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Archaic admixture in

1 1,2

Jeffrey D Wall and Debora Yoshihara Caldeira Brandt

Modern evolved in Southern or Eastern , and detailed understanding of how and Deniso-

spread from there across the rest of the world. As they van ancestry levels vary across . For example,

expanded across Africa and , they encountered other it has been shown that East Asians have more Neander-

hominin groups. The extent to which modern and ‘archaic’ thal ancestry than do Europeans [3,9]. One recent study

human groups interbred is an area of active research, and while found evidence that Oceanians (i.e., indigenous Austra-

we know that modern humans interbred with and lians and Melanesians) have the highest amount of Ne-



Denisovans, there is not yet agreement on how many admixture anderthal DNA among all non-African groups [10 ].

events there were or on how much Neanderthal or Interestingly, another study published almost simulta-

DNA can be found in contemporary . Here we review neously concluded that Melanesians have less Neander-



what is known about archaic admixture in , with a thal DNA than other non-African groups [11 ], while

focus on what has been discovered in the past 2 . another performed two separate analyses showing either

Addresses that Melanesians have less Neanderthal DNA than other

1

Institute for Human , University of California, San Francisco, non-African groups (S07 [12]), or that they have an

513 Parnassus Avenue, San Francisco, CA 94143, amount of Neanderthal DNA intermediate between Eur-

2

Department of Integrative , University of California, Berkeley,

opeans and East Asians (S10 [12]). There are a couple

Valley Building, Berkeley, CA 94720, United States

different potential explanations for these conflicting



results. Vernot et al. [11 ] analyzed samples from the

Corresponding author: Wall, Jeffrey D ([email protected])



Bismarck Archipelago, while Sankararaman et al. [10 ]

analyzed Papuans, indigenous Australians and Bougain-

Current Opinion in Genetics & Development 2016, 41:93–97

ville islanders, and Malaspinas et al. [12] analyzed

This review comes from a themed issue on Genetics of human origin Papuans and indigenous Australians. While historical

Edited by Joshua Akey and Anna Di Rienzo differences between various Oceanian populations could

in principle explain the different amounts of Neanderthal

ancestry found in them, this seems unlikely. Instead,

differences in the methodology for identifying archaic

http://dx.doi.org/10.1016/j.gde.2016.07.002 human admixture tracts seem to be a more plausible

0959-437/# 2016 Elsevier Ltd. All rights reserved. explanation. Two comparisons could help distinguish

between these competing claims. First, if all of the

genomes contained in the three studies were combined,

with identical filtering and variant calling pipelines, then

analyses could determine if variability among Oceanian

groups explains the published observations. In addition,

Introduction thorough simulation studies could answer whether any of

Two archaic human genomes have been sequenced to the inference methods used have particular biases in

high coverage so far: a Neanderthal [1,2] and a under or overestimating the amount Neanderthal ances-

Denisovan genome [3,4], and both of the groups these try in different human populations.

genomes represent contributed DNA to present-day

humans. Neanderthal ancestry is present in all non-Afri- As for Denisovan ancestry outside of Oceanians, small

can populations, comprising between 1.5 and 2.1% of amounts (e.g., <0.2%) have been detected in East Asians



their genomes [2]. Conversely, modern human DNA is [13], Native Americans [2,14] and South Asians [10 ].



also found in Neanderthals [5 ]. Denisovan ancestry Further sampling of genomes from around the world, as

though is mostly restricted to Oceanian populations, as additional analyses, will be needed to understand

which have between 4 and 6% Denisovan DNA [4]. what is causing this observation.

There have been several recent reviews on topics related

to archaic admixture [6–8]. Rather than repeat all of the Explaining patterns of Neanderthal admixture

same topics here, we will focus on some issues raised by Several different explanations have been proposed to

recent research without trying to be comprehensive. account for the varying amount of Neanderthal DNA

present in different non-African populations (Figure 1).

