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Key Points Before the development of second-generation sequencing, the consensus opinion based on both fossil evidence and genetic evidence (which is based on single-locus and multilocus data) regarding human origins tended to favour a single recent African origin over a multiregional evolution model. The sequencing of the archaic Neanderthal and Denisovan genomes has shown that much more complex intermediate models are needed to explain the data. The genome of an Australian Aborigine seems to provide evidence for two waves of migration through Asia shortly after anatomically modern humans (AMHs) left Africa ~60,000–50,000 years ago. However, recent estimates of the human mutation rate have raised the question of whether population divergence dates between Africans and non-Africans that are estimated from genetic data reflect the movement of people out of Africa or a much more complex demographic scenario that involves substantial ancient population structure and back migration. Whole-genome sequencing (WGS) data from modern hunter-gatherers in Africa show that the click-speaking Khoe–Sans, followed by African Pygmies, are the most diverged AMH population alive today and that the Khoe–Sans maintain some genetic link with other click-speakers in Tanzania. However, robust inference of population history in Africa will require approaches that take into account 'ghost' archaic hominins from which ancient DNA is unlikely to be retrieved in the near future. The geographical distribution of classical markers, non-recombining portions of the Y chromosome and mitochondrial DNA has resulted in substantial debate regarding the relative contributions of Paleolithic and Neolithic populations to the genetic ancestry of modern Europeans. Second-generation sequencing of ancient samples from these two prehistoric periods seems to suggest a major reshaping of European genetic diversity as part of the transition to a farming way of life. WGS of ancient genomes is providing evidence that the prehistoric colonization of the Americas involved multiple waves of migrations over the Bering Strait and that the source populations are likely to derive from a relatively heterogeneous gene pool, which reflects periods of substantial demographic change in East Asia and Siberia since the Last Glacial Maximum. Substantial efforts have been devoted to developing methods for inferring demographic history that can correct for, or are insensitive to, nucleotide calling errors that are produced during second-generation sequencing, especially when examining the allele frequency spectrum using low and medium coverage data sets. In addition, the sequentially Markovian coalescent model is providing the basis for many methods that are attempting to incorporate recombination into analytically novel methods, whereas third-generation sequencing technologies may provide extensive haplotype-phased data to fully exploit such approaches. There continues to be active debate about the timings, locations and details of various events in human population history. This Review describes how whole-genome sequencing of modern and ancient humans has complemented more traditional methods to provide valuable historical insights. Examining patterns of molecular genetic variation in both modern-day and ancient humans has proved to be a powerful approach to learn about our origins. Rapid advances in DNA sequencing technology have allowed us to characterize increasing amounts of genomic information. Although this clearly provides unprecedented power for inference, it also introduces more complexity into the way we use and interpret such data. Here, we review ongoing debates that have been influenced by improvements in our ability to sequence DNA and discuss some of the analytical challenges that need to be overcome in order to fully exploit the rich historical information that is contained in the entirety of the human genome.

Analyses of ancient DNA from extinct humans reveal signals of at least two independent hybridization events in the history of non-African populations. To date, there are very few examples of specific genetic variants that have been rigorously identified as introgressive. Here, we survey DNA sequence variation in the OAS gene cluster on chromosome 12 and provide strong evidence that a haplotype extending for ∼185 kb introgressed from Neandertals. This haplotype is nearly restricted to Eurasians and is estimated to have diverged from the Neandertal sequence ∼125 kya. Despite the potential for novel functional variation, the observed frequency of this haplotype is consistent with neutral introgression. This is the second locus in the human genome, after STAT2, carrying distinct haplotypes that appear to have introgressed separately from both Neandertals and Denisova.

Indonesia, an island nation as large as continental Europe, hosts a sizeable proportion of global human diversity, yet remains surprisingly undercharacterized genetically. Here, we substantially expand on existing studies by reporting genome-scale data for nearly 500 individuals from 25 populations in Island Southeast Asia, New Guinea, and Oceania, notably including previously unsampled islands across the Indonesian archipelago. We use high-resolution analyses of haplotype diversity to reveal fine detail of regional admixture patterns, with a particular focus on the Holocene. We find that recent population history within Indonesia is complex, and that populations from the Philippines made important genetic contributions in the early phases of the Austronesian expansion. Different, but interrelated processes, acted in the east and west. The Austronesian migration took several centuries to spread across the eastern part of the archipelago, where genetic admixture postdates the archeological signal. As with the Neolithic expansion further east in Oceania and in Europe, genetic mixing with local inhabitants in eastern Indonesia lagged behind the arrival of farming populations. In contrast, western Indonesia has a more complicated admixture history shaped by interactions with mainland Asian and Austronesian newcomers, which for some populations occurred more than once. Another layer of complexity in the west was introduced by genetic contact with South Asia and strong demographic events in isolated local groups.

