疾病的單基因遺傳

MonogenicInheritancesingle-genedisorder

ormonogenicdisorder

Somedisordersresultwhenamutationcausestheproductofasinglegenetobealteredormissing.ThesedisordersareinheritedinsimplepatternssimilartooridenticalwiththosedescribedbyMendelforcertaindiscretecharacteristicsingardenpeas.Therefore,it’salsocalledMendeliandiseases.BasicPatternofSingleGeneInheritance

AutosomalDominant

AutosomalRecessiveX-linkedDominantX-linkedRecessiveY-linked1.PedigreeandProband

Humansareuniqueamongorganismsinmanyways,butonewaywhichisnearanddeartoageneticist'sheartisthathumansarenotsusceptibletogeneticexperimentation.ThestudyofinheritedMendeliantraitsinhumansmustrelyonobservationsmadewhileworkingwithindividualfamilies.ClassicalcrossfertilizationbreedingexperimentsasperformedbyMendelarenotallowedinhumans!Humangeneticistsarenotallowedtoselectivelybreedforthetraitstheywishtostudy!Oneofmostpowerfultoolsinhumangeneticstudiesispedigreeanalysis.pedigree

Theyaregraphicrepresentationsofafamilytreewhichshowthebiologicalrelationshipoftheindexcase,orprobandorpropositus

totherestoftheindividuals.Afamilytreediagramthatshowshowaparticulargenetictraitordiseasehasbeeninherited.Whenhumangeneticistsfirstbegantopublishfamilystudies,theyusedavarietyofsymbolsandconventions.Nowthereareagreeduponstandardsfortheconstructionofpedigrees.Symbols2.autosomaldominantinheritanceThepatternofautosomaldominantinheritanceisperhapstheeasiesttypeofMendelianinheritancetorecognizeinapedigree.Onedoseofthemutantgene,onemutantallele,isallthatisrequiredfortheexpressionofthephenotype.Therearethreereasonswhyanindividualwithanautosomaldominantdiseaseshouldalwaysbeconsideredasbeingaheterozygoteuntilprovenotherwise.A.Thediseaseisusuallyrare,withonlyabout1/10,000individualsaffectedasanorderofmagnitude.Affectedindividualsaremostlikelytocomefromaffectedbynormalmatings.Thenormalparentishomozygousrecessive,thusassuringthateachproductofthematinghasatleastonenormalgene.

B.Intheextremelyrareinstanceswheretwoaffectedindividualshavemated,thehomozygousaffectedindividualsusuallyaresoseverelyaffectedtheyarenotcompatiblewithlife.Theexceptionsaretheautosomaldominantdiseasescausedbythesomaticexpansionoftrinucleotiderepeatsequences(e.g.,Huntington'sdisease)thatwewillstudylater.

C.Thematingofverycloselyrelatedindividuals,themostlikelywayfortwoaffectedindividualstoknoweachother,isforbiddeninoursociety.

Withtheunderstandingthatalmostallaffectedindividualsareheterozygotes,andthatinmostmatingsinvolvingapersonwithanautosomaldominanttraittheotherpartnerwillbehomozygousnormal,therearefourhallmarksofautosomaldominantinheritance.Therearefourhallmarksofautosomaldominantinheritance:(1)Exceptfornewmutations,whicharerareinnatureandextremelyrareonexaminationpedigrees,andthecomplexitiesofincompletepenetrancetobediscussedlater,everyaffectedindividualhasanaffectedbiologicalparent.Thereisnoskippingofgenerations.

(2)Malesandfemaleshaveanequallylikelychanceofinheritingthemutantalleleandbeingaffected.Therecurrenceriskofeachchildofanaffectedparentis1/2.

(3)Normalsiblingsofaffectedindividualsdonottransmitthetraittotheiroffspring.

(4)Thedefectiveproductofthegeneisusuallyastructuralprotein,notanenzyme.Structuralproteinsareusuallydefectivewhenoneoftheallelicproductsisnonfunctional;enzymesusuallyrequirebothallelicproductstobenonfunctionaltoproduceamutantphenotype.

