The Genetic Cost of Neanderthal Introgression

Harris, Kelley; Nielsen, Rasmus

doi:10.1534/genetics.116.186890

Cited by 376 publications

(460 citation statements)

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“…This suggests that small population size over a long period of time can indeed lead to increased load even if all alleles have an additive effect. Our results are concordant with recent results from Harris and Nielsen (2016) who found a large significant decrease in additive fitness among Neanderthals relative to humans due to a severe population size reduction in Neanderthals. Further, our results are also concordant with those of Marsden et al (2016) who, using simulations, showed that bottlenecks associated with dog domestication could result in a 2-3% increase in additive genetic load in dogs compared to wolves.…”

Section: Simulation Of Genetic Loadsupporting

confidence: 93%

The Effect of an Extreme and Prolonged Population Bottleneck on Patterns of Deleterious Variation: Insights from the Greenlandic Inuit

et al. 2017

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The genetic consequences of population bottlenecks on patterns of deleterious genetic variation in human populations are of tremendous interest. Based on exome sequencing of 18 Greenlandic Inuit we show that the Inuit have undergone a severe 20,000-year-long bottleneck. This has led to a markedly more extreme distribution of allele frequencies than seen for any other human population tested to date, making the Inuit the perfect population for investigating the effect of a bottleneck on patterns of deleterious variation. When comparing proxies for genetic load that assume an additive effect of deleterious alleles, the Inuit show, at most, a slight increase in load compared to European, East Asian, and African populations. Specifically, we observe ,4% increase in the number of derived deleterious alleles in the Inuit. In contrast, proxies for genetic load under a recessive model suggest that the Inuit have a significantly higher load (20% increase or more) compared to other less bottlenecked human populations. Forward simulations under realistic models of demography support our empirical findings, showing up to a 6% increase in the genetic load for the Inuit population across all models of dominance. Further, the Inuit population carries fewer deleterious variants than other human populations, but those that are present tend to be at higher frequency than in other populations. Overall, our results show how recent demographic history has affected patterns of deleterious variants in human populations.

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Section: Simulation Of Genetic Loadsupporting

confidence: 93%

The Effect of an Extreme and Prolonged Population Bottleneck on Patterns of Deleterious Variation: Insights from the Greenlandic Inuit

et al. 2017

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“…For example, Prüfer et al (14) estimate that the Neanderthal population was very small-declining toward extinction. This view receives additional support from research showing elevated frequencies of nonsynonymous (and presumably deleterious) mutations among Neanderthals (22)(23)(24). This abundance of deleterious alleles implies that drift was strong and thus that population size was small.…”

Section: Discussionmentioning

confidence: 91%

Early history of Neanderthals and Denisovans

Rogers

Bohlender

Huff

2017

Proc. Natl. Acad. Sci. U.S.A.

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Extensive DNA sequence data have made it possible to reconstruct human evolutionary history in unprecedented detail. We introduce a method to study the past several hundred thousand years. Our results show that (i) the Neanderthal-Denisovan lineage declined to a small size just after separating from the modern lineage, (ii) Neanderthals and Denisovans separated soon thereafter, and (iii) the subsequent Neanderthal population was large and deeply subdivided. They also (iv) support previous estimates of gene flow from Neanderthals into modern Eurasians. These results suggest an archaic human diaspora early in the Middle Pleistocene.human evolution | archaic admixture | introgression | Neanderthals | Denisovans A round 600 kya, Europe was invaded by large-brained hominins using Acheulean stone tools (1, 2). They were probably African immigrants, because similar fossils and tools occur earlier in Africa. They have been called archaic Homo sapiens, Homo heidelbergensis, and early Neanderthals, yet they remain mysterious. They may have been ancestors of Neanderthals and modern humans (3), or ancestors of Neanderthals only (4, 5), or an evolutionary dead end. According to this last hypothesis, they were replaced later in the Middle Pleistocene by a wave of African immigrants that separated Neanderthals from modern humans and introduced the Levallois stone tool tradition to Europe (6, 7). To address this controversy, we introduce a statistical method and use it to study genetic data of Africans, Eurasians, Neanderthals, and Denisovans.Our method extends an idea introduced by Reich et al. (8,9). Their "ABBA-BABA" statistics infer admixture from the frequency with which derived alleles are shared by pairs of samples. As we have shown (10), these estimators have large biases when populations receive gene flow from more than one source. The magnitudes of these biases depend on the sizes and separation times of ancestral populations. Our method avoids bias by estimating these parameters simultaneously.To accomplish this, our method uses an expanded dataset. ABBA-BABA statistics summarize allele sharing by pairs of samples. We extend this approach to include larger subsets, such as trios of samples, and to use all available subsets. This opens a rich and heretofore unused window into population history. Nucleotide Site PatternsAlthough our method can accommodate complex models, we work here with a four-population model of history (Fig. 1A), which has broad empirical support (11,12). In this model, Neanderthals (N ) contribute genes to Eurasians (Y ) but not to Africans (X ). The model allows no gene flow from Denisovans (D), for reasons explained below. Combinations of uppercase letters, such as ND, refer to the population ancestral to N and D. Lowercase letters, such as n and d , refer to individual haploid genomes sampled from these populations.The gene tree describes how genes coalesce within the tree of populations. Fig. 1B illustrates one of many possible gene trees. Although closely linked nucleotide sites tend to share...

