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Genomic analyses of Neanderthals have previously provided insights into their population history and relationship to modern humans1–8, but the social organization of Neanderthal communities remains poorly understood. Here we present genetic data for 13 Neanderthals from two Middle Palaeolithic sites in the Altai Mountains of southern Siberia: 11 from Chagyrskaya Cave9,10 and 2 from Okladnikov Cave11—making this one of the largest genetic studies of a Neanderthal population to date. We used hybridization capture to obtain genome-wide nuclear data, as well as mitochondrial and Y-chromosome sequences. Some Chagyrskaya individuals were closely related, including a father–daughter pair and a pair of second-degree relatives, indicating that at least some of the individuals lived at the same time. Up to one-third of these individuals’ genomes had long segments of homozygosity, suggesting that the Chagyrskaya Neanderthals were part of a small community. In addition, the Y-chromosome diversity is an order of magnitude lower than the mitochondrial diversity, a pattern that we found is best explained by female migration between communities. Thus, the genetic data presented here provide a detailed documentation of the social organization of an isolated Neanderthal community at the easternmost extent of their known range.

After the main Out-of-Africa event, humans interbred with Neanderthals leaving 1–2% of Neanderthal DNA scattered in small fragments in all non-African genomes today. Here we investigate what can be learned about human demographic processes from the size distribution of these fragments. We observe differences in fragment length across Eurasia with 12% longer fragments in East Asians than West Eurasians. Comparisons between extant populations with ancient samples show that these differences are caused by different rates of decay in length by recombination since the Neanderthal admixture. In concordance, we observe a strong correlation between the average fragment length and the mutation accumulation, similar to what is expected by changing the ages at reproduction as estimated from trio studies. Altogether, our results suggest differences in the generation interval across Eurasia, by up 10–20%, over the past 40,000 years. We use sex-specific mutation signatures to infer whether these changes were driven by shifts in either male or female age at reproduction, or both. We also find that previously reported variation in the mutational spectrum may be largely explained by changes to the generation interval. We conclude that Neanderthal fragment lengths provide unique insight into differences among human populations over recent history., Historical interbreeding between Neanderthals and humans should leave signatures of historical demographics in modern human genomes. Analysing the size distribution of Neanderthal fragments in non-African genomes suggests consistent differences in the generation interval across Eurasia, and that this could explain mutational spectrum variation.

The Massim, a cultural region that includes the southeastern tip of mainland Papua New Guinea (PNG) and nearby PNG offshore islands, is renowned for a trading network called Kula, in which different valuable items circulate in different directions among some of the islands. Although the Massim has been a focus of anthropological investigation since the pioneering work of Malinowski in 1922, the genetic background of its inhabitants remains relatively unexplored. To characterize the Massim genomically, we generated genome-wide SNP data from 192 individuals from 15 groups spanning the entire region. Analyzing these together with comparative data, we found that all Massim individuals have variable Papuan-related (indigenous) and Austronesian-related (arriving ∼3,000 years ago) ancestries. Individuals from Rossel Island in southern Massim, speaking an isolate Papuan language, have the highest amount of a distinct Papuan ancestry. We also investigated the recent contact via sharing of identical by descent (IBD) genomic segments and found that Austronesian-related IBD tracts are widely distributed geographically, but Papuan-related tracts are shared exclusively between the PNG mainland and Massim, and between the Bismarck and Solomon Archipelagoes. Moreover, the Kula-practicing groups of the Massim show higher IBD sharing among themselves than do groups that do not participate in Kula. This higher sharing predates the formation of Kula, suggesting that extensive contact between these groups since the Austronesian settlement may have facilitated the formation of Kula. Our study provides the first comprehensive genome-wide assessment of Massim inhabitants and new insights into the fascinating Kula system.

Principal component analysis (PCA) and

Proteins associated with the spindle apparatus, a cytoskeletal structure that ensures the proper segregation of chromosomes during cell division, experienced an unusual number of amino acid substitutions in modern humans after the split from the ancestors of Neandertals and Denisovans. Here, we analyze the history of these substitutions and show that some of the genes in which they occur may have been targets of positive selection. We also find that the two changes in the kinetochore scaffold 1 (KNL1) protein, previously believed to be specific to modern humans, were present in some Neandertals. We show that the KNL1 gene of these Neandertals shared a common ancestor with present-day Africans about 200,000 years ago due to gene flow from the ancestors (or relatives) of modern humans into Neandertals. Subsequently, some non-Africans inherited this modern human-like gene variant from Neandertals, but none inherited the ancestral gene variants. These results add to the growing evidence of early contacts between modern humans and archaic groups in Eurasia and illustrate the intricate relationships among these groups.

