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\"The first book for general readers about the Denisovans\"-- Provided by publisher.

Denisovans, a sister group of Neandertals, have been described on the basis of a nuclear genome sequence from a finger phalanx (Denisova 3) found in Denisova Cave in the Altai Mountains. The only other Denisovan specimen described to date is a molar (Denisova 4) found at the same site. This tooth carries a mtDNA sequence similar to that ofDenisova 3. Here we present nuclear DNA sequences fromDenisova 4and a morphological description, as well as mitochondrial and nuclear DNA sequence data, from another molar (Denisova 8) found in Denisova Cave in 2010. This new molar is similar toDenisova 4in being very large and lacking traits typical of Neandertals and modern humans. Nuclear DNA sequences from the two molars form a clade withDenisova 3. The mtDNA ofDenisova 8is more diverged and has accumulated fewer substitutions than the mtDNAs of the other two specimens, suggesting Denisovans were present in the region over an extended period. The nuclear DNA sequence diversity among the three Denisovans is comparable to that among six Neandertals, but lower than that among present-day humans.

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.

Although initial studies suggested that Denisovan ancestry was found only in modern human populations from island Southeast Asia and Oceania, more recent studies have suggested that Denisovan ancestry may be more widespread. However, the geographic extent of Denisovan ancestry has not been determined, and moreover the relationship between the Denisovan ancestry in Oceania and that elsewhere has not been studied. Here we analyze genome-wide single nucleotide polymorphism data from 2,493 individuals from 221 worldwide populations, and show that there is a widespread signal of a very low level of Denisovan ancestry across Eastern Eurasian and Native American (EE/NA) populations. We also verify a higher level of Denisovan ancestry in Oceania than that in EE/NA; the Denisovan ancestry in Oceania is correlated with the amount of New Guinea ancestry, but not the amount of Australian ancestry, indicating that recent gene flow from New Guinea likely accounts for signals of Denisovan ancestry across Oceania. However, Denisovan ancestry in EE/NA populations is equally correlated with their New Guinea or their Australian ancestry, suggesting a common source for the Denisovan ancestry in EE/NA and Oceanian populations. Our results suggest that Denisovan ancestry in EE/NA is derived either from common ancestry with, or gene flow from, the common ancestor of New Guineans and Australians, indicating a more complex history involving East Eurasians and Oceanians than previously suspected.

A key question in biology is why genomic variation persists in a population for extended periods. Recent studies have identified examples of genomic deletions that have remained polymorphic in the human lineage for hundreds of millennia, ostensibly owing to balancing selection. Nevertheless, genome-wide investigation of ancient and possibly adaptive deletions remains an imperative exercise. Here, we demonstrate an excess of polymorphisms in present-day humans that predate the modern human-Neanderthal split (ancient polymorphisms), which cannot be explained solely by selectively neutral scenarios. We analyze the adaptive mechanisms that underlie this excess in deletion polymorphisms. Using a previously published measure of balancing selection, we show that this excess of ancient deletions is largely owing to balancing selection. Based on the absence of signatures of overdominance, we conclude that it is a rare mode of balancing selection among ancient deletions. Instead, more complex scenarios involving spatially and temporally variable selective pressures are likely more common mechanisms. Our results suggest that balancing selection resulted in ancient deletions harboring disproportionately more exonic variants with GWAS (genome-wide association studies) associations. We further found that ancient deletions are significantly enriched for traits related to metabolism and immunity. As a by-product of our analysis, we show that deletions are, on average, more deleterious than single nucleotide variants. We can now argue that not only is a vast majority of common variants shared among human populations, but a considerable portion of biologically relevant variants has been segregating among our ancestors for hundreds of thousands, if not millions, of years. The persistence of versions of genes that cause severe disease in human populations has long perplexed scientists. It is common for many versions of a gene to exist. But scientists expect that over time natural selection will eliminate versions of genes harmful to human health. Sometimes, there are good reasons that a disease-causing gene may persist. For example, having two copies of a particular gene variant causes a condition, called sickle cell disease. But having one sickle cell-causing copy of the gene and one non-disease-causing copy protects against malaria. As a result, the version of the gene that causes sickle cell is more common in people from areas where malaria is prevalent despite the risks to people who end up with two copies. Scientists call this phenomenon balancing selection because trade-offs in the gene’s benefits and risks cause it to persist in the population. Aqil et al. show that balancing selection has likely caused many ancient gene variants to persist in human populations. In the experiments, Aqil et al. scoured the genomes of hundreds of modern humans from around the world and four groups of ancient human ancestors, including Neanderthals and Denisovans. The experiments looked for structural changes in genes, like deletions, that date back to more than 700,000 years ago – before modern humans split from their ancestors. They found large numbers of such ancient genes in modern humans. Using computer modeling, Aqil et al. showed that these ancient genes likely persist because of balancing selection. Many of these ancient genes regulate the immune response and metabolism. These genes may protect against infectious diseases outbreaks and starvation, which have occurred periodically throughout human history. But these same genes may cause immune or metabolic diseases in modern humans not currently facing these threats. The experiments show how such biological trade-offs have shaped human evolution and reveal that modern human populations, regardless of race or region of origin, share the same genetic variation that already our ancestors carried within them.

