.
Thespontaneousoriginofpolyploidindividualsplaysanimportantroleintheevolution
ofplants.
Bothfishesandamphibianshavepolyploidspecies.
Recently,researchersinChilehaveidentifiedanewrodentspeciesthatmaybe
tetraploid.

Polyploidsaremorenearlynormalinphenotypethananeuploids.
Oneextraormissingchromosomeapparentlyupsetsthegeneticbalanceduring
developmentmorethandoesanentireextrasetofchromosomes.

2.Alterationsofchromosomestructurecausesomegeneticdisorders.

Breakageofachromosomecanleadtofourtypesofchangesinchromosomestructure.
Adeletionoccurswhenachromosomefragmentlackingacentromereislostduringcell
division.
Thischromosomewillbemissingcertaingenes.
Aduplicationoccurswhenafragmentbecomesattachedasanextrasegmenttoasister
chromatid.
Alternatively,adetachedfragmentmayattachtoanonsisterchromatidofa
homologouschromosome.
IG Lecture Outline 15-8

Inthiscase,theduplicatedsegmentswillnotbeidenticalifthehomologuescarry
differentalleles.
Aninversionoccurswhenachromosomalfragmentreattachestotheoriginal
chromosome,butinthereverseorientation.
Intranslocation,achromosomalfragmentjoinsanonhomologouschromosome.

Deletionsandduplicationsareespeciallylikelytooccurduringmeiosis.
Homologouschromatidsmaybreakandrejoinatincorrectplacesduringcrossingover,so
thatonechromatidlosesmoregenesthanitreceives.
Theproductsofsuchanonreciprocalcrossoverareonechromosomewithadeletionand
onechromosomewithaduplication.

Adiploidembryothatishomozygousforalargedeletionoramalewithalargedeletion
toitssingleXchromosomeisusuallymissingmanyessentialgenes.
Thisisusuallylethal.

Duplicationsandtranslocationsaretypicallyharmful.

Reciprocaltranslocationorinversioncanalterphenotypebecauseagenesexpressionis
influencedbyitslocationamongneighboringgenes.
3.Humandisordersareduetochromosomealterations.
Severalserioushumandisordersareduetoalterationsofchromosomenumberand
structure.
Althoughthefrequencyofaneuploidzygotesmaybequitehighinhumans,mostofthese
alterationsaresodisastroustodevelopmentthattheembryosarespontaneouslyabortedlong
beforebirth.
Severedevelopmentalproblemsresultfromanimbalanceamonggeneproducts.
Certainaneuploidconditionsupsetthebalanceless,makingsurvivaltobirthandbeyond
possible.
Survivingindividualshaveasetofsymptomsasyndromecharacteristicofthetypeof
aneuploidy.
Geneticdisorderscausedbyaneuploidycanbediagnosedbeforebirthbyfetaltesting.
Oneaneuploidcondition,Downsyndrome,isduetothreecopiesofchromosome21or
trisomy21.
Itaffectsonein700childrenbornintheUnitedStates.
Althoughchromosome21isthesmallesthumanchromosome,trisomy21severelyalters
anindividualsphenotypeinspecificways.
IndividualswithDownsyndromehavecharacteristicfacialfeatures,shortstature,heart
defects,susceptibilitytorespiratoryinfection,mentalretardation,andincreasedriskof
developingleukemiaandAlzheimersdisease.
Mostaresexuallyunderdevelopedandsterile.
MostcasesofDownsyndromeresultfromnondisjunctionduringgameteproductionin
oneparent.

ThefrequencyofDownsyndromeincreaseswiththeageofthemother.
Thismaybelinkedtosomeagedependentabnormalityinthespindlecheckpointduring
meiosisI,leadingtonondisjunction.

Trisomiesofotherchromosomesalsoincreaseinincidencewithmaternalage,butitis
rareforinfantswiththeseautosomaltrisomiestosurviveforlong.
IG Lecture Outline 15-9

 Nondisjunctionofsexchromosomesproducesavarietyofaneuploidconditionsin
humans.

Thisaneuploidyupsetsthegeneticbalancelessseverelythatautosomalaneuploidy.
ThismaybebecausetheYchromosomecontainsrelativelyfewgenesandbecauseextra
copiesoftheXchromosomebecomeinactivatedasBarrbodiesinsomaticcells.

AnXXYmalehasKlinefelterssyndrome,whichoccursonceinevery2,000livebirths.
Theseindividualshavemalesexorgans,buthaveabnormallysmalltestesandaresterile.
AlthoughtheextraXisinactivated,somebreastenlargementandotherfemale
characteristicsarecommon.
Affectedindividualshavenormalintelligence.

MaleswithanextraYchromosome(XYY)tendtobesomewhattallerthanaverage.

TrisomyX(XXX),whichoccursonceinevery2,000livebirths,produceshealthy
females.

MonosomyXorTurnersyndrome(X0)occursonceinevery5,000births.
Thisistheonlyknownviablemonosomyinhumans.
X0individualsarephenotypicallyfemalebutaresterilebecausetheirsexorgansdonot
mature.
Whenprovidedwithestrogenreplacementtherapy,girlswithTurnersyndromedevelop
secondarysexcharacteristics.
Mostareofnormalintelligence.

Structuralalterationsofchromosomescanalsocausehumandisorders.

Deletions,eveninaheterozygousstate,cancausesevereproblems.

