Archaeogenomic distinctiveness of the Isthmo-Colombian area.

The recently enriched genomic history of Indigenous groups in the Americas is still meager concerning continental Central America. Here, we report ten pre-Hispanic (plus two early colonial) genomes and 84 genome-wide profiles from seven groups presently living in Panama. Our analyses reveal that pre-Hispanic demographic events contributed to the extensive genetic structure currently seen in the area, which is also characterized by a distinctive Isthmo-Colombian Indigenous component. This component drives these populations on a specific variability axis and derives from the local admixture of different ancestries of northern North American origin(s). Two of these ancestries were differentially associated to Pleistocene Indigenous groups that also moved into South America, leaving heterogenous genetic footprints. An additional Pleistocene ancestry was brought by a still unsampled population of the Isthmus (UPopI) that remained restricted to the Isthmian area, expanded locally during the early Holocene, and left genomic traces up to the present day.

Reconstructing Prehistoric African Population Structure.

We assembled genome-wide data from 16 prehistoric Africans. We show that the anciently divergent lineage that comprises the primary ancestry of the southern African San had a wider distribution in the past, contributing approximately two-thirds of the ancestry of Malawi hunter-gatherers ∼8,100-2,500 years ago and approximately one-third of the ancestry of Tanzanian hunter-gatherers ∼1,400 years ago. We document how the spread of farmers from western Africa involved complete replacement of local hunter-gatherers in some regions, and we track the spread of herders by showing that the population of a ∼3,100-year-old pastoralist from Tanzania contributed ancestry to people from northeastern to southern Africa, including a ∼1,200-year-old southern African pastoralist. The deepest diversifications of African lineages were complex, involving either repeated gene flow among geographically disparate groups or a lineage more deeply diverging than that of the San contributing more to some western African populations than to others. We finally leverage ancient genomes to document episodes of natural selection in southern African populations. PAPERCLIP.

Metastable epialleles in humans.

First identified in isogenic mice, metastable epialleles (MEs) are loci where the extent of DNA methylation (DNAm) is variable between individuals but correlates across tissues derived from different germ layers within a given individual. This property, termed systemic interindividual variation (SIV), is attributed to stochastic methylation establishment before germ layer differentiation. Evidence suggests that some putative human MEs are sensitive to environmental exposures in early development. In this review we introduce key concepts pertaining to human MEs, describe methods used to identify MEs in humans, and review their genomic features. We also highlight studies linking DNAm at putative human MEs to early environmental exposures and postnatal (including disease) phenotypes.

Population structure and migration in the Eastern Highlands of Papua New Guinea, a region impacted by the kuru epidemic.

Populations of the Eastern Highlands of Papua New Guinea (EHPNG, area 11,157 km2) lived in relative isolation from the rest of the world until the mid-20th century, and the region contains a wealth of linguistic and cultural diversity. Notably, several populations of EHPNG were devastated by an epidemic prion disease, kuru, which at its peak in the mid-twentieth century led to some villages being almost depleted of adult women. Until now, population genetic analyses to learn about genetic diversity, migration, admixture, and the impact of the kuru epidemic have been restricted to a small number of variants or samples. Here, we present a population genetic analysis of the region based on genome-wide genotype data of 943 individuals from 21 linguistic groups and 68 villages in EHPNG, including 34 villages in the South Fore linguistic group, the group most affected by kuru. We find a striking degree of genetic population structure in the relatively small region (average FST between linguistic groups 0.024). The genetic population structure correlates well with linguistic grouping, with some noticeable exceptions that reflect the clan system of community organization that has historically existed in EHPNG. We also detect the presence of migrant individuals within the EHPNG region and observe a significant excess of females among migrants compared to among non-migrants in areas of high kuru exposure (p = 0.0145, chi-squared test). This likely reflects the continued practice of patrilocality despite documented fears and strains placed on communities as a result of kuru and its associated skew in female incidence.

Methods for Assessing Population Relationships and History Using Genomic Data.

Genetic data contain a record of our evolutionary history. The availability of large-scale datasets of human populations from various geographic areas and timescales, coupled with advances in the computational methods to analyze these data, has transformed our ability to use genetic data to learn about our evolutionary past. Here, we review some of the widely used statistical methods to explore and characterize population relationships and history using genomic data. We describe the intuition behind commonly used approaches, their interpretation, and important limitations. For illustration, we apply some of these techniques to genome-wide autosomal data from 929 individuals representing 53 worldwide populations that are part of the Human Genome Diversity Project. Finally, we discuss the new frontiers in genomic methods to learn about population history. In sum, this review highlights the power (and limitations) of DNA to infer features of human evolutionary history, complementing the knowledge gleaned from other disciplines, such as archaeology, anthropology, and linguistics.

