醫(yī)學遺傳學教學課件：Population Genetics

PopulationGeneticsEmphasisGeneFrequency&GenotypicFrequencyLawofGeneticEquilibriumFactorsthatAlterGeneticEquilibrium——Mutation,SelectionConsanguineousMarriagePopulationGenetics

Populationgeneticsisthestudyofthedistributionofgenesinpopulationsandofhowthefrequenciesofgenesandgenotypesaremaintainedorchanged.MendelianPopulation

Mendelianpopulationisagroupofinterbreedingindividuals,wholiveinthesameplaceandshareacommonsetofgenes(genepool).1．GeneFrequency&GenotypicFrequencyGenefrequency（基因頻率）Thefrequencyofagivenalleleatagivenlocusinapopulation.1．GeneFrequency&GenotypicFrequencyGenefrequencyGenotypicfrequency（基因型頻率）Thenumberofindividualswithoneparticulargenotypedividedbythetotalnumberofindividualsinthepopulation.1．GeneFrequency&GenotypicFrequencyApairofallelesAanda1．GeneFrequency&GenotypicFrequencyApairofallelesAandaCodominance&SemidominanceDerivingGeneFrequencies

fromGenotypicFrequencies

MNBloodGroupCo-dominanttraitEachphenotypecorrespondstouniquegenotype.Twoalleles(MandN)BloodTypeNumberofPeopleGenotypeGenotypicFrequencyM

N

M

250MM0．5(MM)5000MN

150MN0．3(MN)150150N100NN0．2(NN)0200Total500

650350GeneFrequency

0.650.35

1.0

Genotypicfrequencies:

MM=0.5MN=0.3NN=0.2Genefrequencies:p＝MM+1/2MN=0.5+1/2×0.3=0.65

q＝NN+1/2MN=0.2+1/2×0.3=0.352．LawofGeneticEquilibrium（遺傳平衡定律）Hardy-WeinberglawHardyGHWeinbergWExplainshowMendeliansegregationinfluencesallelicandgenotypicfrequenciesinapopulation.2．LawofGeneticEquilibriumHardy-Weinberglaw2．LawofGeneticEquilibriumLargepopulationRandommatingNonaturalselectionNomutationNomigrationIfassumptionsaremet,populationwillbeingeneticequilibrium.2．LawofGeneticEquilibriumAllelefrequenciesdonotchangeovergenerations.ThedistributionofgenotypicfrequencySpermf(A)=pf(a)=qEggf(A)=pp2

(AA)pq

(Aa)f(a)=qpq

(Aa)q2

(aa)2．LawofGeneticEquilibriumAllelefrequenciesdonotchangeovergenerations.Thedistributionofgenotypicfrequencyp2:FrequencyofAA2pq:FrequencyofAaq2:Frequencyofaa2．LawofGeneticEquilibriumGenotypicfrequenciesdonotchangeovergenerations.ThedistributionofconnubialtypesGenotypeofmalesAA

(p2)Aa

(2pq)aa(q2)GenotypeoffemalesAA

(p2)p42p3qp2q2Aa

(2pq)2p3q4p2q22pq3aa(q2)p2q22pq3q4

MatingTypesOffspringMotherFatherFrequencyAAAaaa

AAAAp2×p2=p41(p4)AAAap2×2pq=2p3q1/2(2p3q)1/2(2p3q)AaAA2pq×p2=2p3q1/2(2p3q)1/2(2p3q)AAaap2×q2=p2q21(p2q2)aaAAp2×q2=p2q21(p2q2)AaAa2pq×2pq=4p2q21/4(4p2q2)1/2(4p2q2)1/4(4p2q2)Aaaa2pq×q2=2pq31/2(2pq3)1/2(2pq3)aaAa2pq×q2=2pq31/2(2pq3)1/2(2pq3)aaaaq2

×q2=q41(q4)

Genotypesresultingfromp22pq

q2AllpossiblematingSumofAAoffspring=p4+2p3q+p2q2

=

p2(p2

+2pq+q2)

=p2(p

+q)2=

p2SumofAaoffspring=2p3q+4p2q2

+2pq3=2pq(p2

+2pq+q2)

=2pq(p

+q)2=2pqSumofaa

offspring=p2q2

+2pq3+q4=q2(p2

+2pq+q2)

=q2(p

+q)2=q2GenotypicfrequenciesremainunchangedAfteronlyonegenerationofrandommating,populationwillbeingeneticequilibrium.2．LawofGeneticEquilibriumGeneticEquilibriumforautosomicgene

2．LawofGeneticEquilibrium2．LawofGeneticEquilibrium2．LawofGeneticEquilibriumMultipleallele(A,B,O)BloodgroupABOABGenotypeAA,AOBB,BOOOABGenotypicfrequencyp2+2prq2+2qrr

22pq2．LawofGeneticEquilibriumX-linkedallelesXA(p)Xa(q)YXA(p)XAXA

(p2)XAXa(pq)XAY

(p)Xa(q)XAXa

(pq)XaXa

(q2)XaY

(q)Males:Genotypefrequenciesarethesameasallelefrequencies:(p+q

)GeneticEquilibriumforX-linkedGene

Whentheallelefrequencyinthemalepopulationequalsthatinthefemalepopulation,thewholepopulationreachesequilibriumfrequency.2．LawofGeneticEquilibrium2.1．ADdiseasesAlmostalloftheaffectedofADdiseaseareheterozygote.Patient:AA

p2;Aa2pq2．LawofGeneticEquilibrium2.2．ARdiseasesTheheterozygotecarrierfrequencyistwicethefrequencyofthemutantallele.2．LawofGeneticEquilibrium2.2．ARdiseasesThenumberofheterozygotecarriersinthepopulationismuchlargerthantheaffected.Theratioincreasesasthediseasefrequencydecreases.Patient:aaq2