Onesyndrome,criduchat,resultsfromaspecificdeletioninchromosome5.
Theseindividualsarementallyretarded,havesmallheadswithunusualfacialfeatures,
andhaveacrylikethemewingofadistressedcat.
Thissyndromeisfatalininfancyorearlychildhood.

Chromosomaltranslocationsbetweennonhomologouschromosomesarealsoassociated
withhumandisorders.
Chromosomaltranslocationshavebeenimplicatedincertaincancers,includingchronic
myelogenousleukemia(CML).
CMLoccurswhenalargefragmentofchromosome22switchesplaceswithasmall
fragmentfromthetipofchromosome9.
Theresultingshort,easilyrecognizedchromosome22iscalledthePhiladelphia
chromosome.
4.Thephenotypiceffectsofsomemammaliangenesdependonwhethertheyareinherited
fromthemotherorthefather.
Formostgenes,itisareasonableassumptionthataspecificallelewillhavethesame
effectregardlessofwhetheritisinheritedfromthemotherorfather.
However,forafewdozenmammaliantraits,phenotypevariesdependingonwhich
parentpassedalongtheallelesforthosetraits.
ThegenesinvolvedarenotnecessarilysexlinkedandmayormaynotlieontheX
chromosome.

IG Lecture Outline 15-10

 Variationinphenotypedependingonwhetheranalleleisinheritedfromthemaleor
femaleparentiscalledgenomicimprinting.
Genomicimprintingoccursduringformationofgametesandresultsinthesilencingof
certaingenes.
Imprintedgenesarenotexpressed.
Becausedifferentgenesareimprintedinspermandova,somegenesinazygoteare
maternallyimprinted,andothersarepaternallyimprinted.
Thesematernalandpaternalimprintsaretransmittedtoallbodycellsduring
development.
Foramaternallyimprintedgene,onlythepaternalalleleisexpressed.
Forapaternallyimprintedgene,onlythematernalalleleisexpressed.

Patternsofimprintingarecharacteristicofagivenspecies.

Thegeneforinsulinlikegrowthfactor2(Igf2)isoneofthefirstimprintedgenestobe
identified.
Althoughthegrowthfactorisrequiredfornormalprenatalgrowth,onlythepaternal
alleleisexpressed.
EvidencethattheIgf2alleleisimprintedinitiallycamefromcrossesbetweenwildtype
miceanddwarfmicehomozygousforarecessivemutationintheIgf2gene.
Thephenotypesofheterozygousoffspringdiffer,dependingonwhetherthemutantallele
comesfromthemotherorthefather.
TheIgf2alleleisimprintedineggs,turningoffexpressionoftheimprintedallele.
Insperm,theIgf2alleleisnotimprintedandfunctionsnormally.

Whatexactlyisagenomicimprint?

Inmanycases,itconsistsofmethyl(CH3)groupsthatareaddedtothecytosine
nucleotidesofoneofthealleles.
Thehypothesisthatmethylationdirectlysilencesanalleleisconsistentwiththeevidence
thatheavilymethylatedgenesareusuallyinactive.
Othermechanismsmayleadtosilencingofimprintedgenes.

Mostoftheknownimprintedgenesarecriticalforembryonicdevelopment.

Inexperimentswithmice,embryosengineeredtoinheritbothcopiesofcertain
chromosomesfromthesameparentdiebeforebirth,whethertheirloneparentismaleor
female.

Normaldevelopmentrequiresthatembryoniccellshaveoneactivecopyofcertaingenes.

Aberrantimprintingisassociatedwithabnormaldevelopmentandcertaincancers.

5.ExtranucleargenesexhibitanonMendelianpatternofinheritance.
Notallofaeukaryotecellsgenesarelocatedonnuclearchromosomes,oreveninthe
nucleus.

ExtranucleargenesarefoundinsmallcirclesofDNAinmitochondriaandchloroplasts.

Theseorganellesreproducethemselvesandtransmittheirgenestodaughterorganelles.
TheircytoplasmicgenesdonotdisplayMendelianinheritance,becausetheyarenot
distributedtooffspringaccordingtothesamerulesthatdirectdistributionofnuclear
chromosomesduringmeiosis.
IG Lecture Outline 15-11

 KarlCorrensfirstobservedcytoplasmicgenesinplantsin1909whenhestudiedthe
inheritanceofpatchesofyelloworwhiteontheleavesofanotherwisegreenplant.
Hedeterminedthatthecolorationoftheoffspringwasdeterminedbyonlythematernal
parent.
Thesecolorationpatternsareduetogenesintheplastidsthatareinheritedonlyviathe
ovum,notviathespermnucleusinthepollen.
Becauseazygoteinheritsallitsmitochondriafromtheovum,allmitochondrialgenesin
mammalsdemonstratematernalinheritance.

SeveralrarehumandisordersareproducedbymutationstomitochondrialDNA.
TheseprimarilyimpactATPsupplybyproducingdefectsintheelectrontransportchain
orATPsynthase.
Tissuesthatrequirehighenergysupplies(thenervoussystemandmuscles)maysuffer
energydeprivationfromthesedefects.
Forexample,apersonwithmitochondrialmyopathysuffersweakness,intoleranceof
exercise,andmuscledeterioration.
Othermitochondrialmutationsmaycontributetodiabetes,heartdisease,andother
diseasesofaging.

IG Lecture Outline 15-12