Ancient West African foragers in the context of African population history.

Our knowledge of ancient human population structure in sub-Saharan Africa, particularly prior to the advent of food production, remains limited. Here we report genome-wide DNA data from four children-two of whom were buried approximately 8,000 years ago and two 3,000 years ago-from Shum Laka (Cameroon), one of the earliest known archaeological sites within the probable homeland of the Bantu language group1-11. One individual carried the deeply divergent Y chromosome haplogroup A00, which today is found almost exclusively in the same region12,13. However, the genome-wide ancestry profiles of all four individuals are most similar to those of present-day hunter-gatherers from western Central Africa, which implies that populations in western Cameroon today-as well as speakers of Bantu languages from across the continent-are not descended substantially from the population represented by these four people. We infer an Africa-wide phylogeny that features widespread admixture and three prominent radiations, including one that gave rise to at least four major lineages deep in the history of modern humans.

An efficient method to identify, date, and describe admixture events using haplotype information.

We present fastGLOBETROTTER, an efficient new haplotype-based technique to identify, date, and describe admixture events using genome-wide autosomal data. With simulations, we show how fastGLOBETROTTER reduces computation time by an order of magnitude relative to the related technique GLOBETROTTER without suffering loss of accuracy. We apply fastGLOBETROTTER to a cohort of more than 6000 Europeans from 10 countries, revealing previously unreported admixture signals. In particular, we infer multiple periods of admixture related to East Asian or Siberian-like sources, starting >2000 yr ago, in people living in countries north of the Baltic Sea. In contrast, we infer admixture related to West Asian, North African, and/or Southern European sources in populations south of the Baltic Sea, including admixture dated to ∼300-700 CE, overlapping the fall of the Roman Empire, in people from Belgium, France, and parts of Germany. Our new approach scales to analyzing hundreds to thousands of individuals from a putatively admixed population and, hence, is applicable to emerging large-scale cohorts of genetically homogeneous populations.

Tissue- and ethnicity-independent hypervariable DNA methylation states show evidence of establishment in the early human embryo.

We analysed DNA methylation data from 30 datasets comprising 3474 individuals, 19 tissues and 8 ethnicities at CpGs covered by the Illumina450K array. We identified 4143 hypervariable CpGs ('hvCpGs') with methylation in the top 5% most variable sites across multiple tissues and ethnicities. hvCpG methylation was influenced but not determined by genetic variation, and was not linked to probe reliability, epigenetic drift, age, sex or cell heterogeneity effects. hvCpG methylation tended to covary across tissues derived from different germ-layers and hvCpGs were enriched for proximity to ERV1 and ERVK retrovirus elements. hvCpGs were also enriched for loci previously associated with periconceptional environment, parent-of-origin-specific methylation, and distinctive methylation signatures in monozygotic twins. Together, these properties position hvCpGs as strong candidates for studying how stochastic and/or environmentally influenced DNA methylation states which are established in the early embryo and maintained stably thereafter can influence life-long health and disease.

Disentangling Signatures of Selection Before and After European Colonization in Latin Americans.

Throughout human evolutionary history, large-scale migrations have led to intermixing (i.e., admixture) between previously separated human groups. Although classical and recent work have shown that studying admixture can yield novel historical insights, the extent to which this process contributed to adaptation remains underexplored. Here, we introduce a novel statistical model, specific to admixed populations, that identifies loci under selection while determining whether the selection likely occurred post-admixture or prior to admixture in one of the ancestral source populations. Through extensive simulations, we show that this method is able to detect selection, even in recently formed admixed populations, and to accurately differentiate between selection occurring in the ancestral or admixed population. We apply this method to genome-wide SNP data of ∼4,000 individuals in five admixed Latin American cohorts from Brazil, Chile, Colombia, Mexico, and Peru. Our approach replicates previous reports of selection in the human leukocyte antigen region that are consistent with selection post-admixture. We also report novel signals of selection in genomic regions spanning 47 genes, reinforcing many of these signals with an alternative, commonly used local-ancestry-inference approach. These signals include several genes involved in immunity, which may reflect responses to endemic pathogens of the Americas and to the challenge of infectious disease brought by European contact. In addition, some of the strongest signals inferred to be under selection in the Native American ancestral groups of modern Latin Americans overlap with genes implicated in energy metabolism phenotypes, plausibly reflecting adaptations to novel dietary sources available in the Americas.