THEPUNNETSQUARE

In1910,Punnettdevelopedasimplemethodofdepictingthepossiblegenotypesonecouldgetfromvariousmatings.WecallitthePunnettSquare.Supposeafatherisheterozygousforanautosomaldominantgene,withalleleD,themutantdominantallele,andalleled,therecessivenormalallele.Hecanproducetwotypesofgametes,Dandd.Supposealsohiswifeishomozygousnormal,havingbothdalleles.ThePunnettSquareisconstructedasfollows:Onegametecomesfromeachparenttoproducethegenotypeoftheoffspring.Twooutofthefourpossiblecombinationsareaffected;twooutoffourarenormal.

SamplePedigree

neurofibroma

marfan‘ssyndrome

3.AUTOSOMALRECESSIVEINHERITANCE

Thefirst,andmostimportant,thingtorememberaboutautosomalrecessiveinheritanceisthatmost,ifnotall,affectedindividualshaveparentswithnormalphenotypes.Supposethediseaseaffectsoneintenthousandlivebirths,agoodorderofmagnitudeestimateformostautosomalrecessivediseases.Thatwouldmaketheheterozygotefrequencyinthepopulationoneinfifty(seepopulationgeneticsforcalculations).Thelikelihoodoftwoaffectedpersonsmatingwouldbe1/10,000x1/10,000or1/100,000,000.BychancealonetheremightbetwosuchmatingsintheUnitesStates,butnomorethan2.Thelikelihoodofanaffectedandaheterozygotematingwouldbe1/10,000x1/50x2(sinceeitherparentcouldbetheaffected)or1/250,000.Thelikelihoodoftwoheterozygotes(heterozygotesareusuallycalled"carriers")matingis1/50x1/50or1/2500,morethan99%ofallpossiblematings.ThePunnettSquareforautosomalrecessivediseaseswithanaffectedchildinthefamilyalmostalwayslookslikethefollowing:WherethefatherandmotherarebothDd(ddistherecessiveaffectedindividual,Ddtheheterozygouscarrierindividual,andDDthehomozygousnormalindividual).ThePunnetSquareshowstheoriginofthefamousMendelianrationof3/4normalto1/4affected.Formostautosomalrecessivediseases,butnotall,theheterozygotecannotbedistinguishedfromthenormalhomozygote.InthenormalphenotypecategoriesofoffspringintheabovePunnettSquare(Dd

andDDproducethesamenormalphenotype),pleasenotethattwoofthethreeareheterozygotes(carriers);oneofthethreeishomozygousnormal.Withinthenormalsiblingsofanaffectedindividualtheprobabilityofbeingacarrieris2/3.Therearefivehallmarksofautosomalrecessiveinheritance:

(1)Malesandfemalesareequallylikelytobeaffected.

(2)Onaverage,therecurrencerisktotheunbornsiblingofanaffectedindividualis1/4.

(3)Thetraitischaracteristicallyfoundinsiblings,notparentsofaffectedortheoffspringofaffected.

(4)Parentsofaffectedchildrenmayberelated.Therarerthetraitinthegeneralpopulation,themorelikelyaconsanguineousmatingisinvolved.

(5)Thetraitmayappearasanisolated(sporadic)eventinsmallsibships.Samplepedigree

Whenconsanguinityisinvolved,i.e.,matingsbetweenrelatedindividuals,intheproductionofanaffectedchildtheassignmentofprobabilitieschanges,especiallyintherarerautosomalrecessivediseases.Samplepedigreeamaurotic

idilcy

Wilson’sdisease4.X-LINKEDDOMINANTINHERITANCE

WhenanX-linkedgeneissaidtoexpressdominantinheritance,itmeansthatasingledoseofthemutantallelewillaffectthephenotypeofthefemale.ArecessiveX-linkedgenerequirestwodosesofthemutantalleletoaffectthefemalephenotype.Affectedfatherxnormalmother.

Affectedmotherxnormalfather.ThefollowingarethehallmarksofX-linkeddominantinheritance:

(1)Thetraitisneverpassedfromfathertoson.

(2)Alldaughtersofanaffectedmaleandanormalfemaleareaffected.Allsonsofanaffectedmaleandanormalfemalearenormal.