In most macaques, females are philopatric and males migrate from their natal ranges, which results in pronounced divergence of mitochondrial genomes within and among species. We therefore predicted that some nuclear genes would have to acquire compensatory mutations to preserve compatibility with diverged interaction partners from the mitochondria. We additionally expected that these sex-differences would have distinctive effects on gene flow in the X and autosomes. Using new genomic data from 29 individuals from eight species of Southeast Asian macaque, we identified evidence of natural selection associated with mitonuclear interactions, including extreme outliers of interspecies differentiation and metrics of positive selection, low intraspecies polymorphism and atypically long runs of homozygosity associated with nuclear-encoded genes that interact with mitochondria-encoded genes. In one individual with introgressed mitochondria, we detected a small but significant enrichment of autosomal introgression blocks from the source species of her mitochondria that contained genes which interact with mitochondria-encoded loci. Our analyses also demonstrate that sex-specific demography sculpts genetic exchange across multiple species boundaries. These findings show that behaviour can have profound but indirect effects on genome evolution by influencing how interacting components of different genomic compartments (mitochondria, the autosomes and the sex chromosomes) move through time and space.

Neandertal DNA makes up 2–3% of the genomes of all non-African individuals. The patterns of Neandertal ancestry in modern humans have been used to estimate that this is the result of gene flow that occurred during the expansion of modern humans into Eurasia, but the precise dates of this event remain largely unknown. Here, we introduce an extended admixture pulse model that allows joint estimation of the timing and duration of gene flow. This model leads to simple expressions for both the admixture segment distribution and the decay curve of ancestry linkage disequilibrium, and we show that these two statistics are closely related. In simulations, we find that estimates of the mean time of admixture are largely robust to details in gene flow models, but that the duration of the gene flow can only be recovered if gene flow is very recent and the exact recombination map is known. These results imply that gene flow from Neandertals into modern humans could have happened over hundreds of generations. Ancient genomes from the time around the admixture event are thus likely required to resolve the question when, where, and for how long humans and Neandertals interacted.

Human genetic diversity is shaped by our complex history. Data-driven methods such as Principal Component Analysis (PCA) are an important population genetic tool to understand this method. Here, I contrast PCA with a set of statistics motivated by trees (F-statistics). Here, I show that these two methods are closely related, and I derive explicit connections between the two approaches. I show thatF-statistics have a simple geometrical interpretation in the context of PCA, and that orthogonal projections are the key concept to establish this link. I illustrate my results on two examples, one of local, and one of global human diversity. In both examples, I find that just using the first few PCs provides good population structure is sparse, and only a few components contribute to most statistics. Based on these results, I develop novel visualizations that allow for investigating specific hypotheses, checking the assumptions of more sophisticated models. My results extendF-statistics to non-discrete populations, moving towards more complete and less biased descriptions of human genetic variation.

The value of dirty DNA Environmental DNA can identify the presence of species, even from the distant past. Surveying three cave sites in western Europe and southern Siberia, Vernot et al. identified nuclear DNA and confirmed that it is from the close relatives of anatomically modern humans—Neanderthal and Denisovan individuals. A phylogenetic analysis and modeling show that the DNA in sediment samples from several layers corresponds to previously studied skeletal remains. These results demonstrate that environmental data can be applied to study the population genetics of the extinct Neanderthal and Denisovan lineages, identifying a turnover of Neanderthal populations ∼100,000 years ago. Science , this issue p. eabf1667

Modern humans appeared in Europe by at least 45,000 years ago1–5, but the extent of their interactions with Neanderthals, who disappeared by about 40,000 years ago6, and their relationship to the broader expansion of modern humans outside Africa are poorly understood. Here we present genome-wide data from three individuals dated to between 45,930 and 42,580 years ago from Bacho Kiro Cave, Bulgaria1,2. They are the earliest Late Pleistocene modern humans known to have been recovered in Europe so far, and were found in association with an Initial Upper Palaeolithic artefact assemblage. Unlike two previously studied individuals of similar ages from Romania7 and Siberia8 who did not contribute detectably to later populations, these individuals are more closely related to present-day and ancient populations in East Asia and the Americas than to later west Eurasian populations. This indicates that they belonged to a modern human migration into Europe that was not previously known from the genetic record, and provides evidence that there was at least some continuity between the earliest modern humans in Europe and later people in Eurasia. Moreover, we find that all three individuals had Neanderthal ancestors a few generations back in their family history, confirming that the first European modern humans mixed with Neanderthals and suggesting that such mixing could have been common., Genome-wide data for the three oldest known modern human remains in Europe, dated to around 45,000 years ago, shed light on early human migrations in Europe and suggest that mixing with Neanderthals was more common than is often assumed.

