The Combined Landscape of Denisovan and Neanderthal Ancestry in Present-Day Humans

29 Pages·2016·2.66 MB·English

by  Sriram Sankararaman

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The Combined Landscape of Denisovan and
Neanderthal Ancestry in Present-Day Humans
Highlights Authors
d Denisovanadmixtureintomodernhumansoccurredafter SriramSankararaman,
Neanderthaladmixture SwapanMallick,NickPatterson,
DavidReich
d ThereismoreDenisovanancestryinSouthAsiansthan
expectedfromcurrentmodels
Correspondence
[email protected](S.S.),
d Denisovanancestryhasbeensubjecttopositiveand
[email protected](D.R.)
negativeselectionafteradmixture
In Brief
d Maleinfertilitymostlikelyoccurredaftermodernhuman
interbreedingwithDenisovans Sankararamanetal.presentamapof
DenisovanandNeanderthalancestryin
120diversepopulationsandshowthat
Denisovanadmixturepost-dated
Neanderthaladmixture.SouthAsians
havemoreDenisovanancestrythan
expected.Therewasselectionbothfor
andagainstarchaicancestry.
HybridizationwithDenisovanswas
probablyassociatedwithreducedmale
fertility.
Sankararamanetal.,2016,CurrentBiology26,1–7
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Current Biology
Report
The Combined Landscape of Denisovan
and Neanderthal Ancestry in Present-Day Humans
SriramSankararaman,1,2,*SwapanMallick,3,4,5NickPatterson,4andDavidReich3,4,5,*
1DepartmentofComputerScience,UniversityofCalifornia,LosAngeles,LosAngeles,CA90095,USA
2DepartmentofHumanGenetics,UniversityofCalifornia,LosAngeles,LosAngeles,CA90095,USA
3DepartmentofGenetics,HarvardMedicalSchool,Boston,MA02115,USA
4BroadInstituteofMITandHarvard,Cambridge,MA02142,USA
5HowardHughesMedicalInstitute,HarvardMedicalSchool,Boston,MA02115,USA
*Correspondence:[email protected](S.S.),[email protected](D.R.)
http://dx.doi.org/10.1016/j.cub.2016.03.037
SUMMARY mentsandthusthedateofadmixture.ThedateofNeanderthal
admixturehasbeenestimated[3–5],buttherehasbeennostudy
Some present-day humans derive up to (cid:1)5% [1] thathasestimatedthedateofDenisovanadmixture.
of their ancestry from archaic Denisovans, an To estimate the date of Denisovan admixture, we exploited
evenlargerproportionthanthe(cid:1)2%fromNeander- the fact that sites at which Denisovans carry a derived allele
thals[2].Wedevelopedmethodsthatcandisambig- not seen in both the Altai Neanderthal and a large panel of
uate the locations of segments of Denisovan and sub-SaharanAfricansarehighlylikelytoderivefromDenisovan
introgression[6].Wesimilarlyidentifysiteslikelytoderivefrom
Neanderthal ancestry in present-day humans and
Neanderthalintrogression.Withineachclass,wefitanexponen-
applied them to 257 high-coverage genomes from
tialfunctiontothedecayoflinkagedisequilibriumwithgenetic
120diversepopulations,amongwhichwere20indi-
distance. The inverse of the decay constant translates to the
vidualOceanianswithhighDenisovanancestry[3].In
averagedateofgeneflowingenerations(SupplementalExperi-
Oceanians,theaveragesizeofDenisovanfragments
mental Procedures, ‘‘Estimating the date of archaic gene flow
is larger than Neanderthal fragments, implying a intoOceanianpopulations’’).InOceanians,therateofdecayat
more recent average date of Denisovan admixture sitesinformativeofDenisovanancestryisestimatedtobeslower
in the history of these populations (p = 0.00004). than the rate at sites informative of Neanderthal ancestry
We document more Denisovan ancestry in South (p=0.00004forthenullhypothesisofthetwodatesbeingequal,
Asia than is expected based on existing models basedonatwo-sidedtestusingblockjackknife)(Figure1).We
of history, reflecting a previously undocumented cautionthatthenominaldateestimateof1,000±8generations
agoforDenisovanadmixtureand1,121±16generationsagofor
mixturerelatedtoarchaichumans(p=0.0013).Deni-
Neanderthal admixture are likely to be biased. One source of
sovan ancestry, just like Neanderthal ancestry, has
biasarisesfromthefactthaterrorsinthegeneticmapcanpro-
beendeleterious onamodernhuman geneticback-
ducesystematicunderestimatesofdatesinferredbasedonlink-
ground, as reflected by its depletion near genes.