(3)Matingsofaffectedfemalesandnormalmalesproduce1/2thesonsaffectedand1/2thedaughtersaffected.

(4)Malesareusuallymoreseverelyaffectedthanfemales.Thetraitmaybelethalinmales.

(5)Inthegeneralpopulation,femalesaremorelikelytobeaffectedthanmales,evenifthediseaseisnotlethalinmales.

Samplepedigreeincontinentia

pigmenti

vitaminD-resistantRickets5.X-LINKEDRECESSIVEINHERITANCE

EveryonehasheardofsomeX-linkedrecessivediseaseeventhoughtheyare,ingeneral,rare.Hemophilia,Duchennemusculardystrophy,Beckermusculardystrophy,andLesch-Nyhansyndromearerelativelyrareinmostpopulations,butbecauseofadvancesinmoleculargeneticstheyreceiveattentioninthemedia.Morecommontraits,suchasglucose-6-phosphatedehydrogenase

deficienceorcolorblindness,mayoccurfrequentlyenoughinsomepopulationstoproduceafewaffectedfemales.However,theireffectonindividualsisrarelylifethreateningandmedicalinterventionisnotneeded.Pedigree7showsonetypicalinheritancepatternforarareX-linkedrecessivedisease.thehallmarksofX-linkedrecessiveinheritance(1)AswithanyX-linkedtrait,thediseaseisneverpassedfromfathertoson.

(2)Malesaremuchmorelikelytobeaffectedthanfemales.Ifaffectedmalescannotreproduce,onlymaleswillbeaffected.

(3)Allaffectedmalesinafamilyarerelatedthroughtheirmothers.

(4)Traitordiseaseistypicallypassedfromanaffectedgrandfather,throughhiscarrierdaughters,tohalfofhisgrandsons.Samplepedigreehemophilia6.Y-linkedAgeneontheYchromosome.AY-linkedgeneisbynecessitypassedfromfathertoson,sincetheYchromosomecanonlybetransmittedbyamantohismaleprogeny.IthasoftenbeensaidthatlittleisknownaboutwhetherspecificgenesareorarenotY-linked.anumberofgeneswereknowntobeY-linkedincluding:

ASMTY(acetylserotonin

methyltransferase),TSPY(testis-specificprotein),IL3RAY(interleukin-3receptor),SRY(sex-determiningregion),TDF(testisdeterminingfactor),ZFY(zincfingerprotein),PRKY(proteinkinase,Y-linked),AMGL(amelogenin),CSF2RY(granulocyte-macrophagecolony-stimulatingfactorreceptor,alphasubunitontheYchromosome),ANT3Y(adeninenucleotidetranslocator-3ontheY),AZF2(azoospermiafactor2),BPY2(basicproteinontheYchromosome),AZF1(azoospermiafactor1),DAZ(deletedinazoospermia),RBM1(RNAbindingmotifprotein,Ychromosome,family1,memberA1),RBM2(RNAbindingmotifprotein2)andUTY(ubiquitouslytranscribedTPRgeneonYchromosome).Samplepedigree7.SPECIALFEATURESPenetranceThelikelihoodagivengenewillresultindisease.Forexample,ifhalf(50%)ofthepeoplewiththeneurofibromatosis(NF)genehavethediseaseNF,thepenetranceoftheNFgeneis0.5.ExpressivityTheconsistencyofageneticdisease.Forexample,Marfandiseaseshowsvariableexpressivity.SomepersonswithMarfan'smerelyhavelongfingersandtoeswhileothershavethefull-blowndiseasewithdislocationofthelensanddissectinganeurysmoftheaorta.Phenocopy(1)Anenvironmentalconditionthatimitates(copies)oneproducedbyagene.(2)Thepersonwhohasanenvironmentally-producedconditionthatmimicsoneproducedbyagene.Geneticheterogeneity

Hereasimilarclinicalpicturemaybeproducedbydifferentmutationsatthesamelocusoratdifferentloci.Retinitispigmentosamaybecausedbybothautosomaldominantorrecessiveinheritance.Anticipation

Aremarkablephenomenoninwhichageneticdiseaseappearsearlierappearanceandwithincreasedfromwitheachsucceedin