After the main out-of-Africa event, humans interbred with Neanderthals leaving 1-2% of Neanderthal DNA scattered in small fragments in all non-African genomes today1,2. Here we investigate the size distribution of these fragments in non-African genomes3. We find consistent differences in fragment length distributions across Eurasia with 11% longer fragments in East Asians than in West Eurasians. By comparing extant populations and ancient samples, we show that these differences are due to a different rate of decay in length by recombination since the Neanderthal admixture. In line with this, we observe a strong correlation between the average fragment length and the accumulation of derived mutations, similar to what is expected by changing the ages at reproduction as estimated from trio studies4. Altogether, our results suggest consistent differences in the generation interval across Eurasia, by up to 20% (e.g. 25 versus 30 years), over the past 40,000 years. We use sex-specific accumulations of derived alleles to infer how these changes in generation intervals between geographical regions could have been mainly driven by shifts in either male or female age of reproduction, or both. We also find that previously reported variation in the mutational spectrum5 may be largely explained by changes to the generation interval and not by changes to the underlying mutational mechanism. We conclude that Neanderthal fragment lengths provide unique insight into differences of a key demographic parameter among human populations over the recent history.

We generated induced excitatory neurons (iNeurons, iNs) from chimpanzee, bonobo, and human stem cells by expressing the transcription factor neurogenin-2 (NGN2). Single-cell RNA sequencing showed that genes involved in dendrite and synapse development are expressed earlier during iNs maturation in the chimpanzee and bonobo than the human cells. In accordance, during the first 2 weeks of differentiation, chimpanzee and bonobo iNs showed repetitive action potentials and more spontaneous excitatory activity than human iNs, and extended neurites of higher total length. However, the axons of human iNs were slightly longer at 5 weeks of differentiation. The timing of the establishment of neuronal polarity did not differ between the species. Chimpanzee, bonobo, and human neurites eventually reached the same level of structural complexity. Thus, human iNs develop slower than chimpanzee and bonobo iNs, and this difference in timing likely depends on functions downstream of NGN2., eLife, 10, ISSN:2050-084X

SummaryContamination from present-day DNA is a fundamental issue when studying ancient DNA from historical or archaeological material, and quantifying the amount of contamination is essential for downstream analyses. We present AuthentiCT, a command-line tool to estimate the proportion of present-day DNA contamination in ancient DNA datasets generated from single-stranded DNA libraries. The prediction is based solely on the patterns of post-mortem damage observed on ancient DNA sequences. The method has the power to quantify contamination from as few as 10,000 mapped sequences, making it particularly useful for analysing specimens that are poorly preserved or for which little data is available.Contactstephane.peyregne@gmail.com

Significance We present the third high-quality genome to be determined from a Neandertal. Patterns of variation in the genome suggest that her ancestors lived in relatively isolated populations of less than 60 individuals. When we analyze this genome together with two previously sequenced Neandertal genomes, we find that genes expressed in the striatum of the brain may have changed especially much, suggesting that the striatum may have evolved unique functions in Neandertals., We sequenced the genome of a Neandertal from Chagyrskaya Cave in the Altai Mountains, Russia, to 27-fold genomic coverage. We show that this Neandertal was a female and that she was more related to Neandertals in western Eurasia [Prüfer et al., Science 358, 655–658 (2017); Hajdinjak et al., Nature 555, 652–656 (2018)] than to Neandertals who lived earlier in Denisova Cave [Prüfer et al., Nature 505, 43–49 (2014)], which is located about 100 km away. About 12.9% of the Chagyrskaya genome is spanned by homozygous regions that are between 2.5 and 10 centiMorgans (cM) long. This is consistent with the fact that Siberian Neandertals lived in relatively isolated populations of less than 60 individuals. In contrast, a Neandertal from Europe, a Denisovan from the Altai Mountains, and ancient modern humans seem to have lived in populations of larger sizes. The availability of three Neandertal genomes of high quality allows a view of genetic features that were unique to Neandertals and that are likely to have been at high frequency among them. We find that genes highly expressed in the striatum in the basal ganglia of the brain carry more amino-acid-changing substitutions than genes expressed elsewhere in the brain, suggesting that the striatum may have evolved unique functions in Neandertals.