age disequilibrium; however, as both types of ancestry have
Finally, the reduction of both archaic ancestries is
beendecayinginthesamepopulation,thiswillbiastheinference
especially pronounced on chromosome X and near of Denisovan and Neanderthal admixture dates in exactly the
genes more highly expressed in testes than other sameway,andhencewillnotcontributetoanartifactualinfer-
tissues (p = 1.2 3 10(cid:3)7 to 3.2 3 10(cid:3)7 for Denisovan ence of one date being more recent than the other. A second
and2.2310(cid:3)3to2.9310(cid:3)3forNeanderthalancestry source of bias can arise due to extreme demographic events
even after controlling for differences in level of since admixture [4]. We carried out coalescent simulations to
selective constraint across gene classes). This sug- explorethispossibilityandfoundthataslowerlinkagedisequilib-
rium decay provides unambiguous evidence of more recent
gests that reduced male fertility may be a general
admixture,eventakingintoaccountbiasesarisingduetoplau-
feature of mixtures of human populations diverged
sibledifferencesinthedemographichistoryofDenisovansand
by>500,000years.
Neanderthals (Supplemental Experimental Procedures, ‘‘Simu-
lations’’;TableS1).Further,weverifiedthattheobservationof
RESULTSANDDISCUSSION a more recent date of Denisovan admixture is unchanged
when we fit a two-pulse model of admixture (we obtained
TheDateofDenisovanAdmixtureintotheAncestorsof nominal date estimates of 986 and 21,808 generations for
Oceanians Denisovan admixture and 1,197 and 90,262 generations for
Inordertodetectsegmentsofarchaicancestryinmodernhu- Neanderthaladmixture).Toobtainaroughestimateofthedate
mans, it is important to know the size scale of these ancestry ofDenisovanadmixture—cognizantofthefactthatforOcean-
segments,whichinturnreflectsthenumberofgenerationsdur- ians we do not have the information needed to fully correct
ingwhichrecombinationhasthechancetobreakuptheseseg- for uncertainty in the genetic map—we calibrated to previous
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Figure 1. More Recent Date of Denisovan
thanNeanderthalAdmixture
Averagelinkagedisequilibrium(Lewontin’sD)asa
functionofdistanceinOceaniansforSNPsinfor-
mativeofNeanderthal(red)andDenisovan(blue)
ancestry.TheDenisovadecayisslower,implying
amorerecentdate.SeealsoTableS1.
in South Asians, both in the Himalayan
region and in South and Central India
(Figure 2A). The highest estimate is in
Sherpas(0.10%),whohaveaDenisovan
point estimate about one-tenth of that
seen in Papuans (1.12%) (Table S3).