A long-debated question concerns the fate of archaic forms of the genus HOMO: did they go extinct without interbreeding with anatomically modern humans, or are their genes present in contemporary populations? This question is typically focused on the genetic contribution of archaic forms outside of Africa. Here we use DNA sequence data gathered from 61 noncoding autosomal regions in a sample of three sub-Saharan African populations (Mandenka, Biaka, and San) to test models of African archaic admixture. We use two complementary approximate-likelihood approaches and a model of human evolution that involves recent population structure, with and without gene flow from an archaic population. Extensive simulation results reject the null model of no admixture and allow us to infer that contemporary African populations contain a small proportion of genetic material (≈2%) that introgressed ≈35 kya from an archaic population that split from the ancestors of anatomically modern humans ≈700 kya. Three candidate regions showing deep haplotype divergence, unusual patterns of linkage disequilibrium, and small basal clade size are identified and the distributions of introgressive haplotypes surveyed in a sample of populations from across sub-Saharan Africa. One candidate locus with an unusual segment of DNA that extends for >31 kb on chromosome 4 seems to have introgressed into modern Africans from a now-extinct taxon that may have lived in central Africa. Taken together our results suggest that polymorphisms present in extant populations introgressed via relatively recent interbreeding with hominin forms that diverged from the ancestors of modern humans in the Lower-Middle Pleistocene.

Neanderthals were a group of archaic hominins that occupied most of Europe and parts of Western Asia from ∼30,000 to 300,000 years ago (KYA). They coexisted with modern humans during part of this time. Previous genetic analyses that compared a draft sequence of the Neanderthal genome with genomes of several modern humans concluded that Neanderthals made a small (1–4%) contribution to the gene pools of all non-African populations. This observation was consistent with a single episode of admixture from Neanderthals into the ancestors of all non-Africans when the two groups coexisted in the Middle East 50–80 KYA. We examined the relationship between Neanderthals and modern humans in greater detail by applying two complementary methods to the published draft Neanderthal genome and an expanded set of high-coverage modern human genome sequences. We find that, consistent with the recent finding of Meyer et al. (2012), Neanderthals contributed more DNA to modern East Asians than to modern Europeans. Furthermore we find that the Maasai of East Africa have a small but significant fraction of Neanderthal DNA. Because our analysis is of several genomic samples from each modern human population considered, we are able to document the extent of variation in Neanderthal ancestry within and among populations. Our results combined with those previously published show that a more complex model of admixture between Neanderthals and modern humans is necessary to account for the different levels of Neanderthal ancestry among human populations. In particular, at least some Neanderthal–modern human admixture must postdate the separation of the ancestors of modern European and modern East Asian populations.

Dravet syndrome (DS) is a rare, devastating form of childhood epilepsy that is often associated with mutations in the voltage-gated sodium channel gene, SCN1A. There is considerable variability in expressivity within families, as well as among individuals carrying the same primary mutation, suggesting that clinical outcome is modulated by variants at other genes. To identify modifier gene variants that contribute to clinical outcome, we sequenced the exomes of 22 individuals at both ends of a phenotype distribution (i.e., mild and severe cognitive condition). We controlled for variation associated with different mutation types by limiting inclusion to individuals with a de novo truncation mutation resulting in SCN1A haploinsufficiency. We performed tests aimed at identifying 1) single common variants that are enriched in either phenotypic group, 2) sets of common or rare variants aggregated in and around genes associated with clinical outcome, and 3) rare variants in 237 candidate genes associated with neuronal excitability. While our power to identify enrichment of a common variant in either phenotypic group is limited as a result of the rarity of mild phenotypes in individuals with SCN1A truncation variants, our top candidates did not map to functional regions of genes, or in genes that are known to be associated with neurological pathways. In contrast, we found a statistically-significant excess of rare variants predicted to be damaging and of small effect size in genes associated with neuronal excitability in severely affected individuals. A KCNQ2 variant previously associated with benign neonatal seizures is present in 3 of 12 individuals in the severe category. To compare our results with the healthy population, we performed a similar analysis on whole exome sequencing data from 70 Japanese individuals in the 1000 genomes project. Interestingly, the frequency of rare damaging variants in the same set of neuronal excitability genes in healthy individuals is nearly as high as in severely affected individuals. Rather than a single common gene/variant modifying clinical outcome in SCN1A-related epilepsies, our results point to the cumulative effect of rare variants with little to no measurable phenotypic effect (i.e., typical genetic background) unless present in combination with a disease-causing truncation mutation in SCN1A.

