Popula'onGenomicsofHumanAdapta'on,Part2

Tes'ngForAdap'veEvolu'on

1)  Ka/Ks>12)  Ka/Ks>Pa/Ps

Tes'ngForAdap'veEvolu'on

1)  Ka/Ks>12)  Ka/Ks>Pa/Ps

-BOTH METHODS REQUIRE RECURRENT ADAPTIVE EVOLUTION

Tes'ngForAdap'veEvolu'on

1)  Ka/Ks>12)  Ka/Ks>Pa/Ps

-BOTH METHODS REQUIRE RECURRENT ADAPTIVE EVOLUTION -PICK UP GENES SUBJECT TO RECURRENT ADAPTATION, E.G. IMMUNITY AND REPRODUCTIVE GENES

Tes'ngForAdap'veEvolu'on

1)  Ka/Ks>12)  Ka/Ks>Pa/Ps

-BOTH METHODS REQUIRE RECURRENT ADAPTIVE EVOLUTION -PICK UP GENES SUBJECT TO RECURRENT ADAPTATION, E.G. IMMUNITY AND REPRODUCTIVE GENES -WHAT ABOUT UNIQUE EVENTS OF ADAPTIVE EVOLUTION?

Tes'ngForAdap'veEvolu'on

1)  Ka/Ks>12)  Ka/Ks>Pa/Ps

-BOTH METHODS REQUIRE RECURRENT ADAPTIVE EVOLUTION -PICK UP GENES SUBJECT TO RECURRENT ADAPTATION, E.G. IMMUNITY AND REPRODUCTIVE GENES -WHAT ABOUT UNIQUE EVENTS OF ADAPTIVE EVOLUTION? -WHAT ABOUT RECENT POSITIVE SELECTION ACTING WITHIN HUMAN POPULATIONS (local adaptation)?

Tes'ngForAdap'veEvolu'on

1)  Ka/Ks>12)  Ka/Ks>Pa/Ps3)  NEUTRALPOLYMORPHISM!

EffectofPosi'veSelec'ononNEUTRALPOLYMORPHISM

EffectofPosi'veSelec'ononNEUTRALPOLYMORPHISM

Neutral variation is reduced with positive selection

EffectsofPosi'veSelec'ononNeutralPolymorphism

increase in linkage disequilibrium

EffectsofPosi'veSelec'ononNeutralPolymorphism

shift in SNP frequencies

EffectsofPosi'veSelec'ononNeutralPolymorphism

Increased differentiation among populations

Posi'veselec'oneffects

1)  Reduceddiversity2)  shiPsinSNPfrequencies(excesslow

frequency)3)  Increaseinlinkagedisequilibrium4)  increaseinpopula'ondifferen'a'on

Dis'nguishingNaturalSelec'onvs.Demographichistory:Genome-widepa\ernsofdiversity

•  demographiceffectsshouldactgenome-wide,inaconsistentmanner

Dis'nguishingNaturalSelec'onvs.Demographichistory:Genome-widepa\ernsofdiversity

•  demographiceffectsshouldactgenomewide,inaconsistentmanner

•  naturalselec'oncausesinconsistenciesamonggenesintheirpa\ernsofdiversity

Dis'nguishingNaturalSelec'onvs.Demographichistory:Genome-widepa\ernsofdiversity

•  demographiceffectsshouldactgenomewide,inaconsistentmanner

•  naturalselec'oncausesinconsistenciesamonggenesintheirpa\ernsofdiversity

•  challenge:howcanweusethisprincipletounderstandtheroleofselec'onvs.demographyonpa\ernsofdiversity?

Dis'nguishingNaturalSelec'onvs.Demographichistory:Genome-widepa\ernsofdiversity

•  demographiceffectsshouldactgenomewide,inaconsistentmanner

•  naturalselec'oncausesinconsistenciesamonggenesintheirpa\ernsofdiversity

•  challenge:howcanweusethisprincipletounderstandtheroleofselec'onvs.demographyonpa\ernsofdiversity?

characterizegenomicdistribu'onofpa\ernsofgene'c

diversity

Dis'nguishingDemographyandSelec'on

•  Inagenomiccontext,cantheresultsbeexplainedbyasinglehistoricalmodel,orarethereinconsistenciesacrossgenesintheirhistory?

