Modern humans have admixed with multiple archaic hominins. Papuans, in particular, owe up to 5% of their genome to Denisovans, a sister group to Neanderthals whose remains have only been identified ...in Siberia and Tibet. Unfortunately, the biological and evolutionary significance of these introgression events remain poorly understood. Here we investigate the function of both Denisovan and Neanderthal alleles characterised within a set of 56 genomes from Papuan individuals. By comparing the distribution of archaic and non-archaic variants we assess the consequences of archaic admixture across a multitude of different cell types and functional elements. We observe an enrichment of archaic alleles within cis-regulatory elements and transcribed regions of the genome, with Denisovan variants strongly affecting elements active within immune-related cells. We identify 16,048 and 10,032 high-confidence Denisovan and Neanderthal variants that fall within annotated cis-regulatory elements and with the potential to alter the affinity of multiple transcription factors to their cognate DNA motifs, highlighting a likely mechanism by which introgressed DNA can impact phenotypes. Lastly, we experimentally validate these predictions by testing the regulatory potential of five Denisovan variants segregating within Papuan individuals, and find that two are associated with a significant reduction of transcriptional activity in plasmid reporter assays. Together, these data provide support for a widespread contribution of archaic DNA in shaping the present levels of modern human genetic diversity, with different archaic ancestries potentially affecting multiple phenotypic traits within non-Africans.
Genome sequences are known for two archaic hominins—Neanderthals and Denisovans—which interbred with anatomically modern humans as they dispersed out of Africa. We identified high-confidence archaic ...haplotypes in 161 new genomes spanning 14 island groups in Island Southeast Asia and New Guinea and found large stretches of DNA that are inconsistent with a single introgressing Denisovan origin. Instead, modern Papuans carry hundreds of gene variants from two deeply divergent Denisovan lineages that separated over 350 thousand years ago. Spatial and temporal structure among these lineages suggest that introgression from one of these Denisovan groups predominantly took place east of the Wallace line and continued until near the end of the Pleistocene. A third Denisovan lineage occurs in modern East Asians. This regional mosaic suggests considerable complexity in archaic contact, with modern humans interbreeding with multiple Denisovan groups that were geographically isolated from each other over deep evolutionary time.
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•A new dataset of 161 genomes covering the understudied Indonesia-New Guinea region•Introgressing Denisovans comprise at least three genetically divergent groups•Papuans carry haplotypes from two Denisovan groups, with one unique to Oceania•Some Denisovan introgression was recent and likely occurred in New Guinea or Wallacea
Genome sequences from Island Southeast Asia suggest two independent Denisovan lineages, distinct from the Altai Denisovan, that have contributed to modern Papuan genomes, with one group potentially present east of the Wallace Line and thus capable of crossing geographical barriers.
Indonesia is the world's fourth most populous country, host to striking levels of human diversity, regional patterns of admixture, and varying degrees of introgression from both Neanderthals and ...Denisovans. However, it has been largely excluded from the human genomics sequencing boom of the last decade. To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide CpG methylation and gene expression measurements in over 100 individuals from three locations that capture the major genomic and geographical axes of diversity across the Indonesian archipelago. Investigating between- and within-island differences, we find up to 10.55% of tested genes are differentially expressed between the islands of Sumba and New Guinea. Variation in gene expression is closely associated with DNA methylation, with expression levels of 9.80% of genes correlating with nearby promoter CpG methylation, and many of these genes being differentially expressed between islands. Genes identified in our differential expression and methylation analyses are enriched in pathways involved in immunity, highlighting Indonesia's tropical role as a source of infectious disease diversity and the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-island variation in DNA methylation and gene expression, likely driven by fine-scale environmental differences across sampling sites. Together, these results strongly suggest complex relationships between DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the environment. This has implications for the application of genomic medicine, both in critically understudied Indonesia and globally, and will allow a better understanding of the interacting roles of genomic and environmental factors shaping molecular and complex phenotypes.