We generated induced excitatory sensory neurons (iNeurons, iNs) from chimpanzee, bonobo and human stem cells by expressing the transcription factor neurogenin-2 (NGN2). Single cell-RNA sequencing showed that genes involved in dendrite and synapse development are expressed earlier during iNs maturation in the chimpanzee than the human cells. In accordance, during the first two weeks of differentiation, chimpanzee and bonobo iNs showed repetitive action potentials and more spontaneous excitatory activity than human iNs, and extended neurites of higher total length. However, the axons of human iNs were slightly longer at 5 weeks of differentiation. The timing of the establishment of neuronal polarity did not differ between the species. Chimpanzee, bonobo and human neurites eventually reached the same level of structural complexity. Thus, human iNs develop slower than chimpanzee and bonobo iNs and this difference in timing likely depends on functions downstream of NGN2.

DNA analyses of an early East Asian Ancient, anatomically modern humans interbred with the archaic hominins Neanderthals and Denisovans. However, the extent of this interbreeding and how it affects modern populations is not well understood. Massilani et al. generated genome-wide data from a 34,000-year-old female individual from the Salkhit Valley in eastern Mongolia and conducted a detailed modeling of her ancestry with regard to other Pleistocene human genomes. They found evidence for Denisovan ancestry in ancient human genomes from at least 6000 years before the Salkhit individual lived and determined that the Denisovan contribution differed from that of another ancient Asian individual, as well as from the ancient Denisovan contribution to extant Australasians. This reference point helps us to understand the early history of our species in Eurasia, especially Eastern Eurasia, for which genomic evidence remains scarce. Science , this issue p. 579

Manuel, Marc de et al., Our closest living relatives, chimpanzees and bonobos, have a complex demographic history. We analyzed the high-coverage whole genomes of 75 wild-born chimpanzees and bonobos from 10 countries in Africa. We found that chimpanzee population substructure makes genetic information a good predictor of geographic origin at country and regional scales. Multiple lines of evidence suggest that gene flow occurred from bonobos into the ancestors of central and eastern chimpanzees between 200,000 and 550,000 years ago, probably with subsequent spread into Nigeria-Cameroon chimpanzees. Together with another, possibly more recent contact (after 200,000 years ago), bonobos contributed less than 1% to the central chimpanzee genomes. Admixture thus appears to have been widespread during hominid evolution., M.d.M. is supported by a Formació de personal Investigador fellowship from Generalitat de Catalunya (FI_B01111). M.K. is supported by a Deutsche Forschungsgemeinschaft fellowship (KU 3467/1-1). V.C.S., I.D., and L.E. are supported by Swiss National Science Foundation grants 31003A-143393 and 310030B-16660. T.D. is funded by the Gates Cambridge Trust. O.L. is supported by a Ramón y Cajal grant from Ministerio de Economía y Competitividad (MINECO) (RYC-2013-14797) and MINECO grant BFU2015-68759-P [Fondo Europeo de Desarrollo Region (FEDER)]. P.H. is supported by Estonian Research Council grant PUT1036. J.M.S., A.M.A., and S.C. are funded by the Max Planck Society. J.P.-M., C.T.-S., and Y.X. were supported by The Wellcome Trust (098051). J.M.H.-G. is supported by the María de Maeztu Programme (MDM-2014-0370). A.S. is supported by an Isaac Newton Trust/Wellcome Trust Institutional Strategic Support Fund Joint Research Grant. J.N. had support from a U.S. NIH U01CA198933 grant, and B.M.P. is supported by a Swiss National Science Foundation postdoctoral fellowship. A.N. is supported by MINECO grant BFU2015-68649-P. The collection of fecal samples was supported by the Max Planck Society and Krekeler Foundation’s generous funding for the Pan African Programme. T.M.-B. thanks ICREA; the European Molecular Biology Organization Young Investigator Programme 2013; MINECO grants BFU2014-55090-P (FEDER), BFU2015-7116-ERC, and BFU2015-6215-ERCU01; U.S. NIH grant MH106874; Fundacio Zoo Barcelona; and Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya for the support to his laboratory.