Although this is notable in light of the
likely Denisovan origin of the EPAS1
allele that confers high-altitude adapta-
tion in Tibetans [12, 13], EPAS1 is not
sufficient to explain the observation as
Sherpashavethehighestpointestimate
even without chromosome 2, on which
EPAS1 resides. To determine whether
thepeakofDenisovanancestryinSouth
Asia is significant, we tested whether
estimates of the date of Neanderthal admixture, under the the Denisovan ancestry proportion in diverse mainland Eur-
simplifyingassumptionthatthedateofNeanderthaladmixture asians can be explained by differential proportions of non-
in the history of New Guineans is the same as the 50,000– West Eurasian ancestry (as it is already known that there is
60,000 years ago estimated for a radiocarbon-dated Upper more Denisovan ancestry in East Eurasians than in West
Paleolithic Siberian [3]. Rescaling by1,000/1,121,weestimate Eurasians [6]). For each Eurasian population X, we computed
44,000–54,000yearsagoforDenisovanadmixture. an allele frequency correlation statistic that is proportional to
easternnon-Africanancestry(Figure2B;SupplementalExperi-
DenisovanandNeanderthalIntrogressionMaps mental Procedures, ‘‘Modeling the variation in Denisovan
TostudytheimpactoftheDenisovanandNeanderthaladmix- ancestry across populations’’). We regressed the proportion
ture events simultaneously, we developed methods that allow of confidently inferred Denisovan ancestry against this sta-
us to distinguish these two sources of archaic ancestry. We tistic. Although the proportion of Denisovan ancestry in these
appliedthesemethodstotheSimonsGenomeDiversityProject populations is correlated with non-West Eurasian ancestry
(SGDP) dataset: 257 high-quality genomes from 120 non- (r =0.832,blockjackknifep=3.6310(cid:3)10forthecorre-
Pearson
African populations, including 20 Oceanian individuals from lation coefficient being non-zero), South Asian groups as a
populations knownto have high Denisovan admixture (unpub- whole have significantly more Denisovan ancestry than ex-
lished data; Supplemental Experimental Procedures, ‘‘Data pected (block jackknife Z score for residuals = 3.2, p =
Processing’’). 0.0013 by a two-sided test for the null hypothesis that the
For each individual, we inferred archaic ancestry segments Denisovan ancestry estimate in South Asians is predicted by
across the autosomes (chromosomes 1–22) and chromosome their proportion of non-West Eurasian ancestry; Figure 2B;
X (our method did not allow us to test for archaic ancestry on Supplemental Experimental Procedures, ‘‘Modeling the varia-
chromosome Y because the archaic genomes are from fe- tioninDenisovanancestryacrosspopulations’’).Thesignalre-
males). Figure 2A plots the estimates of the proportion of mains significant (Z = 3.1) when we remove from the analysis
confidentlyinferredDenisovanancestryonamap,andTable1 fivepopulationsthathaveancestryverydifferentfromthema-
tabulates the results for six population pools (Table S2 tabu- jority of South Asians (Tibetan, Sherpa, Hazara, Kusunda, and
lates the results for each population). Denisovan ancestry in Onge); however, the signals are non-significant for Central
Oceanians is greater than in other non-Africans [1] (Table 1). Asians (Z = 1.2) and Native Americans (Z = 0.1). Taken
Both Neanderthal and Denisovan ancestry are greater in together, the evidence of Denisovan admixture in modern hu-
eastern non-Africans than in West Eurasians [6–10] (Supple- manscouldintheorybeexplainedbyasingleDenisovanintro-
mental Experimental Procedures, ‘‘Variation in the genome- gression into modern humans,followed by dilution to different
wideproportionsofarchaicancestry’’;TableS3).Wereplicate extentsinOceanians,SouthAsians,andEastAsiansbypeople
previous findings of substantial Denisovan ancestry in New withlessDenisovanancestry.Ifdilutiondoesnotexplainthese
GuineansandAustralians,aswellasinpopulationsthatharbor patterns,however,aminimumofthreedistinctDenisovanintro-
admixtures of New Guinean ancestry [11]. However, we were gressions into the ancestors of modern humans must have
surprised to detect a peak of Denisovan ancestry estimates occurred.
2 CurrentBiology26,1–7,May9,2016
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Figure2. VariationinDenisovanAncestryProportion
(A)ProportionofthegenomeinferredtobeDenisovaninancestryindiversenon-Africans.ThecolorscaleisnotlineartoallowsaturationofthehighDenisova
proportionsinOceania(brightred)andbettervisualizationofthepeakofDenisovaproportioninSouthAsia.
(B)ProportionofthegenomeconfidentlyinferredtobeDenisovaninancestryinmainlandEurasiansplottedagainsttherateofallelesharingofeachsamplewith
non-WestEurasiansasmeasuredbyanf4statistic.Errorbars(1SE)wereobtainedfromablockjackknife.TheDenisovanancestryestimatesinSouthAsiansare
systematicallyaboveexpectation(fittedtrendline)(p=0.0013).
SeealsoTableS3.