Structure and ancestry patterns of Ethiopians in genome-wide autosomal DNA.

We review some of the current insights derived from the analyses of new large-scale, genome-wide autosomal variation data studies incorporating Ethiopians. Consistent with their substantial degree of cultural and linguistic diversity, genetic diversity among Ethiopians is higher than that seen across much larger geographic regions worldwide. This genetic variation is associated in part with ethnic identity, geography and linguistic classification. Numerous and varied admixture events have been inferred in Ethiopian groups, for example, involving sources related to present-day groups in West Eurasia and North Africa, with inferred dates spanning a few hundred to more than 4500 years ago. These disparate inferred ancestry patterns are correlated in part with groups' broad linguistic classifications, though with some notable exceptions. While deciphering these complex genetic signals remains challenging with available data, these studies and other projects focused on resolving competing hypotheses on the origins of specific ethnolinguistic groups demonstrate how genetic analyses can complement findings from anthropological and linguistic studies on Ethiopians.

Continental-scale genomic analysis suggests shared post-admixture adaptation in the Americas.

American populations are one of the most interesting examples of recently admixed groups, where ancestral components from three major continental human groups (Africans, Eurasians and Native Americans) have admixed within the last 15 generations. Recently, several genetic surveys focusing on thousands of individuals shed light on the geography, chronology and relevance of these events. However, even though gene flow could drive adaptive evolution, it is unclear whether and how natural selection acted on the resulting genetic variation in the Americas. In this study, we analysed the patterns of local ancestry of genomic fragments in genome-wide data for ~ 6000 admixed individuals from 10 American countries. In doing so, we identified regions characterized by a divergent ancestry profile (DAP), in which a significant over or under ancestral representation is evident. Our results highlighted a series of genomic regions with DAPs associated with immune system response and relevant medical traits, with the longest DAP region encompassing the human leukocyte antigen locus. Furthermore, we found that DAP regions are enriched in genes linked to cancer-related traits and autoimmune diseases. Then, analysing the biological impact of these regions, we showed that natural selection could have acted preferentially towards variants located in coding and non-coding transcripts and characterized by a high deleteriousness score. Taken together, our analyses suggest that shared patterns of post admixture adaptation occurred at a continental scale in the Americas, affecting more often functional and impactful genomic variants.

Population structure and hybridisation in a population of Hawaiian feral chickens.

Chickens are believed to have inhabited the Hawaiian island of Kauai since the first human migrations around 1200AD, but numbers have peaked since the tropical storms Iniki and Iwa in the 1980s and 1990s that destroyed almost all the chicken coops on the island and released large numbers of domestic chickens into the wild. Previous studies have shown these now feral chickens are an admixed population between Red Junglefowl (RJF) and domestic chickens. Here, using genetic haplotypic data, we estimate the time of the admixture event between the feral population on the island and the RJF to 1981 (1976-1995), coinciding with the timings of storm Iwa and Iniki. Analysis of genetic structure reveals a greater similarity between individuals inhabiting the northern and western part of the island to RJF than individuals from the eastern part of the island. These results point to the possibility of introgression events between feral chickens and the wild chickens in areas surrounding the Koke'e State Park and the Alaka'i plateau, posited as two of the major RJF reservoirs in the island. Furthermore, we have inferred haplotype blocks from pooled data to determine the most plausible source of the feral population. We identify a clear contribution from RJF and layer chickens of the White Leghorn (WL) breed. This work provides independent confirmation of the traditional hypothesis surrounding the origin of the feral populations and draws attention to the possibility of introgression of domestic alleles into the wild reservoir.

Inferring Population Histories for Ancient Genomes Using Genome-Wide Genealogies.

Ancient genomes anchor genealogies in directly observed historical genetic variation and contextualize ancestral lineages with archaeological insights into their geography and cultural associations. However, the majority of ancient genomes are of lower coverage and cannot be directly built into genealogies. Here, we present a fast and scalable method, Colate, the first approach for inferring ancestral relationships through time between low-coverage genomes without requiring phasing or imputation. Our approach leverages sharing patterns of mutations dated using a genealogy to infer coalescence rates. For deeply sequenced ancient genomes, we additionally introduce an extension of the Relate algorithm for joint inference of genealogies incorporating such genomes. Application to 278 present-day and 430 ancient DNA samples of >0.5x mean coverage allows us to identify dynamic population structure and directional gene flow between early farmer and European hunter-gatherer groups. We further show that the previously reported, but still unexplained, increase in the TCC/TTC mutation rate, which is strongest in West Eurasia today, was already present at similar strength and widespread in the Late Glacial Period ~10k-15k years ago, but is not observed in samples >30k years old. It is strongest in Neolithic farmers, and highly correlated with recent coalescence rates between other genomes and a 10,000-year-old Anatolian hunter-gatherer. This suggests gene-flow among ancient peoples postdating the last glacial maximum as widespread and localizes the driver of this mutational signal in both time and geography in that region. Our approach should be widely applicable in future for addressing other evolutionary questions, and in other species.