Many questions about human genetic history can be addressed by examining the patterns of shared genetic variation between sets of populations. A useful methodological framework for this purpose is F-statistics that measure shared genetic drift between sets of two, three, and four populations and can be used to test simple and complex hypotheses about admixture between populations. This article provides context from phylogenetic and population genetic theory. I review how F-statistics can be interpreted as branch lengths or paths and derive new interpretations, using coalescent theory. I further show that the admixture tests can be interpreted as testing general properties of phylogenies, allowing extension of some ideas applications to arbitrary phylogenetic trees. The new results are used to investigate the behavior of the statistics under different models of population structure and show how population substructure complicates inference. The results lead to simplified estimators in many cases, and I recommend to replace F3 with the average number of pairwise differences for estimating population divergence.

Empowered by modern genotyping and large samples, population structure can be accurately described and quantified even when it only explains a fraction of a percent of total genetic variance. This is especially relevant and interesting for humans, where fine-scale population structure can both confound disease-mapping studies and reveal the history of migration and divergence that shaped our species’ diversity. Here we review notable recent advances in the detection, use, and understanding of population structure. Our work addresses multiple areas where substantial progress is being made: improved statistics and models for better capturing differentiation, admixture, and the spatial distribution of variation; computational speed-ups that allow methods to scale to modern data; and advances in haplotypic modeling that have wide ranging consequences for the analysis of population structure. We conclude by outlining four important open challenges: The limitations of discrete population models, uncertainty in individual origins, the incorporation of both fine-scale structure and ancient DNA in parametric models, and the development of efficient computational tools, particularly for haplotype-based methods.

Ambient temperature is a critical environmental factor for all living organisms. It was likely an important selective force as modern humans recently colonized temperate and cold Eurasian environments. Nevertheless, as of yet we have limited evidence of local adaptation to ambient temperature in populations from those environments. To shed light on this question, we exploit the fact that humans are a cosmopolitan species that inhabit territories under a wide range of temperatures. Focusing on cold perception–which is central to thermoregulation and survival in cold environments–we show evidence of recent local adaptation on TRPM8. This gene encodes for a cation channel that is, to date, the only temperature receptor known to mediate an endogenous response to moderate cold. The upstream variant rs10166942 shows extreme population differentiation, with frequencies that range from 5% in Nigeria to 88% in Finland (placing this SNP in the 0.02% tail of the FST empirical distribution). When all populations are jointly analyzed, allele frequencies correlate with latitude and temperature beyond what can be explained by shared ancestry and population substructure. Using a Bayesian approach, we infer that the allele originated and evolved neutrally in Africa, while positive selection raised its frequency to different degrees in Eurasian populations, resulting in allele frequencies that follow a latitudinal cline. We infer strong positive selection, in agreement with ancient DNA showing high frequency of the allele in Europe 3,000 to 8,000 years ago. rs10166942 is important phenotypically because its ancestral allele is protective of migraine. This debilitating disorder varies in prevalence across human populations, with highest prevalence in individuals of European descent–precisely the population with the highest frequency of rs10166942 derived allele. We thus hypothesize that local adaptation on previously neutral standing variation may have contributed to the genetic differences that exist in the prevalence of migraine among human populations today., Author summary Some human populations were likely under strong pressure to adapt biologically to cold climates during their colonization of non-African territories in the last 50,000 years. Such putative adaptations required genetic variation in genes that could mediate adaptive responses to cold. TRPM8 is potentially one such gene, being the only known receptor for the sensation of moderate cold temperature. We show that a likely regulatory genetic variant nearby TRPM8 has several signatures of positive selection raising its frequency in Eurasian populations during the last 25,000 years. While the genetic variant was and is rare in Africa, it is now common outside of Africa, with frequencies that strongly correlate with latitude and are highest in northern European populations. Interestingly, this same genetic variant has previously been strongly associated with migraine. This suggests that adaptation to cold has potentially contributed to the variation in migraine prevalence that exists among human groups today.