TilingPathofDenisovanandNeanderthalAncestry correlations at large spatial scales among the Neanderthal
InferredfromModernGenomes maps and weaker correlations between the Neanderthal and
TheunionofdetectedDenisovanhaplotypesspans257Mbin Denisovanmaps(Figure3B).
Oceanians(SupplementalExperimentalProcedures,‘‘Coverage
of archaic haplotypes’’). The union of Neanderthal haplotypes RegionswithElevatedProportionsofArchaicAncestry
spans 673 Mb over all non-Africans, which is smaller than the We scanned all maps for windows with elevated proportions
1.1 Gb found in 1000 Genomes Project phase 1 data [14], of archaic ancestry (average marginal probability R 0.30
mostlikelyduetothefactthatthetotalnumberofnon-Africans over a 100 kb window based on a published threshold [4];
genomes analyzed here is smaller. The positions of archaic Supplemental Experimental Procedures, ‘‘Genomic regions
ancestry are correlated across populations, with the strongest with elevated archaic ancestry’’; Table S4). We identified 238
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Table1. Genome-wideEstimatesofArchaicAncestry
NeanderthalAncestry(%) DenisovanAncestry(%)
Population Individuals Autosomes X Autosomes X
America 29 1.37±0.11 0.26±0.18 0.05±0.01 0.00±0.00
CentralAsia 27 1.40±0.12 0.23±0.18 0.05±0.01 0.00±0.00
EastAsia 50 1.39±0.11 0.32±0.28 0.06±0.02 0.00±0.01
Oceania 26 1.54±0.12 0.42±0.36 0.85±0.43 0.18±0.17
SouthAsia 48 1.19±0.11 0.40±0.26 0.06±0.03 0.01±0.03
WestEurasia 77 1.06±0.12 0.18±0.19 0.02±0.01 0.00±0.00
WeestimatedtheprobabilityofNeanderthalandDenisovanancestryforeachphasedgenomeineachpopulation.WereportthemeanandSDofthe
proportionofconfidentlyinferredarchaicalleles(marginalprobability>50%)acrossdiploidindividualswithineachpopulation.Thehighestpoint
estimateofNeanderthalancestryisinOceania,andalthoughthisestimateissignificantlyhigherthanthatinWestEurasia(Z=3.9),consistentwith
previousreports[7,8],itisnothigherthanthatinEastAsia(Z=0.7).SeealsoTableS2.
windowswithelevatedNeanderthalancestryinapoolofallnon- ancestry with B-statistics’’; Table S6), as does Denisovan
Africansand48withelevatedDenisovanancestryinOceanians. ancestryinOceanians(r =0.26,TableS6),mostlikelyre-
Spearman
Regions with elevated archaic ancestry may represent loci flectinggreaterselectionagainstNeanderthalancestryinlowB
where archaic alleles have experienced positive selection, but statistic regions [14–17]. Power to detect archaic ancestry is
aformaltestischallengingduetothefactthatarchaicalleles, elevatedclosetoregionsoflinkedselectionduetoareduction
onaverage,donotevolveneutrally[14–17].Wealsotestedfor in the rates of incomplete lineage sorting caused bythe lower
setsofgenesthathaveamongthe5%highestarchaicancestry effectivepopulationsizeintheseregions[14],sotheseresults
(hypergeometric test implemented in FUNC [18]; we report are not artifacts of reduced power. Thus, similar processes
p<0.05aftermultipletestingcorrection;SupplementalExperi- appeartohaveworkedtoremoveNeanderthalandDenisovan
mental Procedures, section S4). Genes involved in keratin ancestryneargenes.
filamentformationrelatedtoskinandhairareenrichedforNean-
derthal ancestry, generalizing the results of previous analyses Archaic-ModernAdmixtureWasMostLikelyAssociated
thatwerelimitedtoEuropeansandEastAsians[14,15].Genes withReducedMaleFertility
involvedinphospholipidtransporteractivityrelatedtofatmeta- Ourstudyprovidesnewevidenceinsupportofthehypothesis
bolismandintrace-aminereceptoractivityrelatedtodetecting thatreducedmalefertilitymaybeacommonfeatureofadmix-
subtlescentsaresignificantlyenrichedforDenisovanancestry ture between human populations diverged by at least a half
(TableS5). millionyears,ahypothesisthatwaspreviouslysuggestedbased
on genetic patterns associated with the hybridization between
DesertsofArchaicAncestry Neanderthalsandmodernhumans[14,21].Weshowthatqual-
Someofthemoststrikingfeaturesoftheintrogressionmapsare itativelysimilarsignalsareassociatedwithDenisovanadmixture.