Carrier:Aa2pq2．LawofGeneticEquilibrium2.2．ARdiseasesDiseaseGenefrequencyGenotypicfrequencyAa/aaA(p)a(q)AA(p2)Aa(2pq)aa(q2)2pq/q2Alcaptonuria0.9990.0010.9980.0020.0000012000AlbinismIA0.9950.0050.9900.0100.0000025400PKU0.9900.0100.9800.0200.0001200Tay-Sachs0.9830.0170.9660.0330.0003110Sicklecellanemia0.9500.0500.9020.0950.0025382．LawofGeneticEquilibrium2.2．ARdiseasesDiseaseGenefrequencyGenotypicfrequencyAa/aaA(p)a(q)AA(p2)Aa(2pq)aa(q2)2pq/q2Alcaptonuria0.9990.0010.9980.0020.0000012000AlbinismIA0.9950.0050.9900.0100.0000025400PKU0.9900.0100.9800.0200.0001200Tay-Sachs0.9830.0170.9660.0330.0003110Sicklecellanemia0.9500.0500.9020.0950.002538Exercises

Theincidencerateofalbinoinapopulationis1/1000000.Assumingthispopulationisingeneticequilibrium,whatwouldbethefrequencyofthecarriers?Whatistheratioofcarriertopatients?2．LawofGeneticEquilibrium2.3．XDdiseasesTheratioofaffectedfemalestothemalesisapproximately2to1.Affectedfemale:XAXAp2;XAXa2pq

Affectedmale:XAY

p2．LawofGeneticEquilibrium2.4．XRdiseasesMoreaffectedmalesthanaffectedfemales.Theratioincreasesasthediseasefrequencydecreases.Affectedfemale:XaXaq2

Affectedmale:XaY

qExercise Red-greencolor-blindnessisX-linkedrecessivetrait.Theincidencerateamongmalesis0.01.Whatisthefrequencyintheequilibriumpopulationfor 1.FemaleR-Gcolor-blindness? 2.Male/Femalepatientratio?3．FactorsthatInfluence

GeneticEquilibriumMutationSelectionSmallpopulationsizeMigrationConsanguineousMarriage3.1．MutationMutationrateThenumberofgeneundergomutationamongamilliongenesinageneration.

n×10-6/generation

3.1．MutationApairofallelesAandaf(A)isp,themutationrateisu,q

=puf(a)isq,themutationrateisv,p=qvp=q,pandqremainunchanged

Ifpu>qv，qincreasesovergenerationsIfpu<qv，qdecreasesovergenerations3.1．MutationNeutralmutationAmutationthathasnoeffectontheDarwinianfitnessofitscarriers.Amutationthathasnophenotypiceffect.3.2．SelectionSelectionrepresentstheactionofenvironmentalfactorsonaparticularphenotype.Selectionmaybepositiveornegative,ascanbemeasuredbythebiologicalfitness(?).3.2．SelectionFitness(f

):Thepotentialforindividualsofagivengenotypetosurviveandreproduceinthefaceofnaturalselection.Selectioncoefficient(S

):Ameasureoftheloseoffitnessandisdefinedas1-??=1(thefitnessofnormalallele)?=0(ageneticlethal)MutationpressureThecontinuedproductionofanallelebymutation.3.2．SelectionSelectionpressureTheeffectivenessofnaturalselectioninalteringthegeneticcompositionofapopulationoveraseriesofgenerations.3.2．Selection01234567891011NumberofDeleteriousMutationsMutationSelectionFrequencyMutationwillpushthemeanofthisdistributionupSelectionwillpushthemeandown.ADdiseaseARdiseaseXRdiseaseXDdisease3.2．SelectionTheBalancebetweenSelectionandMutationExercises

Inapopulationatgeneticequilibrium,theincidencerateforhemophilia(XR)inmalesis0.00008.Thefitnessforthisdiseaseis0.25.Whatisthecontrollingmutationforthispopulation?3.3．

SmallpopulationsizeGeneticdrift

（遺傳漂變）:Thefluctuation(randomchange)ofallelefrequencyaswellasgenotypicfrequenciesinapopulationfromgenerationtogenerationduetoitssmallsize.RandomGeneticDrift0.5InitialFrequency25PopulationSizeRandomGeneticDrift0.5InitialFrequency100PopulationSizeRandomGeneticDrift0.5InitialFrequency500PopulationSize3.3．SmallpopulationsizeThelargerapopulationthelowertheprobabilitythatgeneticdriftwillalteritsallelefrequencies.Aspopulationsizeincreasestheeffectsofgeneticdriftdecrease.3.3．SmallpopulationsizeFoundereffect（奠基者效應）Ahighfrequencyofamutantgeneinapopulationfoundedbyasmallancestralgroup(founders).3.4．MigrationMigrationpressureInageneticsense,themovementofallelesbetweenpopulations.ThedifferenceofallelefrequencybetweentwopopulationsSizesofimmigrators(gene)3.5．ConsanguineousMarriageCloserelativeCloserelativesreferstorelationshipsbyblood.ConsanguineousMarriageConsanguineousmarriageistheunionofindividualshavingacommonancestor.Theprobabilitythatanindividualhasapairofallelesthatareidenticalbydescentfromacommonancestor.3.5．ConsanguineousMarriage3.5.1．InbreedingCoefficient(F)Brother-SisterMarriageS3.5．ConsanguineousMarriage3.5.2．FofAutosomalAlleleF=4×(1/2)4=1/4CousinMarriage（F=1/16）3.5．ConsanguineousMa