Neanderthal and Denisovan ancestry in Pru¨ fer et al. [2] suggested that the greater amount of

non-African populations Neanderthal DNA found in East Asian genomes relative

As genomic data on more human populations have be- to European genomes could be the result of a single pulse

come available, we have been able to obtain a more of Neanderthal admixture followed by differing levels of

www.sciencedirect.com Current Opinion in Genetics & Development 2016, 41:93–97

94 Genetics of human origin

Figure 1

Neanderthal admixture that postdates the split time of

European and East Asian populations (i.e., separate admix-

(a) ture events in the of European populations and

the ancestors of East Asian populations), (2) a single pulse

of admixture in all non-Africans followed by a separate

Neanderthal admixture event (i.e., the ‘multiple admixture

model) in the ancestors of East Asian populations, or (3) a

single pulse of admixture in all non-African populations,

followed by admixture with a with less Nean-

derthal ancestry (i.e., the ‘dilution’ model) in the ancestors

of modern day Europeans [9,17,18]. The first explanation is

unlikely, given that recent estimates of the time of admix-

ture are earlier than the generally accepted population split

times [12,19]. The third explanation is also somewhat

Denisovans Neanderthals

unlikely, in that no candidate diluting populations have

been proposed. While some European genomes are known Europeans

Africans Oceanians

Americans Asians

to contain a small (2–3%) amount of sub-Saharan African

ancestry [20], and sub-Saharan African genomes are known

to contain much less Neanderthal DNA, the effect of this

admixture is expected to be much less than what would be

needed to explain the lesser amount of Neanderthal an-

(b) cestry found in European populations [15]. Finally, similar

multiple admixture and dilution models have been pro-

posed to explain the differing amount of Neanderthal

 

ancestry found in Melanesians [10 ,11 ].

Archaic ancestry informs models of migration

out of Africa

Knowledge about archaic admixture in the genomes of

modern humans can shed light on past migratory routes. If

two populations shared a past migratory route where

admixture with other hominins occurred, they will prob-

ably share introgressed archaic DNA.

Neanderthals Denisovans

In the case of the first modern (s) out of Americans Oceanians Asians

Europeans

Africans Africa, two main routes have been hypothesized: a north-

ern route through Egypt and Sinai, and a southern route

from through the . When

similar amounts of Neanderthal DNA were found in all

Current Opinion in Genetics & Development non-African populations, it was suggested that inter-

breeding with Neanderthals occurred in a single popula-

Alternative hypothesis of archaic admixture events in modern human

tion ancestral to all present-day non-Africans [1]. This was

history. (a) Three admixture events with Neanderthals, and early split

seen as support for a single migration out-of-Africa [21].

of Oceanian populations from non-Africans. Under this model

On the other , evidence of modern human introgres-

Oceanian populations are expected to have less Neanderthal

introgressed DNA than other non-Africans. (b) Asians and Oceanians sion into East Asian Neanderthals 100 thousand years ago

as sister groups, and two admixture events with Neanderthals (the supports a second, more ancient dispersal out of Africa

most recent one either into Asians or the common of Asians 

[5 ]. This is in line with the conclusions of a study on

and Oceanians). represent admixture events with Neanderthals

modern human populations that found evidence for two

(red), Denisovans (blue) and between modern humans (gray). Note that

waves of migration out of Africa: the first one through the

in this figure Denisovan ancestry in East Asian populations is assumed

to have come from (more recent) with Oceanians. South, followed by a northern migration [22].

Similarly, there is a debate on whether the peopling of

Southeast Asia and was through one or multiple

purifying selection in the two populations. However, two waves. The study of Denisovan ancestry in Asia and

simulation-based studies concluded that this model can- Oceania is helping to clarify this debate. Varying amounts

not explain the observed patterns of Neanderthal admix- of Denisovan DNA were found in populations of South-

ture [15,16]. Other proposed explanations include (1) east Asia and Oceania, which has been interpreted as

Current Opinion in Genetics & Development 2016, 41:93–97 www.sciencedirect.com

Archaic admixture in human history Wall and Yoshihara Caldeira Brandt 95

evidence that humans occupied this part of the planet in seems to be quite rare (reviewed in [6]), with perhaps the

at least two waves of migration [12,21]. most striking example the EPAS1 in Tibetans,

which is involved in to living at high altitudes

Recent studies on the amount of Neanderthal ancestry in and was probably inherited from Denisovans [25].