Key Points Over the past two decades, phylogenetic analyses of mitochondrial DNA and Y-chromosome polymorphisms supported a simple model of human origins, called the single origin hypothesis. The single origin model proposes that anatomically modern humans trace their ancestry to a single small population that lived in Africa, and that, following a speciation bottleneck, the population expanded and completely replaced archaic forms of humans. More sophisticated methods of analysis, based on the coalescent approach, are being applied to a plethora of new genomic sequence data. These new analyses of multilocus sequence data show a large variance in the shape and depth of genealogies for X-chromosomal and autosomal loci, and present a more complex picture of human demographic history. Non-African populations have reduced diversity and fewer rare polymorphisms than African populations, suggesting a history of bottlenecks. By contrast, African populations do not exhibit the predicted patterns of polymorphism after a speciation bottleneck. These genome-scale patterns could be best accounted for by models that involve low levels of gene flow among archaic populations before the emergence of anatomically modern humans — that is, they imply the existence of ancestral population structure. There is also growing evidence that some highly divergent genetic lineages might have entered our genome through hybridization between an expanding anatomically modern human population and archaic forms of humans. Further tests of the predictions of these models await more systematic surveys of DNA sequence variation in multiple human populations, along with more sophisticated methods of population genetic inference. The availability of new genome sequence data and sophisticated analysis methods are enriching our understanding of human demographic history. The emerging model is more complex than the single origin hypothesis, and instead invokes a degree of gene flow between subpopulations. Analyses of recently acquired genomic sequence data are leading to important insights into the early evolution of anatomically modern humans, as well as into the more recent demographic processes that accompanied the global radiation of Homo sapiens . Some of the new results contradict early, but still influential, conclusions that were based on analyses of gene trees from mitochondrial DNA and Y-chromosome sequences. In this review, we discuss the different genetic and statistical methods that are available for studying human population history, and identify the most plausible models of human evolution that can accommodate the contrasting patterns observed at different loci throughout the genome.

Variants implicated in childhood epilepsy have been identified in all four voltage-gated sodium channels that initiate action potentials in the central nervous system. Previous research has focused on the functional effects of particular variants within the most studied of these channels (NaV1.1, NaV1.2 and NaV1.6); however, there have been few comparative studies across channels to infer the impact of mutations in patients with epilepsy. Here we compare patterns of variation in patient and public databases to test the hypothesis that regions of known functional significance within voltage-gated sodium (NaV) channels have an increased burden of deleterious variants. We assessed mutational burden in different regions of the Nav channels by (1) performing Fisher exact tests on odds ratios to infer excess variants in domains, segments, and loops of each channel in patient databases versus public \"control\" databases, and (2) comparing the cumulative distribution of variant sites along DNA sequences of each gene in patient and public databases (i.e., independent of protein structure). Patient variant density was concordant among channels in regions known to play a role in channel function, with statistically significant higher patient variant density in S4-S6 and DIII-DIV and an excess of public variants in SI-S3, DI-DII, DII-DIII. On the other hand, channel-specific patterns of patient burden were found in the NaV1.6 inactivation gate and NaV1.1 S5-S6 linkers, while NaV1.2 and NaV1.6 S4-S5 linkers and S5 segments shared patient variant patterns that contrasted with those in NaV1.1. These different patterns may reflect different roles played by the NaV1.6 inactivation gate in action potential propagation, and by NaV1.1 S5-S6 linkers in loss of function and haploinsufficiency. Interestingly, NaV1.2 and NaV1.6 both lack amino acid substitutions over significantly long stretches in both the patient and public databases suggesting that new mutations in these regions may cause embryonic lethality or a non-epileptic disease phenotype.

Recent analysis of DNA extracted from two Eurasian forms of archaic human shows that more genetic variants are shared with humans currently living in Eurasia than with anatomically modern humans in sub-Saharan Africa. Although these genome-wide average measures of genetic similarity are consistent with the hypothesis of archaic admixture in Eurasia, analyses of individual loci exhibiting the signal of archaic introgression are needed to test alternative hypotheses and investigate the admixture process. Here, we provide a detailed sequence analysis of the innate immune gene OAS1, a locus with a divergent Melanesian haplotype that is very similar to the Denisova sequence from the Altai region of Siberia. We resequenced a 7-kb region encompassing the OAS1 gene in 88 individuals from six Old World populations (San, Biaka, Mandenka, French Basque, Han Chinese, and Papua New Guineans) and discovered previously unknown and ancient genetic variation. The 5′ region of this gene has unusual patterns of diversity, including 1) higher levels of nucleotide diversity in Papuans than in sub-Saharan Africans, 2) very deep ancestry with an estimated time to the most recent common ancestor of >3 myr, and 3) a basal branching pattern with Papuan individuals on either side of the rooted network. A global geographic survey of >1,500 individuals showed that the divergent Papuan haplotype is nearly restricted to populations from eastern Indonesia and Melanesia. Polymorphic sites within this haplotype are shared with the draft Denisova genome over a span of ∼90 kb and are associated with an extended block of linkage disequilibrium, supporting the hypothesis that this haplotype introgressed from an archaic source that likely lived in Eurasia.

The digital era offers many opportunities to the wind energy industry and research community and digitalisation is one of the key drivers for reducing project costs and risks. The WeDoWind framework has been developed in order to address one of the main challenges to a successful exploitation of digitalisation in wind energy - data sharing and collaboration. The main innovation of this framework is the way it creates tangible incentives to motivate different types of people to actually share data and knowledge in practice. In this work, we carry out a detailed analysis of the strengths and weaknesses of the WeDoWind framework based on a survey filled out by participants of two use case studies and observations from the WeDoWind development team. The results show that the framework successfully enhances collaboration and data sharing in the sector. The results allowed a set of practical data sharing recommendations for the wind energy sector to be developed, which are being continuously improved based on our experience with the WeDoWind framework. They can be applied by anyone wishing to share data effectively and efficiently.