Borneo was a crossroad of ancient dispersals, with some of the earliest Southeast Asian human remains and rock art. The island is home to traditionally hunter-gatherer Punan communities, whose ...origins, whether of subsistence reversion or long-term foraging, are unclear. The connection between its past and present-day agriculturalist inhabitants, who currently speak Austronesian languages and have composite and complex genetic ancestry, is equally opaque. Here, we analyze the genetic ancestry of the northeastern Bornean Punan Batu (who still practice some mobile hunting and gathering), Tubu, and Aput. We find deep ancestry connections, with a shared Asian signal outgrouping modern and ancient Austronesian-ancestry proxies, suggesting a time depth of more than 7,500 years. They also largely lack the mainland Southeast Asian signals of agricultural Borneans, who are themselves genetically heterogeneous. Our results support long-term inhabitation of Borneo by some Punan ancestors and reveal unexpected complexity in the origins and dispersal of Austronesian-expansion-related ancestry.
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•Northeast Bornean Punan communities show strong genetic ancestry connections•These communities outgroup modern and ancient Austronesian genetic proxies•Results support long-term occupation of Borneo by Punan-related people•Results are also inconsistent with recent subsistence reversion among Punan peoples
Anthropologists have long debated the origins of the traditional Punan hunter-gatherers of Borneo. Kusuma et al. show unique genetic ancestry shared between communities, supporting their long-term habitation on the island and rejecting the idea that they are agriculturalists who underwent recent subsistence reversion.
The aim of this study is to identify genetic variants that harbour signatures of recent positive selection and may facilitate physiological adaptations to hypobaric hypoxia. To achieve this, we ...conducted whole genome sequencing and lung function tests in 19 Argentinean highlanders (>3500 m) comparing them to 16 Native American lowlanders. We developed a new statistical procedure using a combination of population branch statistics (PBS) and number of segregating sites by length (nSL) to detect beneficial alleles that arose since the settlement of the Andes and are currently present in 15-50% of the population. We identified two missense variants as significant targets of selection. One of these variants, located within the GPR126 gene, has been previously associated with the forced expiratory volume/forced vital capacity ratio. The other novel missense variant mapped to the EPAS1 gene encoding the hypoxia inducible factor 2α. EPAS1 is known to be the major selection candidate gene in Tibetans. The derived allele of GPR126 is associated with lung function in our sample of highlanders (p < 0.05). These variants may contribute to the physiological adaptations to hypobaric hypoxia, possibly by altering lung function. The new statistical approach might be a useful tool to detect selected variants in population studies.
During a selective sweep, characteristic patterns of linkage disequilibrium can arise in the genomic region surrounding a selected locus. These have been used to infer past selective sweeps. However, ...the recombination rate is known to vary substantially along the genome for many species. We here investigate the effectiveness of current (Kelly's Formula: see text and Formula: see text) and novel statistics at inferring hard selective sweeps based on linkage disequilibrium distortions under different conditions, including a human-realistic demographic model and recombination rate variation. When the recombination rate is constant, Kelly's Formula: see text offers high power, but is outperformed by a novel statistic that we test, which we call Formula: see text We also find this statistic to be effective at detecting sweeps from standing variation. When recombination rate fluctuations are included, there is a considerable reduction in power for all linkage disequilibrium-based statistics. However, this can largely be reversed by appropriately controlling for expected linkage disequilibrium using a genetic map. To further test these different methods, we perform selection scans on well-characterized HapMap data, finding that all three statistics-Formula: see text Kelly's Formula: see text and Formula: see text-are able to replicate signals at regions previously identified as selection candidates based on population differentiation or the site frequency spectrum. While Formula: see text replicates most candidates when recombination map data are not available, the Formula: see text and Formula: see text statistics are more successful when recombination rate variation is controlled for. Given both this and their higher power in simulations of selective sweeps, these statistics are preferred when information on local recombination rate variation is available.
