Anatomically modern humans overlapped and mated with Neandertals such that non-African humans inherit ∼1 to 3% of their genomes from Neandertal ancestors. We identified Neandertal lineages that ...persist in the DNA of modern humans, in whole-genome sequences from 379 European and 286 East Asian individuals, recovering more than 15 gigabases of introgressed sequence that spans ∼20% of the Neandertal genome (false discovery rate = 5%). Analyses of surviving archaic lineages suggest that there were fitness costs to hybridization, admixture occurred both before and after divergence of non-African modern humans, and Neandertals were a source of adaptive variation for loci involved in skin phenotypes. Our results provide a new avenue for paleogenomics studies, allowing substantial amounts of population-level DNA sequence information to be obtained from extinct groups, even in the absence of fossilized remains.
Identifying targets of positive selection in humans has, until recently, been frustratingly slow, relying on the analysis of individual candidate genes. Genomics, however, has provided the necessary ...resources to systematically interrogate the entire genome for signatures of natural selection. To date, 21 genome-wide scans for recent or ongoing positive selection have been performed in humans. A key challenge is to begin synthesizing these newly constructed maps of positive selection into a coherent narrative of human evolutionary history and derive a deeper mechanistic understanding of how natural populations evolve. Here, I chronicle the recent history of the burgeoning field of human population genomics, critically assess genome-wide scans for positive selection in humans, identify important gaps in knowledge, and discuss both short- and long-term strategies for traversing the path from the low-resolution, incomplete, and error-prone maps of selection today to the ultimate goal of a detailed molecular, mechanistic, phenotypic, and population genetics characterization of adaptive alleles.
Germline mutations are the principal cause of heritable disease and the ultimate source of evolutionary change. Similarly, somatic mutations are the primary cause of cancer and may contribute to the ...burden of human disease more broadly than previously appreciated. Here, we review recent insights into the rates, spectrum, and determinants of genomic mutations and how these parameters inform our understanding of both Mendelian and complex human diseases. We also consider models for conceptualizing mutational consequences and outline several key areas for future research, including the development of new technologies to access and quantify the full spectrum of mutations, as well as to better interpret the consequences of mutations with respect to molecular functionality, evolutionary fitness, and disease pathogenicity.
Advances in the sequencing and the analysis of the genomes of both modern and ancient peoples have facilitated a number of breakthroughs in our understanding of human evolutionary history. These ...include the discovery of interbreeding between anatomically modern humans and extinct hominins; the development of an increasingly detailed description of the complex dispersal of modern humans out of Africa and their population expansion worldwide; and the characterization of many of the genetic adaptions of humans to local environmental conditions. Our interpretation of the evolutionary history and adaptation of humans is being transformed by analyses of these new genomic data.
Anatomically modern humans interbred with Neanderthals and with a related archaic population known as Denisovans. Genomes of several Neanderthals and one Denisovan have been sequenced, and these ...reference genomes have been used to detect introgressed genetic material in present-day human genomes. Segments of introgression also can be detected without use of reference genomes, and doing so can be advantageous for finding introgressed segments that are less closely related to the sequenced archaic genomes. We apply a new reference-free method for detecting archaic introgression to 5,639 whole-genome sequences from Eurasia and Oceania. We find Denisovan ancestry in populations from East and South Asia and Papuans. Denisovan ancestry comprises two components with differing similarity to the sequenced Altai Denisovan individual. This indicates that at least two distinct instances of Denisovan admixture into modern humans occurred, involving Denisovan populations that had different levels of relatedness to the sequenced Altai Denisovan.
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•Asian genomes carry introgressed DNA from Denisovans and Neanderthals•East Asians show evidence of introgression from two distinct Denisovan populations•South Asians and Oceanians carry introgression from one Denisovan population
Two waves of Denisovan ancestry have shaped present-day humans.
Recent analyses have found that a substantial amount of the Neandertal genome persists in the genomes of contemporary non-African individuals. East Asians have, on average, higher levels of ...Neandertal ancestry than do Europeans, which might be due to differences in the efficiency of purifying selection, an additional pulse of introgression into East Asians, or other unexplored scenarios. To better define the scope of plausible models of archaic admixture between Neandertals and anatomically modern humans, we analyzed patterns of introgressed sequence in whole-genome data of 379 Europeans and 286 East Asians. We found that inferences of demographic history restricted to neutrally evolving genomic regions allowed a simple one-pulse model to be robustly rejected, suggesting that differences in selection cannot explain the differences in Neandertal ancestry. We show that two additional demographic models, involving either a second pulse of Neandertal gene flow into the ancestors of East Asians or a dilution of Neandertal lineages in Europeans by admixture with an unknown ancestral population, are consistent with the data. Thus, the history of admixture between modern humans and Neandertals is most likely more complex than previously thought.