Abstract It has been proposed that the phenotypic differences in cognitive abilities between humans and our closest living relatives, chimpanzees, are largely due to changes in the regulation of neurodevelopmental genes. We have previously found that the neurodevelopmental transcription factor gene NPAS3 accumulates the largest number of human accelerated regions (HARs), suggesting it may play some role in the phenotypic evolution of the human nervous system. In this work, we performed a comparative functional analysis of NPAS3-HAR202 using enhancer reporter assays in transgenic zebrafish and mice. We found that the Homo sapiens HAR202 ortholog failed to drive reporter expression to the zebrafish nervous system, in high contrast to the strong expression displayed by the rest of the vertebrate ortholog sequences tested. Remarkably, the HAR202 ortholog from archaic humans (Neanderthals/Denisovans) also displayed a pan-vertebrate expression pattern, despite the fact that archaic and modern humans have only one nucleotide substitution. Moreover, similar results were found when comparing enhancer activity in transgenic mice, where we observed a loss of activity of the modern human version in the mouse developing brain. To investigate the functional importance of HAR202, we generated mice lacking HAR202 and found a remarkable decrease of Npas3 expression in the forebrain during development. Our results place HAR202 as one of the very few examples of a neurodevelopmental transcriptional enhancer displaying functional evolution in the brain as a result of a fast molecular evolutionary process that specifically occurred in the human lineage.

The Neanderthal and Denisovan genomes enabled the discovery of sequences that differ between modern and archaic humans, the majority of which are noncoding. However, our understanding of the regulatory consequences of these differences remains limited, in part due to the decay of regulatory marks in ancient samples. Here, we used a massively parallel reporter assay in embryonic stem cells, neural progenitor cells, and bone osteoblasts to investigate the regulatory effects of the 14,042 single-nucleotide modern human-specific variants. Overall, 1791 (13%) of sequences containing these variants showed active regulatory activity, and 407 (23%) of these drove differential expression between human groups. Differentially active sequences were associated with divergent transcription factor binding motifs, and with genes enriched for vocal tract and brain anatomy and function. This work provides insight into the regulatory function of variants that emerged along the modern human lineage and the recent evolution of human gene expression.

Abstract The Tibetan Plateau is populated by diverse ethnic groups, but most of them are underrepresented in genomics studies compared with the Tibetans (TIB). Here, to gain further insight into the genetic diversity and evolutionary history of the people living in the Tibetan Plateau, we sequenced 54 whole genomes of the Deng people with high coverage (30–60×) and analyzed the data together with that of TIB and Sherpas, as well as 968 ancient Asian genomes and available archaic and modern human data. We identified 17.74 million novel single-nucleotide variants from the newly sequenced genomes, although the Deng people showed reduced genomic diversity and a relatively small effective population size. Compared with the other Tibetan highlander groups which are highly admixed, the Deng people are dominated by a sole ancestry that could be traced to some ancient northern East Asian populations. The divergence between Deng and Tibetan people (∼4,700–7,200 years) was more recent than that between highlanders and the Han Chinese (Deng-HAN, ∼9,000–14,000 years; TIB-HAN, 7,200–10,000 years). Adaptive genetic variants (AGVs) identified in the Deng are only partially shared with those previously reported in the TIB like HLA-DQB1, whereas others like KLHL12 were not reported in TIB. In contrast, the top candidate genes harboring AGVs as previously identified in TIB, like EPAS1 and EGLN1, do not show strong positive selection signals in Deng. Interestingly, Deng also showed a different archaic introgression scenario from that observed in the TIB. Our results suggest that convergent adaptation might be prevalent on the Tibetan Plateau.

The traditional concept of long and gradual, glacial–interglacial climate changes during the Quaternary has been challenged since the 1980s. High temporal resolution analysis of marine, terrestrial and ice geological archives has identified rapid, millennial- to centennial-scale, and large-amplitude climatic cycles throughout the last few million years. These changes were global but have had contrasting regional impacts on the terrestrial and marine ecosystems, with in some cases strong changes in the high latitudes of both hemispheres but muted changes elsewhere. Such a regionalization has produced environmental barriers and corridors that have probably triggered niche contractions/expansions of hominin populations living in Eurasia and Africa. This article reviews the long- and short-timescale ecosystem changes that have punctuated the last few million years, paying particular attention to the environments of the last 650,000 years, which have witnessed key events in the evolution of our lineage in Africa and Eurasia. This review highlights, for the first time, a contemporaneity between the split between Denisovan and Neanderthals, at ~650–400 ka, and the strong Eurasian ice-sheet expansion down to the Black Sea. This ice expansion could form an ice barrier between Europe and Asia that may have triggered the genetic drift between these two populations.

Abstract Structural variants have a considerable impact on human genomic diversity. However, their evolutionary history remains mostly unexplored. Here, we developed a new method to identify potentially adaptive structural variants based on a similarity-based analysis that incorporates genotype frequency data from 26 populations simultaneously. Using this method, we analyzed 57,629 structural variants and identified 576 structural variants that show unusual population differentiation. Of these putatively adaptive structural variants, we further showed that 24 variants are multiallelic and overlap with coding sequences, and 20 variants are significantly associated with GWAS traits. Closer inspection of the haplotypic variation associated with these putatively adaptive and functional structural variants reveals deviations from neutral expectations due to: 1) population differentiation of rapidly evolving multiallelic variants, 2) incomplete sweeps, and 3) recent population-specific negative selection. Overall, our study provides new methodological insights, documents hundreds of putatively adaptive variants, and introduces evolutionary models that may better explain the complex evolution of structural variants.