Geographic patterns in human genetic diversity carry footprints of population history1,2 and provide insights for genetic medicine and its application across human populations3,4. Summarizing and visually representing these patterns of diversity has been a persistent goal for human geneticists5–10, and has revealed that genetic differentiation is frequently correlated with geographic distance. However, most analytical methods to represent population structure11–15 do not incorporate geography directly, and it must be considered post hoc alongside a visual summary. Here, we use a recently developed spatially explicit method to estimate “effective migration” surfaces to visualize how human genetic diversity is geographically structured (the EEMS method16). The resulting surfaces are “rugged”, which indicates the relationship between genetic and geographic distance is heterogenous and distorted as a rule. Most prominently, topographic and marine features regularly align with increased genetic differentiation (e.g. the Sahara desert, Mediterranean Sea or Himalaya at large scales; the Adriatic, interisland straits in near Oceania at smaller scales). In other cases, the locations of historical migrations and boundaries of language families align with migration features. These results provide visualizations of human genetic diversity that reveal local patterns of differentiation in detail and emphasize that while genetic similarity generally decays with geographic distance, there have regularly been factors that subtly distort the underlying relationship across space observed today. The fine-scale population structure depicted here is relevant to understanding complex processes of human population history and may provide insights for geographic patterning in rare variants and heritable disease risk.

The gradual loss of diversity and the establishment of clines in allele frequencies associated with range expansions are patterns observed in many species, including humans. These patterns can result from a series of founder events occurring as populations colonize previously unoccupied areas. We develop a model of an expanding population and, using a branching process approximation, show that spatial gradients reflect different amounts of genetic drift experienced by different subpopulations. We then use this model to measure the net average strength of the founder effect, and we demonstrate that the predictions from the branching process model fit simulation results well. We further show that estimates of the effective founder size are robust to potential confounding factors such as migration between subpopulations. We apply our method to data from Arabidopsis thaliana. We find that the average founder effect is approximately three times larger in the Americas than in Europe, possibly indicating that a more recent, rapid expansion occurred.

Arctic populations live in an environment characterized by extreme cold and the absence of plant foods for much of the year and are likely to have undergone genetic adaptations to these environmental conditions in the time they have been living there. Genome-wide selection scans based on genotype data from native Siberians have previously highlighted a 3 Mb chromosome 11 region containing 79 protein-coding genes as the strongest candidates for positive selection in Northeast Siberians. However, it was not possible to determine which of the genes might be driving the selection signal. Here, using whole-genome high-coverage sequence data, we identified the most likely causative variant as a nonsynonymous G>A transition (rs80356779; c.1436C>T [p.Pro479Leu] on the reverse strand) in CPT1A, a key regulator of mitochondrial long-chain fatty-acid oxidation. Remarkably, the derived allele is associated with hypoketotic hypoglycemia and high infant mortality yet occurs at high frequency in Canadian and Greenland Inuits and was also found at 68% frequency in our Northeast Siberian sample. We provide evidence of one of the strongest selective sweeps reported in humans; this sweep has driven this variant to high frequency in circum-Arctic populations within the last 6–23 ka despite associated deleterious consequences, possibly as a result of the selective advantage it originally provided to either a high-fat diet or a cold environment.

As modern humans migrated out of Africa, they encountered many new environmental conditions, including greater temperature extremes, different pathogens and higher altitudes. These diverse environments are likely to have acted as agents of natural selection and to have led to local adaptations. One of the most celebrated examples in humans is the adaptation of Tibetans to the hypoxic environment of the high-altitude Tibetan plateau. A hypoxia pathway gene, EPAS1, was previously identified as having the most extreme signature of positive selection in Tibetans, and was shown to be associated with differences in haemoglobin concentration at high altitude. Re-sequencing the region around EPAS1 in 40 Tibetan and 40 Han individuals, we find that this gene has a highly unusual haplotype structure that can only be convincingly explained by introgression of DNA from Denisovan or Denisovan-related individuals into humans. Scanning a larger set of worldwide populations, we find that the selected haplotype is only found in Denisovans and in Tibetans, and at very low frequency among Han Chinese. Furthermore, the length of the haplotype, and the fact that it is not found in any other populations, makes it unlikely that the haplotype sharing between Tibetans and Denisovans was caused by incomplete ancestral lineage sorting rather than introgression. Our findings illustrate that admixture with other hominin species has provided genetic variation that helped humans to adapt to new environments.