Genetic legacy of state centralization in the Kuba Kingdom of the Democratic Republic of the Congo.

Few phenomena have had as profound or long-lasting consequences in human history as the emergence of large-scale centralized states in the place of smaller scale and more local societies. This study examines a fundamental, and yet unexplored, consequence of state formation: its genetic legacy. We studied the genetic impact of state centralization during the formation of the eminent precolonial Kuba Kingdom of the Democratic Republic of the Congo (DRC) in the 17th century. We analyzed genome-wide data from over 690 individuals sampled from 27 different ethnic groups from the Kasai Central Province of the DRC. By comparing genetic patterns in the present-day Kuba, whose ancestors were part of the Kuba Kingdom, with those in neighboring non-Kuba groups, we show that the Kuba today are more genetically diverse and more similar to other groups in the region than expected, consistent with the historical unification of distinct subgroups during state centralization. We also found evidence of genetic mixing dating to the time of the Kingdom at its most prominent. Using this unique dataset, we characterize the genetic history of the Kasai Central Province and describe the historic late wave of migrations into the region that contributed to a Bantu-like ancestry component found across large parts of Africa today. Taken together, we show the power of genetics to evidence events of sociopolitical importance and highlight how DNA can be used to better understand the behaviors of both people and institutions in the past.

The fine-scale genetic structure of the British population.

Fine-scale genetic variation between human populations is interesting as a signature of historical demographic events and because of its potential for confounding disease studies. We use haplotype-based statistical methods to analyse genome-wide single nucleotide polymorphism (SNP) data from a carefully chosen geographically diverse sample of 2,039 individuals from the United Kingdom. This reveals a rich and detailed pattern of genetic differentiation with remarkable concordance between genetic clusters and geography. The regional genetic differentiation and differing patterns of shared ancestry with 6,209 individuals from across Europe carry clear signals of historical demographic events. We estimate the genetic contribution to southeastern England from Anglo-Saxon migrations to be under half, and identify the regions not carrying genetic material from these migrations. We suggest significant pre-Roman but post-Mesolithic movement into southeastern England from continental Europe, and show that in non-Saxon parts of the United Kingdom, there exist genetically differentiated subgroups rather than a general 'Celtic' population.

Insular Celtic population structure and genomic footprints of migration.

Previous studies of the genetic landscape of Ireland have suggested homogeneity, with population substructure undetectable using single-marker methods. Here we have harnessed the haplotype-based method fineSTRUCTURE in an Irish genome-wide SNP dataset, identifying 23 discrete genetic clusters which segregate with geographical provenance. Cluster diversity is pronounced in the west of Ireland but reduced in the east where older structure has been eroded by historical migrations. Accordingly, when populations from the neighbouring island of Britain are included, a west-east cline of Celtic-British ancestry is revealed along with a particularly striking correlation between haplotypes and geography across both islands. A strong relationship is revealed between subsets of Northern Irish and Scottish populations, where discordant genetic and geographic affinities reflect major migrations in recent centuries. Additionally, Irish genetic proximity of all Scottish samples likely reflects older strata of communication across the narrowest inter-island crossing. Using GLOBETROTTER we detected Irish admixture signals from Britain and Europe and estimated dates for events consistent with the historical migrations of the Norse-Vikings, the Anglo-Normans and the British Plantations. The influence of the former is greater than previously estimated from Y chromosome haplotypes. In all, we paint a new picture of the genetic landscape of Ireland, revealing structure which should be considered in the design of studies examining rare genetic variation and its association with traits.

Population genomic analysis of elongated skulls reveals extensive female-biased immigration in Early Medieval Bavaria.