the archaic ancestry deserts: windows longer than 10 Mb at Onelineofevidenceforreducedfertilityinmalehybridsisthat
which the archaic ancestry proportion is <1/1000 (Figure 3A; theproportionofarchaicancestryinmodernhumansissignifi-
Supplemental Experimental Procedures, ‘‘Analysis of genomic cantlyreducedonchromosomeXcomparedtotheautosomes.
regionsdeficient inarchaic ancestry’’). Weidentified 18Nean- Thisissuggestiveofreducedmalefertilityaslocicontributingto
derthalancestrydesertsinapoolofallnon-Africanindividuals thisphenotypeareconcentratedonchromosomeXinhybridsof
and 63 Denisovan deserts in Oceanians. Four windows (1:99– otherspecies[22].WeconfirmanextremereductionofNeander-
112 Mb, 3:78–90 Mb, 7:108–128 Mb, and 13:49–61 Mb) are thal ancestry on chromosome X (16%–34% of the autosomes
both Neanderthal andDenisovan ancestry deserts.The desert dependingonthepopulation)[14]andfindaquantitativelysimilar
onchromosome7containstheFOXP2gene,whichhasbeenhy- reductionofDenisovanancestry(21%oftheautosomesinOce-
pothesizedtohavearoleinenablingmodernhumanspeechand anians)(Table1).
language [19] and has been identified as a desert in previous The second line of evidence in support of the hypothesis of
mapsinEuropeansandEastAsians.Ourfindingthatthisregion reducedfertilityinhybridsisthatthereisareductionofarchaic
isalsoadesertofDenisovanancestrystrengthenstheevidence ancestry in genes that are disproportionately expressed in
thatthemodernhumanversionofthisgenemaybecriticalfor testes, a known characteristic of male hybrid fertility [22]. To
modernhumanbiology[14,15]. testforthissignalinourdata,weanalyzedasetofgeneshaving
a significantly higher expression level in testes than any of 15
ArchaicAncestryIsReducedintheGenomicRegions otherstissuesinanRNAsequencingdataset[23].Wedetecta
MostConstrainedbySelection statisticallysignificantdepletionofDenisovan(p=1.21310(cid:3)7
Wetestedtherelationshipbetweenarchaicancestryandregions in Oceanians) and Neanderthal (p = 2.1 3 10(cid:3)3 in Oceanians)
of strong linked selection as measured by a B statistic [20]. ancestryinthesegenesrelativetothegenesintheothertissues
Neanderthal ancestry decreases in proximity to functional ele- (Table S7; Supplemental Experimental Procedures, ‘‘Associa-
mentsinallpopulations(r =0.25–0.29;Figure3C;Sup- tion of Denisovan ancestry with tissue-specific expression’’).
Spearman
plemental Experimental Procedures, ‘‘Correlation of archaic Weconsideredthepossibilitythattheseobservationscouldbe
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Figure3. Fine-ScaleMapsofDenisovanandNeanderthalIntrogression
(A)Non-overlapping100kbwindowsthathavenon-zeroinferredarchaicancestryineachofsixpopulations(blue,Denisova;red,Neanderthal).Intheinnermost
rings,weplotdeserts(windows>10Mb).SeealsoTablesS4andS5.
(B)Correlationofconfidentlyinferredarchaicancestry(Neanderthalancestryinsixnon-AfricanpopulationsandDenisovanancestryinOceanians)across
populationsinnon-overlappingwindowsofsize100kb,1Mb,and10Mb.
(C)WeplotthemedianoftheproportionofDenisovanandNeanderthalancestrywithinquintilesofaBstatisticmeasuringintensityoflinkedselection(lowB
indicatestheregionsmostaffectedbylinkedselection).SeealsoTablesS6andS7.
