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1、Medical Genetics08基因变异的群体行为Population GeneticsMedical GeneticsMedical GeneticsMedical GeneticsWhat is a population from a genetic perspective?A population in the genetic sense,is not just a group of individuals,but a breeding groupMedical Genetics The genetics of a population is concerned not only w
2、ith the genetic constitution of the individuals but also with the transmission of the genes from one generation to the next.Medical Genetics In the transmission the genotypes of the parents are broken down and a new set of genotypes is constituted in the progeny,from the genes transmitted in the gam
3、etes.The genes carried by the population thus have continuity from generation to generation,but the genotypes in which they appear do not.The genetic constitution of a population,referring to the genes it carries,is described by the array of gene frequencies,that is by specification of the alleles p
4、resent at every locus and the numbers or proportions of the different alleles at each locus.Medical GeneticsGoals of Population Genetics 1.Todescribehowthefrequencyofanallelewhichcontrolsatraitchangesovertime；2.Toanalyzethefactorsthatleadtochangesingene(allele)frequencies；3.Todeterminehowchangesinge
5、ne(allele)frequenciesaffectevolutionandspeciation.Medical GeneticsWhy Study Populations and Gene Frequencies 1.Geneticvariabilitynecessaryforevolutionarysuccess;2.Measuringgeneticvariabilityatmanylocicancharacterizeapopulation;3.Variabilityofphenotypicandmoleculartraitsareanalyzed.Medical Genetics1.
6、VariabilityandGene(orAllelic)Frequencies1.VariabilityandGene(orAllelic)Frequencies1.Geneticdataforapopulationcanbeexpressedasgeneorallelicfrequencies;2.Allgeneshaveatleasttwoalleles;3.Summationofalltheallelicfrequenciesforapopulationcanbeconsideredadescriptionofthepopulation;4.Frequenciescanvarywide
7、lyamongtheallelesinapopulation;5.Twopopulationsofthesamespeciesdonothavetohavethesameallelicfrequencies.Medical GeneticsGenotypic frequenciesItdescribesthedistributionofgenotypesinapopulation.Medical GeneticsExampleBloodtypelocus;twoalleles,MorN,andthreeMM,MN,NNgenotypesarepossible(thefollowingdataw
8、ascollectedfromasinglehumanpopulation).Medical GeneticsGenotye#of Individuals Genotypic Frequencies MM1787MM=1787/6129=0.289MN3039MN=3039/6129=0.50NN1303NN=1303/6129=0.21Total6129Medical GeneticsDeriving Gene(or Allelic)FrequenciesTodeterminetheallelicfrequencieswesimplycountthenumberofMorNallelesan
9、ddividebythetotalnumberofalleles.f(M)=(2x1787)+3039/12,258=0.5395f(N)=(2x1303)+3039/12,258=0.4605Byconventiononeoftheallelesisgiventhedesignationpandtheotherq.Alsop+q=1.p=0.5395andq=0.4605Furthermore,apopulationisconsideredbypopulationgeneticiststobepolymorphiciftwoallelesaresegregatingandthefrequen
10、cyofthemostfrequentalleleislessthan0.99.Medical GeneticsDeriving allelic frequencies from genotypic frequenciesThefollowingexamplewillillustratehowtocalculateallelicfrequenciesfromgenotypicfrequencies.Itwillalsodemonstratethattwodifferentpopulationsfromthesamespeciesdonothavetohavethesameallelicfreq
11、uencies.Medical GeneticsLet:p=f(M)andq=f(N)Thus:p=f(MM)+f(MN)andq=f(NN)+f(MN).Percent Allelic Frequencies Location MM MN NN p q Greenland83.515.60.900.9130.087Iceland31.251.517.300.5690.431Medical GeneticsSotheresultsoftheabovedataare:Greenland:p=0.835+(0.156)=0.913andq=0.009+(0.156)=0.087Iceland:p=
12、0.312+(0.515)=0.569andq=0.173+(0.515)=0.431Clearly the allelic frequencies vary between these populations.Medical Genetics2.TheHardy-WeinbergLawThe Hardy-Weinberg LawTheunifyingconceptofpopulationgeneticsNamedafterthetwoscientistswhosimultaneouslydiscoveredthelawThelawpredictshowgenefrequencieswillb
13、etransmittedfromgenerationtogenerationgivenaspecificsetofassumptions.Medical GeneticsIf aninfinitelylarge,randommatingpopulationisfreefromoutsideevolutionaryforces(i.e.mutation,migrationandnaturalselection),then thegenefrequencieswillnotchangeovertime,andthefrequenciesinthenextgenerationwillbe:p2for
14、theAAgenotype2pqfortheAagenotype,andq2fortheaagenotype.Medical GeneticsLetsexaminetheassumptionsandconclusionsinmoredetailstartingfirstwiththeassumptions.Medical GeneticsA.Infinitely large population1.Nosuchpopulationactuallyexists.2.Theeffectthatisofconcernisgeneticdrift(achangeingenefrequencythati
15、stheresultofchancedeviationfromexpectedgenotypicfrequencies)aprobleminsmallpopulations.Medical GeneticsB.Random mating Random mating-matingsinapopulationthatoccurinproportiontotheirallelicfrequencies.Medical GeneticsFor example,iftheallelicfrequenciesinapopulationare:f(M)=0.91f(N)=0.09thentheprobabi