SignalofPosi'veSelec'on:ExampleofFOXP2

•  muta'onsingenewithinhumansknowntoconferspecificaffectsonlanguageaquisi'on/grammarabili'es

•  firstgenepossiblyimplicatedindevelopmentofhumanlanguageability

•  twoaminoaciddifferencesfromchimpanzees,onepossiblyfunc'onal

Enard et al Nature 418, 869-872(22 August 2002)

Pa\ernsofDiversityatFOXP2

•  unusualexcessoflow-frequencypolymorphisms(only1in315referencegenesshowedsuchanextremeexcess)

•  modelingtheselec'vesweepconsistentwithselec'onhappeninginthelast200,000years

Enard et al Nature 418, 869-872(22 August 2002)

Evolu'onofSkinPigmenta'on:LocalAdapta'onAssociatedWithUVradia'on

Evolu'onofSkinPigmenta'on:LocalAdapta'onAssociatedWithUVradia'on

Annual Mean UVB Intensity

Jablonski and Chaplin PNAS May 11, 2010 vol. 107 no. Supplement 2 8962-8968

Tradeoffsassociatedwithlightanddarkpigmenta'on

Jablonski and Chaplin PNAS May 11, 2010 vol. 107 no. Supplement 2 8962-8968

TradeoffsassociatedwithSkinpigmenta'on

•  HighUVradia'on:interfereswithfolate,selectsforincreasedpigmenta'on

•  lowUVradia'on:reducesvitaminDsynthesis,selectsforreducedpigmenta'on

Posi'veSelec'ononSkinPigmenta'on

-SLC24A5 one of approx. 10 genes implicated in pigmentation -reduction in polymorphism in European population -includes one of only two fixed differences between European and East Asian population samples

Lamason et al Science 16 December 2005: Vol. 310 no. 5755 pp. 1782-1786

Scanning the Genome For Positive Selection/Adaptive Fixations

Rasmus Nielsen, UC Berkeley

-CLR statistic: compares probability that a region has its own SNP frequency distribution compared with the probability that it’s part of the genome-wide distribution

Williamson et al (PLoS Genet. 2007 Jun;3(6):e90. Epub 2007 Apr 20)

Evidence for Adaptive Evolution in Pigmentation Genes

Scanning the Genome For Positive Selection/Adaptive Fixations

-Williamson et al (PLoS Genet. 2007 Jun;3(6):e90. Epub 2007 Apr 20) Identified 101 regions showing strong signature of selection -genes under positive selection included pigmentation genes, immunity genes, olfactory receptors -as much as 10% of genome linked to regions subject to selective sweeps??

Whataboutincompletesweeps?

•  veryrecentposi'veselec'onandlocaladapta'onmayoPenNOTshowfixa'onevents

•  scansforallelesathighfrequencywithlowdiversity

EffectsofPosi'veSelec'ononNeutralPolymorphism

increase in linkage disequilibrium

SignalsofongoingPosi'veSelec'on

Advantageous allele at high frequency, found on only one genomic background

Mutations, Phenotype, and fitness: e.g. of G6PD

Mutations, Phenotype, and fitness: e.g. of G6PD

DNA B GTG AAT CTA TGTA A- ATG GAT CTG TGTG

protein (allozymes)

B A-

phenotype B ‘wild type’ A- reduced enzyme activity/resistance to malaria

+

-

Val Asn Leu Met Asp Leu

negative

neutral

RecentPosi'veSelec'onatG6PDlocus

LactasePersistence:Gene/CultureCoevolu'on

•  Lactasegenetypicallydown-regulatedinadults•  pastoralculturesshowlactosetoleranceintoadulthood

SignalsofPosi'veSelec'ononLactasePersistence

Bersaglieri et al, American Journal of Human Genetics Volume 74, Issue 6, June 2004, Pages 1111-1120

•  independentevolu'onoflactosetoleranceinAfricaandEurasia

ConvergentEvolu'onofLactasePersistence

Tishkoff et al Nature Genetics 39, 31 - 40 (2006)

SignatureofPosi'veSelec'ononLactasePersistenceinbothAfrica

andEurasia

-persistence allele shows very low diversity despite being common =high linkage disequilibrium -diversity patterns consistent with selective sweep in past 7000 years

Tishkoff et al Nature Genetics 39, 31 - 40 (2006)

Genome-WideScanforRecentPosi'veSelec'on

Jonathan Pritchard, University of Chicago

Genome-WideScansforPosi'veSelec'on

Voight et al PLoS Biol. 2006 March; 4(3): e72.

WhatGenesShowEvidenceforposi'veselec'on?

•  reproduc'on:Spermmo'lity,spermandeggviability,femaleimmuneresponsetosperm

•  skinpigmenta'on-fourgenesshowevidenceforrecentposi'veselec'oninEuropeanpopula'ons

•  diet:carbohydratemetabolism,processingoffa\yacids

YietalScience2July2010:Vol.329no.5987pp.75-78

Fig. 1 Two-dimensional unfolded site frequency spectrum for SNPs in Tibetan (x axis) and Han (y axis) population samples.

X Yi et al. Science 2010;329:75-78

Published by AAAS

Fig. 2 Population-specific allele frequency change.

X Yi et al. Science 2010;329:75-78

Published by AAAS

GenesSubjecttoAdapta'ontoHighEleva'on

-EPAS1: transcription factor involved in hypoxia response -associated with lower hemoglobin and lower erythrocyte counts at high elevation