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explained by stronger linked selection at testes-expressed AssessingtheAccuracyofArchaicSegmentInference
genes than at random places in the genome. However, when DiscriminatingbetweenNeanderthalandDenisovanancestralcomponentsin
we correlate this pattern to B statistics (which are sensitive to populationsthathaveboth,suchasOceanians,ischallengingbecauseNean-
derthalsandDenisovansaremoresimilartoeachotheronaveragethaneither
linkedselection[20]),wefindthatthegenesetsthataredispro-
istomodernhumans[1,6].Toassesstheaccuracyofourinferences(Supple-
portionally expressed in liver, heart, and skeletal muscle have
mental Experimental Procedures, ‘‘Empirical estimate of the accuracy of
evenloweraverageBstatisticsthanthegenesmostexpressed archaicancestryestimates’’;FigureS1),wedevisedastatisticalprocedure
in testes, and yet they do not show a depletion in archaic thatusespreviousgenome-wideestimatesofarchaicancestrytoestimate
ancestry(TableS7).Wealsoconsideredthepossibilitythatthe theprobabilitythattheCRFinfersDenisovan(orNeanderthal)ancestrywhen
B statistic might not fully capture the degree of selective thetrueancestryisNeanderthal,Denisovan,ormodernhuman.Forexample,
theinferredproportionofNeanderthalancestryinAfricanhunter-gatherers
constraintatthegenesdisproportionatelyexpressedintestes.
whomostlikelyhavenegligible amountsallowsustoestimate therateof
However, when we use logistic regression to control for mea-
misclassificationofmodernhumanancestryasNeanderthal.Similarly,thein-
suresofselectiveconstraint,wefindthatthesignificantreduc- ferredproportionofDenisovanancestryinWestEurasianswhohavenegligible
tion is observed not only when we control for B statistic at amountsallowsustoestimatetherateofmisclassificationofnon-Denisovan
eachgene(p=4.4310(cid:3)7forDenisovans;p=2.8310(cid:3)3for ancestryasDenisovan.Thisprocedureenablesustoestimatethefalsediscov-
Neanderthals).Itisalsoobservedwhenwecontrolforadirect eryrate(FDR)foranancestry(theprobabilitythatsegmentsassignedtoagiven
ancestryaremisclassified;SupplementalExperimentalProcedures,‘‘Empir-
estimateofthedegreeofselectiveconstraint:thegeneticdiver-
icalestimateoftheaccuracyofarchaicancestryestimates’’;FigureS1).In
sityobservedempiricallyateachgeneinsub-SaharanAfricans
Oceanians,atathresholdof0.50ontheCRFprobabilities,theFDRis3%for
(p=3.2310(cid:3)7forDenisovans;p=2.9310(cid:3)3forNeanderthals;
Denisovanancestryand15%forNeanderthalancestry.Ourprocedurealsoen-
Supplemental Experimental Procedures, ‘‘Association of Deni- ablesustoestimatethefractionoftruearchaicancestrythatwedetect.We
sovanancestrywithtissue-specificexpression’’). detect24%oftrueDenisovanand72%oftrueNeanderthalsegments.The
relativelylowpowertodetecttrueDenisovansegmentsislikelytoreflectthe
factthattheSiberianDenisovangenomethatweusefordetectingtheseseg-
Conclusions
mentsisknowntobedeeplydivergentfromtheDenisovanpopulationthat
Ithasbeensuggestedthattheempiricallyobservedreductionin introgressedintotheancestorsofOceanians(muchmoredivergentthanthe
NeanderthalancestryinEuropeansandEastAsiansnearfunc- AltaiNeanderthalgenomeisfromtheintrogressingNeanderthalpopulation)[6].