16、lityofMMindividualsoccurringis0.91x0.91=0.828.Ifasignificantdeviationoccurred,thenrandommatingdidnothappeninthispopulation.Medical GeneticsWithinapopulation,randommatingcanbeoccurringatsomelocibutnotatothers.Examplesofrandommatingloci-bloodtype,RFLPpatternsExamplesofnon-randommatingloci-intelligence
17、,physicalstatureMedical GeneticsC.No evolutionary forces affecting the populationTheprincipalforcesare:1.Mutation2.Migration3.SelectionSomelociinapopulationmaybeaffectedbytheseforces,andothersmaynot;thoselocinotaffectedbytheforcescanbyanalyzedasaHardy-WeinbergpopulationMedical GeneticsMathematical D
18、erivation of the Hardy-Weinberg LawIfpequalsthefrequencyofalleleAinapopulationandqisthefrequencyofalleleainthesamepopulation,unionofgameteswouldoccurwiththefollowinggenotypicfrequencies:Medical Genetics*Thegameteandoffspringgenotypesareinparentheses.Fromthetable,itisclearthatthepredictionregardingge
19、notypicfrequenciesafteronegenerationofrandommatingiscorrect.Thatis:AA=p2;Aa=2pq;andaa=q2Female Gametes*p(A)q(a)MaleGametes p(A)p2(AA)pq(Aa)q(a)pq(Aa)q2(aa)Medical GeneticsPrediction regarding stability of gene frequencies Thefollowingisamathematicalproofofthesecondprediction.Todeterminetheallelicfre
20、quency,theycanbederivedfromthegenotypicfrequenciesasshownabove.p=f(AA)+f(Aa)(substitutefromthetableonpreviouspage)p=p2+(2pq)(factoroutpanddivide)p=p(p+q)(p+q=1;thereforeq=1-p;makethissubstitution)p=pp+(1-p)(subtractandmultiply)p=pMedical GeneticsEvolutionary GeneticsTheHardy-WeinbergLawdescribedapop
21、ulationthatexistsingeneticequilibriumwhereallelicfrequenciesdonotchangefromgenerationtogeneration.Forevolutionofapopulationtooccur,thegenefrequenciesofthatpopulationmustundergochange.Severalfactorscanacttochangefitnessortheabilitytomaintainallelicfrequencies.Viability-abilitytosurviveFertility-abili
22、tytoreproduceByalteringthefitnessofanindividual,thematingdistributionwillchange,andconsequentlytheallelicfrequencieswillchangeandthepopulationwillevolve.Medical Genetics3.FactorsthatAffectStabilityofGeneFrequencies3.FactorsthatAffectStabilityofGeneFrequenciesA.Mutation1.Classifiedasbeneficial,harmfu
23、lorneutral;2.Canoccurbypointmutations;orsmallinsertionsordeletionsofthenucleotidesequence;3.Harmfulmutationsarelostiftheyreducefitness;4.Iffitnessisimprovedbyamutation,thenthefrequencyofthatallelewillincreasefromgenerationtogeneration;5.Themutationcouldbeachangeinonealleletoresembleonecurrentlyinthe
24、population,forexamplefromadominanttoarecessiveallele;Medical Genetics6Themutationcouldgenerateanentirelynewallele.Mostofthesemutationsthoughwillbedetrimentalandlost.Iftheenvironmentchanges,thenewmutantallelemaybefavoredandeventuallybecomethedominantalelleinthatpopulation.Ifthemutationisbeneficialtot
25、hespeciesasawhole,migrationmustoccurforittospreadtootherpopulationsofthespecies.7Geneduplicationfavormutationalevents.Theduplicatedgenecanundergomutationstogenerateanewgenethathasasimilar,butaslightlymodifiedfunctionfortheorganism.Thistypeofevolutiongeneratesmultigenefamilies.(Examples:hemoglobinand
26、musclegenesinhumans,andseedstorageandphotosyntheticgenesinplants)1.Medical GeneticsB.Migration 1.TheHardy-WeinbergLawassumesthepopulationisclosed.Butformanypopulationsthisisnotthecase.2.Migrationwillchangegenefrequenciesbybringinginmorecopiesofanallelealreadyinthepopulationorbybringinginanewalleleth
27、athasarisenbymutation.3.Becausemutationsdonotoccurineverypopulation,migrationwillberequiredforthatalleletospreadthroughoutthatspecies.Medical Genetics1.4.Inageneticcontext,migrationrequirestheintroductionofnewallelesintothepopulation.Thiswillonlyoccurafterthemigranthassuccessfullymatedwithanindividu
28、alinthepopulation.Thetermthatisusedtodescribedthisintroductionofnewallelesisgeneflow.2.5.Thetwoeffectsofmigrationareto:1.(1)increasevariabilitywithinapopulation2.(2)preventapopulationofthatspeciesfromdivergingtotheextentthatitbecomesanewspecies.Medical GeneticsC.Selection1.Mutationcausesnewfunctions
29、fortheindividual.2.Thesenewformsmayormaynotaddtothefitnessoftheindividual.3.Ifthefitnessoftheindividualleadstoareproductiveadvantage,thentheallelespresentinthatindividualwillbemoreprevalentinthenextgenerationofthepopulation.4.Apopulationundergoesselectionwhencertainallelesarepreferentiallyfoundinanewgenerationbecauseoftheincreasedfitnessoftheparent.5.Theallelesintheindividualwithincreasedfitnesswillincreaseinfrequencyinthepopulation.6.InaDarwiniancontext,mutation,migrationandselectionleadtochangesingenefrequencies,andthepopulationevolvesbynaturalselection.