To reconstruct modern human evolutionary history and identify loci that have shaped hunter-gatherer adaptation, we sequenced the whole genomes of five individuals in each of three different ...hunter-gatherer populations at >60× coverage: Pygmies from Cameroon and Khoesan-speaking Hadza and Sandawe from Tanzania. We identify 13.4 million variants, substantially increasing the set of known human variation. We found evidence of archaic introgression in all three populations, and the distribution of time to most recent common ancestors from these regions is similar to that observed for introgressed regions in Europeans. Additionally, we identify numerous loci that harbor signatures of local adaptation, including genes involved in immunity, metabolism, olfactory and taste perception, reproduction, and wound healing. Within the Pygmy population, we identify multiple highly differentiated loci that play a role in growth and anterior pituitary function and are associated with height.
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► 13.4 million variants identified in African hunter-gatherers, many of which are novel ► Evidence of archaic admixture found in the genomes of African hunter-gatherers ► Selection scans implicate loci involved in taste perception, metabolism, and immunity ► Genetic associations with height are found for Pygmy variants located on chromosome 3
Whole-genome sequencing of Africans from different hunter-gatherer groups uncovers millions of variants that had not been previously documented. The findings expand our understanding of human diversity and evolution and indicate which genes harbor signatures of positive selection in these hunter-gatherer populations.
Regulatory variation influencing gene expression is a key contributor to phenotypic diversity, both within and between species. Unfortunately, RNA degrades too rapidly to be recovered from fossil ...remains, limiting functional genomic insights about our extinct hominin relatives. Many Neanderthal sequences survive in modern humans due to ancient hybridization, providing an opportunity to assess their contributions to transcriptional variation and to test hypotheses about regulatory evolution. We developed a flexible Bayesian statistical approach to quantify allele-specific expression (ASE) in complex RNA-seq datasets. We identified widespread expression differences between Neanderthal and modern human alleles, indicating pervasive cis-regulatory impacts of introgression. Brain regions and testes exhibited significant downregulation of Neanderthal alleles relative to other tissues, consistent with natural selection influencing the tissue-specific regulatory landscape. Our study demonstrates that Neanderthal-inherited sequences are not silent remnants of ancient interbreeding but have measurable impacts on gene expression that contribute to variation in modern human phenotypes.
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•We devised a flexible method to quantify allele-specific expression across samples•One-quarter of Neanderthal-introgressed haplotypes show cis-regulatory effects•Introgressed regulatory variants add to genomic complexity and phenotypic diversity•Neanderthal alleles are downregulated in genes expressed in the brain and testes
Genome-wide interrogation of the functional differences between modern human and Neanderthal alleles reveals that Neanderthal-inherited sequences are not silent remnants of ancient interbreeding but have a measurable impact on gene expression that may contribute to phenotypic variation in modern humans.
Although Neandertal sequences that persist in the genomes of modern humans have been identified in Eurasians, comparable studies in people whose ancestors hybridized with both Neandertals and ...Denisovans are lacking. We developed an approach to identify DNA inherited from multiple archaic hominin ancestors and applied it to whole-genome sequences from 1523 geographically diverse individuals, including 35 previously unknown Island Melanesian genomes. In aggregate, we recovered 1.34 gigabases and 303 megabases of the Neandertal and Denisovan genome, respectively. We use these maps of archaic sequences to show that Neandertal admixture occurred multiple times in different non-African populations, characterize genomic regions that are significantly depleted of archaic sequences, and identify signatures of adaptive introgression.
Admixture has played a prominent role in shaping patterns of human genomic variation, including gene flow with now-extinct hominins like Neanderthals and Denisovans. Here, we describe a novel ...probabilistic method called IBDmix to identify introgressed hominin sequences, which, unlike existing approaches, does not use a modern reference population. We applied IBDmix to 2,504 individuals from geographically diverse populations to identify and analyze Neanderthal sequences segregating in modern humans. Strikingly, we find that African individuals carry a stronger signal of Neanderthal ancestry than previously thought. We show that this can be explained by genuine Neanderthal ancestry due to migrations back to Africa, predominately from ancestral Europeans, and gene flow into Neanderthals from an early dispersing group of humans out of Africa. Our results refine our understanding of Neanderthal ancestry in African and non-African populations and demonstrate that remnants of Neanderthal genomes survive in every modern human population studied to date.
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•IBDmix detects archaic ancestry without using a modern human reference population•African individuals have a stronger Neanderthal ancestry signal than previously thought•Evidence of back-to-Africa migrations contributing to Neanderthal ancestry in Africans•Variation in non-African Neanderthal ancestry has been overestimated
Detecting archaic introgression in modern humans without using an unadmixed reference panel reveals higher Neanderthal ancestry in African individuals than previously seen and suggests that back-to-Africa migrations contributed to this signal.
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