Oceanian populations (discussed above) are also relevant



in this context. Vernot et al. [11 ], who found that Mel- Once Neanderthal and Denisovan ancestry tracts have

anesians have less Neanderthal ancestry than other non- been identified from whole-genome sequences, SNPs that

Africans, argued that this result indicated that Melanesian tag these tracts can be genotyped in a much larger collec-

populations diverged from Eurasians before the split tion of . This, combined with medical records, can

between European and East Asian populations. Malaspi- be used to obtain a more detailed understanding of the

nas et al. [12] came to a similar conclusion as well, phenotypic effects of archaic admixture. Simonti et al. [26]

consistent with at least two major migrations of modern presented the first such study, looking at patterns of

humans into . Neanderthal admixture across 28 000 of Eu-

ropean ancestry for which electronic health records were

Functional consequences of archaic available. They found that many SNPs implicated by

admixture GWAS were probably inherited from Neanderthals, in-

After admixture between modern and cluding a significant number associated with actinic kera-

occurred, influenced the amount and tosis, disorders and [26]. The

the pattern of admixture observed in contemporary gen- interpretation of these findings is not straightforward, as

omes. Purifying selection against deleterious archaic most of the identified SNPs are at low frequency and

alleles generally leads to a reduction in the amount of probably not strongly selected for or against. They may

surviving archaic DNA over time, except in the unusual represent weakly deleterious though, and con-



scenario where most mutations are recessive [23 ]. Indi- tribute to the increased genetic load in non-Africans



rect evidence for widespread purifying selection can be to have arisen from Neanderthal admixture [23 ].

found in the distribution of inferred Neanderthal and

Denisovan ancestry tracts across the genome — in partic- Admixture with other archaic human groups

ular, researchers found that highly conserved Our review has focused on admixture with Neanderthals

contain less archaic human DNA, and observed that many and Denisovans, in part because the availability of archaic

large (e.g., >5 Mb) regions of the genome have no appar- human genomes greatly facilitates the identification and

 

ent Neanderthal or Denisovan admixture [10 ,11 ,17,18]. quantification of admixture. However, as modern humans

These ‘archaic ancestry ’ are incompatible with expanded from subSaharan Africa to the rest of the world,

simple models of neutral introgression, and they probably they encountered other archaic human groups both inside

contain important functional elements. The X chromo- Africa and across Eurasia, so there were many potential

some in particular has extremely low levels of Neanderthal opportunities for admixture. For example, there are sev-

and Denisovan introgression, consistent with standard eral fossils with archaic features that date to <50 000 years

evolutionary models of closely related taxa with partial ago in Africa [27–29], and floresiensis occupied the

reproductive isolation. While negative epistatic interac- island of roughly contemporaneously with the

tions (e.g., Bateson–Dobzhansky–Muller Incompatibili- earliest evidence of modern humans in East Asia [30,31].



ties) may be present in these deserts [10 ,17], simple



additive models of selection cannot be ruled out [23 ]. Thus far, studies of admixture with archaic human groups

other than Neanderthals and Denisovans have relied on

More direct evidence for purifying selection can be found searching for unusual patterns of linkage disequilibrium

in the decrease in Neanderthal ancestry in ancient modern (LD) in sequence polymorphism data (cf. [32]). Studies of



human samples over time [24 ], from 4% roughly sub-Saharan African populations have consistently found

40 thousand years ago to the current 1.5-2%. Further evidence for some archaic admixture, though the amount

theoretical work will be needed to reconcile these results and the timing of this admixture has been difficult to

 

on the plausibility of purifying selection [23 ,24 ] with the quantify [32–36]. In practice, patterns of LD caused by

earlier studies claiming that differential levels of purifying ancient admixture are difficult to distinguish from pat-

selection could not explain the differing levels of Nean- terns of LD caused by more recent demographic events,

derthal ancestry in non-African populations [15,16]. such as population structure within modern humans.

Because of this, detecting archaic admixture without a

By contrast, adaptive introgression (i.e., when the archaic reference genome cannot be done accurately without also

allele is advantageous) is expected to lead to an increase in estimating a demographic model incorporating modern

frequency of the introgressed allele; these regions can be human population history [32,35].

identified by finding areas of the genome with extremely

high amounts of archaic ancestry, similar to admixture Going forwards, there are several areas of work that could

mapping techniques. Adaptive introgression in humans improve our ability to detect archaic admixture. The

www.sciencedirect.com Current Opinion in Genetics & Development 2016, 41:93–97

96 Genetics of human origin

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This study, along with Ref. [10 ], developed new methods for identifying

and potential archaic admixture, and specific genomic regions inherited from Neanderthals or Denisovans. The

authors concluded that Melanesians have less Neanderthal ancestry than

quantifies the strength of the evidence (e.g., in a Bayesian

do other non-African groups.

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