We propose a method that uses genetic data to test for the occurrence of a recent range expansion and to infer the location of the origin of the expansion. We introduce a statistic ψ (the directionality index) that detects asymmetries in the two-dimensional allele frequency spectrum of pairs of population. These asymmetries are caused by the series of founder events that happen during an expansion and they arise because low frequency alleles tend to be lost during founder events, thus creating clines in the frequencies of surviving low-frequency alleles. Using simulations, we show that ψ is more powerful for detecting range expansions than both FST and clines in heterozygosity. We also show how we can adapt our approach to more complicated scenarios such as expansions with multiple origins or barriers to migration and we illustrate the utility of ψ by applying it to a data set from modern humans.

Although most natural populations are genetically subdivided, they are often analysed as if they were panmictic units. In particular, signals of past demographic size changes are often inferred from genetic data by assuming that the analysed sample is drawn from a population without any internal subdivision. However, it has been shown that a bottleneck signal can result from the presence of some recent immigrants in a population. It thus appears important to contrast these two alternative scenarios in a model choice procedure to prevent wrong conclusions to be made. We use here an Approximate Bayesian Computation (ABC) approach to infer whether observed patterns of genetic diversity in a given sample are more compatible with it being drawn from a panmictic population having gone through some size change, or from one or several demes belonging to a recent finite island model. Simulations show that we can correctly identify samples drawn from a subdivided population in up to 95% of the cases for a wide range of parameters. We apply our model choice procedure to the case of the chimpanzee (Pan troglodytes) and find conclusive evidence that Western and Eastern chimpanzee samples are drawn from a spatially subdivided population.

Genetic variation harbors signatures of natural selection driven by selective pressures that are often unknown. Estimating the ages of selection signals may allow reconstructing the history of environmental changes that shaped human phenotypes and diseases. We have developed an approximate Bayesian computation (ABC) approach to estimate allele ages under a model of selection on new mutations and under demographic models appropriate for human populations. We have applied it to two resequencing data sets: An ultra-high depth data set from a relatively small sample of unrelated individuals and a lower depth data set in a larger sample with transmission information. In addition to evaluating the accuracy of our method based on simulations, for each SNP, we assessed the consistency between the posterior probabilities estimated by the ABC approach and the ancient DNA record, finding good agreement between the two types of data and methods. Applying this ABC approach to data for eight single nucleotide polymorphisms (SNPs), we were able to rule out an onset of selection prior to the dispersal out-of-Africa for three of them and more recent than the spread of agriculture for an additional three SNPs.

Many questions about human genetic history can be addressed by examining the patterns of shared genetic variation between sets of populations. A useful methodological framework for this purpose are F-statistics, that measure shared genetic drift between sets of two, three and four populations, and can be used to test simple and complex hypotheses about admixture between populations. Here, we put these statistics in context of phylogenetic and population genetic theory. We show how measures of genetic drift can be interpreted as branch lengths, paths through an admixture graph or in terms of the internal branches in coalescent trees. We show that the admixture tests can be interpreted as testing general properties of phylogenies, allowing us to generalize applications for arbitrary phylogenetic trees. Furthermore, we derive novel expressions for the F-statistics, which enables us to explore the behavior of F-statistic under population structure models. In particular, we show that population substructure may complicate inference. Author Summary For the analysis of genetic data from hundreds of populations, a commonly used technique are a set of simple statistics on data from two, three and four populations. These statistics are used to test hypotheses involving the history of populations, in particular whether data is consistent with the history of a set of populations forming a tree. Here, we provide context to these statistics by deriving novel expressions and by relating them to approaches in comparative phylogenetics. These results are useful because they provide a straightforward interpretation of these statistics under many demographic processes and lead to simplified expressions. However, the result also reveals the limitations of F-statistics, in that population substructure may complicate inference.

High-throughput sequencing approaches offer opportunities to better understand the evolutionary processes driving diversification, particularly in nonmodel organisms. In particular, the 100-1000's of loci that can now be sequenced are providing unprecedented power in population, speciation and phylogenetic studies. Here, we apply an exon capture approach to generate >99% complete sequence and SNP data across >2000 loci from a tropical skink, Carlia amax, and exploit these data to identify divergent lineages and infer their relationships and demographic histories. This is especially relevant to low-dispersal tropical taxa that often have cryptic diversity and spatially dynamic histories. For C. amax, clustering of nuclear SNPs and coalescent-based species delimitation analyses identify four divergent lineages, one fewer than predicted based on geographically coherent mtDNA clades (>9.4% sequence divergence). Three of these lineages are widespread and parapatric on the mainland, whereas the most divergent is restricted to islands off the northeast Northern Territory. Tests for population expansion reject an equilibrium isolation-by-distance model for two of the three widespread lineages and infer refugial expansion sources in the relatively mesic northeast Top End and northwest Kimberley. The latter is already recognized as a hotspot of endemism, but our results also suggest that a stronger focus on the northeast Top End, and adjacent islands is warranted. More generally, our results show how genome-reduction methods such as exon capture can yield insights into the pattern and dynamics of biodiversity across complex landscapes with as yet poorly understood biogeographic history and how exon data can link between population and phylogenetic questions.