Modern European genetic structure demonstrates strong correlations with geography, while genetic analysis of prehistoric humans has indicated at least two major waves of immigration from outside the continent during periods of cultural change. However, population-level genome data that could shed light on the demographic processes occurring during the intervening periods have been absent. Therefore, we generated genomic data from 41 individuals dating mostly to the late 5th/early 6th century AD from present-day Bavaria in southern Germany, including 11 whole genomes (mean depth 5.56×). In addition we developed a capture array to sequence neutral regions spanning a total of 5 Mb and 486 functional polymorphic sites to high depth (mean 72×) in all individuals. Our data indicate that while men generally had ancestry that closely resembles modern northern and central Europeans, women exhibit a very high genetic heterogeneity; this includes signals of genetic ancestry ranging from western Europe to East Asia. Particularly striking are women with artificial skull deformations; the analysis of their collective genetic ancestry suggests an origin in southeastern Europe. In addition, functional variants indicate that they also differed in visible characteristics. This example of female-biased migration indicates that complex demographic processes during the Early Medieval period may have contributed in an unexpected way to shape the modern European genetic landscape. Examination of the panel of functional loci also revealed that many alleles associated with recent positive selection were already at modern-like frequencies in European populations ∼1,500 years ago.

The Genetic Legacy of Zoroastrianism in Iran and India: Insights into Population Structure, Gene Flow, and Selection.

Zoroastrianism is one of the oldest extant religions in the world, originating in Persia (present-day Iran) during the second millennium BCE. Historical records indicate that migrants from Persia brought Zoroastrianism to India, but there is debate over the timing of these migrations. Here we present genome-wide autosomal, Y chromosome, and mitochondrial DNA data from Iranian and Indian Zoroastrians and neighboring modern-day Indian and Iranian populations and conduct a comprehensive genome-wide genetic analysis in these groups. Using powerful haplotype-based techniques, we find that Zoroastrians in Iran and India have increased genetic homogeneity relative to other sampled groups in their respective countries, consistent with their current practices of endogamy. Despite this, we infer that Indian Zoroastrians (Parsis) intermixed with local groups sometime after their arrival in India, dating this mixture to 690-1390 CE and providing strong evidence that Iranian Zoroastrian ancestry was maintained primarily through the male line. By making use of the rich information in DNA from ancient human remains, we also highlight admixture in the ancestors of Iranian Zoroastrians dated to 570 BCE-746 CE, older than admixture seen in any other sampled Iranian group, consistent with a long-standing isolation of Zoroastrians from outside groups. Finally, we report results, and challenges, from a genome-wide scan to identify genomic regions showing signatures of positive selection in present-day Zoroastrians that might correlate to the prevalence of particular diseases among these communities.

Dissecting human North African gene-flow into its western coastal surroundings.

North African history and populations have exerted a pivotal influence on surrounding geographical regions, although scant genetic studies have addressed this issue. Our aim is to understand human historical migrations in the coastal surroundings of North Africa. We built a refined genome-wide dataset of North African populations to unearth the fine-scale genetic structure of the region, using haplotype information. The results suggest that the gene-flow from North Africa into the European Mediterranean coast (Tuscany and the Iberian Peninsula) arrived mainly from the Mediterranean coast of North Africa. In Tuscany, this North African admixture date estimate suggests the movement of peoples during the fall of the Roman Empire around the fourth century. In the Iberian Peninsula, the North African component probably reflects the impact of the Arab expansion since the seventh century and the subsequent expansion of the Christian Kingdoms. By contrast, the North African component in the Canary Islands has a source genetically related to present-day people from the Atlantic North African coast. We also find sub-Saharan gene-flow from the Senegambia region in the Canary Islands. Specifically, we detect a complex signal of admixture involving Atlantic, Senegambian and European sources intermixing around the fifteenth century, soon after the Castilian conquest. Our results highlight the differential genetic influence of North Africa into the surrounding coast and show that specific historical events have not only had a socio-cultural impact but additionally modified the gene pool of the populations.

Early farmers from across Europe directly descended from Neolithic Aegeans.

Farming and sedentism first appeared in southwestern Asia during the early Holocene and later spread to neighboring regions, including Europe, along multiple dispersal routes. Conspicuous uncertainties remain about the relative roles of migration, cultural diffusion, and admixture with local foragers in the early Neolithization of Europe. Here we present paleogenomic data for five Neolithic individuals from northern Greece and northwestern Turkey spanning the time and region of the earliest spread of farming into Europe. We use a novel approach to recalibrate raw reads and call genotypes from ancient DNA and observe striking genetic similarity both among Aegean early farmers and with those from across Europe. Our study demonstrates a direct genetic link between Mediterranean and Central European early farmers and those of Greece and Anatolia, extending the European Neolithic migratory chain all the way back to southwestern Asia.