tionallyimportantregionscouldbeexplainedbyagreaterload
ofweaklydeleteriousallelesinNeanderthalsduetothesmaller ACCESSIONNUMBERS
population size of Neanderthals since separation, followed by
Therawdataanalyzedfor277ofthesamplesanalyzedhereareavailable
purgingofdeleteriousNeanderthalallelesinthemixedpopula-
through the EBI European Nucleotide Archive under accession numbers
tion[16,17].Sincewehaveshownthatsimilarpatternsareasso-
EBI-ENA:PRJEB9586andERP010710.Aversionofthegenotypedatawe
ciatedwiththeDenisovanintrogressionevent,itseemsplausible analyzed that is small enough to download by FTP is available at http://
that similar evolutionary forces operated to remove Denisovan reich.hms.harvard.edu/pub/datasets/sgdp/. The remaining 23 samples are
ancestry segments. However, the model of a greater load of onlyavailabletoresearcherswhoprovideasignedletteraffirmingthatthey
deleterious mutations in archaic humans cannot explain the willabidebyspecificrestrictionsforusingthesamples,andtheycanbeac-
cessedbywritingtoD.R.
observedreductionofbothNeanderthalandDenisovanancestry
neargenesthataredisproportionatelyexpressedintestes,sug-
SUPPLEMENTALINFORMATION
gestingthatmalehybridsterilitymayhavebeenassociatedwith
bothintrogressions.Animportantdirectionforfutureresearchis
SupplementalInformationincludesSupplementalExperimentalProcedures,
tounderstandtherelativeimportanceofpurgingofslightlydele- one figure, and seven tables and can be found with this article online at
terious alleles, as well as reduced fertility in hybrid males, in http://dx.doi.org/10.1016/j.cub.2016.03.037.
changingthecontentofgenomesintheaftermathoftheinter-
AUTHORCONTRIBUTIONS
breedingthatoccurredbetweenmodernandarchaichumans.
S.S.andS.M.performedanalyses.N.P.andD.R.supervisedthestudy.S.S.
EXPERIMENTALPROCEDURES andD.R.wrotethemanuscript.
InferringSegmentsofArchaicAncestry ACKNOWLEDGMENTS
Todeterminethepositionsofarchaicancestrysegments,weappliedamachine-
learningalgorithmknownasaconditionalrandomfield(CRF)[24].Theinputdata D.R.wassupportedbyNIHgrantGM100233andbyNSFgrantHOBCS-
consistsofthespatialdistributionacrossthegenomeofderivedallelesatsites 1032255and isaHoward Hughes Medical Institute investigator. S.S. was
informativeaboutarchaicancestry(includingtheNeanderthal-andDenisova- supportedinpartbyNIHgrant5K99GM111744-02and4R00GM111744-03.
informativesites).TheCRFsearchesforrunsofsuchallelesoverthesizescale
expectedforarchaicintrogression.Themethodweuseischangedinimportant Received:February26,2016
wayscomparedtotheCRFpreviouslyimplementedtosolvethesimplerprob- Revised:March10,2016
lemofdetectingNeanderthalancestry(SupplementalExperimentalProcedures, Accepted:March17,2016
‘‘AnimprovedprocedurefordeconvolvingNeanderthalandDenisovanances- Published:March28,2016
tries’’)[14].NotonlydoweusedifferentclassesofSNPs,butwealsodonot
exploitthehaplotype-basedinformationusedbythepreviouslyreportedCRF, REFERENCES
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CurrentBiology26,1–7,May9,2016 7
Current Biology, Volume 26
Supplemental Information
The Combined Landscape of Denisovan
and Neanderthal Ancestry in Present-Day Humans
Sriram Sankararaman, Swapan Mallick, Nick Patterson, and David Reich
0 0
1. l lll lll lll l lllllllllllllllllllll 1.
0.8 0.8 lllllllllllllll
l
l
6 6
Precision 40. Precision 40.
0. 0.
2 2
0. 0.
West Eurasia Neandertal
East Asia Denisova
0 0
0. 0.
0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0
Recall Recall
(a) (b)
Figure S1: Empirical precision-recall curves for archaic local ancestry inference (related to
main text Experimental Procedures). (a) Empirical precision-recall curve of the modified method
for inferring Neanderthal local ancestry in West Eurasian and East Asian populations. (b) Empirical
precision-recall curve of the modified method for inferring Neanderthal and Denisovan local ancestry in
Oceanian (Australians, Papuans and Bougainville Islanders) populations. The method is a modification
ofthepreviouslyproposedCRF[S1]toimprovetheabilitytodeconvolvethecontributionsofNeanderthal
and Denisovan ancestries (described in Section ).