Modern humans have admixed with multiple archaic hominins. Papuans, in particular, owe up to 5% of their genome to Denisovans, a sister group to Neanderthals whose remains have only been identified ...in Siberia and Tibet. Unfortunately, the biological and evolutionary significance of these introgression events remain poorly understood. Here we investigate the function of both Denisovan and Neanderthal alleles characterised within a set of 56 genomes from Papuan individuals. By comparing the distribution of archaic and non-archaic variants we assess the consequences of archaic admixture across a multitude of different cell types and functional elements. We observe an enrichment of archaic alleles within cis-regulatory elements and transcribed regions of the genome, with Denisovan variants strongly affecting elements active within immune-related cells. We identify 16,048 and 10,032 high-confidence Denisovan and Neanderthal variants that fall within annotated cis-regulatory elements and with the potential to alter the affinity of multiple transcription factors to their cognate DNA motifs, highlighting a likely mechanism by which introgressed DNA can impact phenotypes. Lastly, we experimentally validate these predictions by testing the regulatory potential of five Denisovan variants segregating within Papuan individuals, and find that two are associated with a significant reduction of transcriptional activity in plasmid reporter assays. Together, these data provide support for a widespread contribution of archaic DNA in shaping the present levels of modern human genetic diversity, with different archaic ancestries potentially affecting multiple phenotypic traits within non-Africans. Author summary Humans of Papuan ancestry owe roughly 5% of their genome to Denisovans, a poorly characterised archaic hominin. While introgressed DNA segments can be readily identified, understanding their biological consequences remains challenging. By examining the distribution of introgressed DNA against existing functional genomics datasets, it is possible to predict the phenotypes they impact. In Papuans, Denisovan DNA, but not Neanderthal, strongly and consistently affects immune cells and immune-related processes of potential evolutionary relevance. In vitro testing of introgressed variants confirms these predictions, suggesting Denisovan variants can impact gene regulation in vivo. Variation in gene expression might be key to understanding the consequences of admixture between modern humans and archaic hominins, as has been observed with Neanderthal DNA in other human populations.
Ectodysplasin A1 receptor (EDAR) is a TNF receptor family member with roles in the development and growth of hair, teeth and glands. A derived allele of EDAR, single-nucleotide variant rs3827760, ...encodes EDAR:p.(Val370Ala), a receptor with more potent signalling effects than the ancestral EDAR370Val. This allele of rs3827760 is at very high frequency in modern East Asian and Native American populations as a result of ancient positive selection and has been associated with straighter, thicker hair fibres, alteration of tooth and ear shape, reduced chin protrusion and increased fingertip sweat gland density. Here we report the characterisation of another SNV in EDAR, rs146567337, encoding EDAR:p.(Ser380Arg). The derived allele of this SNV is at its highest global frequency, of up to 5%, in populations of southern China, Vietnam, the Philippines, Malaysia and Indonesia. Using haplotype analyses, we find that the rs3827760 and rs146567337 SNVs arose on distinct haplotypes and that rs146567337 does not show the same signs of positive selection as rs3827760. From functional studies in cultured cells, we find that EDAR:p.(Ser380Arg) displays increased EDAR signalling output, at a similar level to that of EDAR:p.(Val370Ala). The existence of a second SNV with partly overlapping geographic distribution, the same in vitro functional effect and similar evolutionary age as the derived allele of rs3827760, but of independent origin and not exhibiting the same signs of strong selection, suggests a northern focus of positive selection on EDAR function in East Asia.
In a tragedy of the commons, individual competition over a resource can reduce the resource itself, and thus reduce the fitness of the whole group. An extreme example is evolutionary suicide, which ...is predicted to occur when the selfish interests of free-riders and cheaters overwhelm cooperative behaviors, and the social good on which they depend ceases to exist. Case studies cite many different and seemingly interacting factors for success. Here we propose an equation-based theoretical model to predict changes in this balance, which determine whether the tragedy of the commons is observed in a particular scenario. Using survey data from 20 Balinese subaks, we explore the explanatory power of two theoretical traditions that are currently used to analyze commons management institutions, revealing multiple regimes with correlated responses to environmental threats. To explore case studies from a comparative perspective requires both theory and methods that can account for differences between regimes and explore transitions between them.
Languages are transmitted through channels created by kinship systems. Given sufficient time, these kinship channels can change the genetic and linguistic structure of populations. In traditional ...societies of eastern Indonesia, finely resolved cophylogenies of languages and genes reveal persistent movements between stable speech communities facilitated by kinship rules. When multiple languages are present in a region and postmarital residence rules encourage sustained directional movement between speech communities, then languages should be channeled along uniparental lines. We find strong evidence for this pattern in 982 individuals from 25 villages on two adjacent islands, where different kinship rules have been followed. Core groups of close relatives have stayed together for generations, while remaining in contact with, and marrying into, surrounding groups. Over time, these kinship systems shaped their gene and language phylogenies: Consistently following a postmarital residence rule turned social communities into speech communities.
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