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“…An exciting future prospect is that our interpretations of observations in nature will be aided by simulation studies (Harris and Nielsen 2016) and empirical studies of the consequences of introgression for phenotype and fitness (McCoy et al 2017). In this context, there are no accurate estimates of the timing of most of the signatures of selection now being detected in the human genome (lactase persistence as an exception; Field et al, 2016;Tishkoff et al, 2007), or good methods for estimating the ages and natures of the environments in which past selection occurred (Corbett et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…For example, the majority of models assume that introgressed blocks are selected independently of each other in the genetic background of the recipient population. However, Harris and Nielsen (2016) showed that much of the selection against introgression may occur in early generations, since early generation hybrids should have complex ancestries in which epistasis can lead to non-additive fitness effects. Another assumption pointed out in this study is that weakly deleterious mutations segregating in the donor population would be the main driver of selection against Neanderthal introgression in humans.…”

Section: Selection Against Introgressed Regions At the Level Of Genommentioning

confidence: 99%

“…Under such a model, the lower effective population size in Neanderthals would have led to the accumulation of weakly deleterious alleles that, once introgressed into humans, would reduce the relative fitness of the hybrid. However, in such context, even if both species bear recessive deleterious alleles but at differing sites, hybrids might have enhanced overdominant fitness variation regardless these deleterious recessives, which leads to the conclusion that Neanderthal introgression may have initially been favoured by selection in humans (Harris & Nielsen, 2016).…”

Section: Selection Against Introgressed Regions At the Level Of Genommentioning

confidence: 99%

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Evolutionary and Medical Consequences of Archaic Introgression into Modern Human Genomes

Dolgova

Lao

2018

Preprint

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The demographic history of anatomically modern humans (AMH) involves multiple migration events, population extinctions and genetic adaptations. As genome-wide data from complete genome sequencing becomes increasingly abundant and available even from extinct hominins, new insights of the evolutionary history of our species are discovered.It is currently known that AMH introgressed with archaic hominins once they left the African continent. Current out of African human genomes carry fragments of archaic origin. This review focuses on the fitness consequences of archaic interbreeding in current human populations. We discuss new insights and challenges that researchers face when interpreting the potential impact of introgression on fitness and testing hypotheses about the role of selection within the context of health and disease.Keywords: archaic introgression, fitness, natural selection, Neanderthal, Denisova, anatomically modern humans. Peer-reviewed version available at Genes 2018, 9, 358; doi:10.3390/genes9070358 2 Widespread interbreeding between homininsThe demographic history of anatomically modern humans (AMH) is complex, and involves a large number of migrations, genetic admixtures and introgressions, population extinctions and genetic adaptations, which overlap both in time and in space (see Figure 1). Due to this complexity, the evolutionary history of humankind is still far from being fully understood (Nielsen et al., 2017). During the last 30 years, the most accepted demographic scenario for explaining recent evolution of AMH has been the Out of Africa model (OOA). According to this model, AMH evolved in Africa around 100-200 thousands years ago (kya) in East Africa and migrated to the rest of the world. Classical "pure" OOA assumes that admixture with other archaic populations such as Neanderthals or Denisovans, present at the time of the rise of AMH, either did not occur or was negligible (Lalueza-Fox & Gilbert, 2011). Figure 1. Family tree of the four groups of early humans living in Eurasia 50,000 years ago and the inferred gene flow between the groups due to interbreeding (based on Prüfer et al., 2014;Mondal et al., 2016;Hsieh et al., 2016; Medina-Gomez et al., 2017). The direction and estimated magnitude of inferred gene flow events are shown. Branch lengths and timing of gene flows are not scaled. The dashed line indicates that it is uncertain whether Denisovan gene flow into modern humans in mainland Asia occurred directly or via Oceania. Light violet color indicates introgression events from unknown archaic populations (Ghost).However, genomic studies of ancient DNA have revealed that AMH interbred with other hominid lineages, such as Neanderthals and Denisovans, present in Eurasia up to ∼30,000-50,000 years ago Quach & Quintana-Murci, 2017;Vattathil & Akey, 2015 New studies based on current genetic diversity are suggesting that the events of archaic introgression in AMH did occur out of Africa with other hidden "ghost" archaic populations (Mondal et al., 2016). Furthermore, there i...

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The Genetic Cost of Neanderthal Introgression

Cited by 376 publications

References 77 publications

The Effect of an Extreme and Prolonged Population Bottleneck on Patterns of Deleterious Variation: Insights from the Greenlandic Inuit

The Effect of an Extreme and Prolonged Population Bottleneck on Patterns of Deleterious Variation: Insights from the Greenlandic Inuit

Early history of Neanderthals and Denisovans

Evolutionary and Medical Consequences of Archaic Introgression into Modern Human Genomes

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