The gradual loss of diversity and the establishment of clines in allele frequencies associated with range expansions are patterns observed in many species, including humans. These patterns can result from a series of founder events occurring as populations colonize previously unoccupied areas. We develop a model of an expanding population and, using a branching process approximation, show that spatial gradients reflect different amounts of genetic drift experienced by different subpopulations. We then use this model to measure the net average strength of the founder effect, and we demonstrate that the predictions from the branching process model fit simulation results well. We further show that estimates of the effective founder size are robust to potential confounding factors such as migration between subpopulations. We apply our method to data from Arabidopsis thaliana. We find that the average founder effect is approximately three times larger in the Americas than in Europe, possibly indicating that a more recent, rapid expansion occurred.

A report on the 64th annual American Society of Human Genetics meeting held in San Diego, USA, 18-22 October, 2014.

An outstanding question in human genetics has been the degree to which adaptation occurs from standing genetic variation or from de novo mutations. Here, we combine several common statistics used to detect selection in an Approximate Bayesian Computation (ABC) framework, with the goal of discriminating between models of selection and providing estimates of the age of selected alleles and the selection coefficients acting on them. We use simulations to assess the power and accuracy of our method and apply it to seven of the strongest sweeps currently known in humans. We identify two genes, ASPM and PSCA, that are most likely affected by selection on standing variation; and we find three genes, ADH1B, LCT, and EDAR, in which the adaptive alleles seem to have swept from a new mutation. We also confirm evidence of selection for one further gene, TRPV6. In one gene, G6PD, neither neutral models nor models of selective sweeps fit the data, presumably because this locus has been subject to balancing selection., Author Summary Considerable effort has been devoted to detecting genes that are under natural selection, and hundreds of such genes have been identified in previous studies. Here, we present a method for extending these studies by inferring parameters, such as selection coefficients and the time when a selected variant arose. Of particular interest is the question whether the selective pressure was already present when the selected variant was first introduced into a population. In this case, the variant would be selected right after it originated in the population, a process we call selection from a de novo mutation. We contrast this with selection from standing variation, where the selected variant predates the selective pressure. We present a method to distinguish these two scenarios, test its accuracy, and apply it to seven human genes. We find three genes, ADH1B, EDAR, and LCT, that were presumably selected from a de novo mutation and two other genes, ASPM and PSCA, which we infer to be under selection from standing variation.

Much remains unknown about the population history of early modern humans in southeast Asia, where the archaeological record is sparse and the tropical climate is inimical to the preservation of ancient human DNA1. So far, only two low-coverage pre-Neolithic human genomes have been sequenced from this region. Both are from mainland Hòabìnhian hunter-gatherer sites: Pha Faen in Laos, dated to 7939–7751 calibrated years before present (yr cal bp; present taken as ad 1950), and Gua Cha in Malaysia (4.4–4.2 kyr cal bp)1. Here we report, to our knowledge, the first ancient human genome from Wallacea, the oceanic island zone between the Sunda Shelf (comprising mainland southeast Asia and the continental islands of western Indonesia) and Pleistocene Sahul (Australia–New Guinea). We extracted DNA from the petrous bone of a young female hunter-gatherer buried 7.3–7.2 kyr cal bp at the limestone cave of Leang Panninge2 in South Sulawesi, Indonesia. Genetic analyses show that this pre-Neolithic forager, who is associated with the ‘Toalean’ technocomplex3,4, shares most genetic drift and morphological similarities with present-day Papuan and Indigenous Australian groups, yet represents a previously unknown divergent human lineage that branched off around the time of the split between these populations approximately 37,000 years ago5. We also describe Denisovan and deep Asian-related ancestries in the Leang Panninge genome, and infer their large-scale displacement from the region today., The palaeogenomic analysis of a pre-Neolithic skeleton associated with a Toalean burial context from Wallacea.