Assessing the limits of local ancestry inference from small reference panels.

Admixture is a common biological phenomenon among populations of the same or different species. Identifying admixed tracts within individual genomes can provide valuable information to date admixture events, reconstruct ancestry-specific demographic histories, or detect adaptive introgression, genetic incompatibilities, as well as regions of the genomes affected by (associative-) overdominance. Although many local ancestry inference (LAI) methods have been developed in the last decade, their performance was accessed using large reference panels, which are rarely available for non-model organisms or ancient samples. Moreover, the demographic conditions for which LAI becomes unreliable have not been explicitly outlined. Here, we identify the demographic conditions for which local ancestries can be best estimated using very small reference panels. Furthermore, we compare the performance of two LAI methods (RFMix and MOSAIC) with the performance of a newly developed approach (simpLAI) that can be used even when reference populations consist of single individuals. Based on simulations of various demographic models, we also determine the limits of these LAI tools and propose post-painting filtering steps to reduce false-positive rates and improve the precision and accuracy of the inferred admixed tracts. Besides providing a guide for using LAI, our work shows that reasonable inferences can be obtained from a single diploid genome per reference under demographic conditions that are not uncommon among past human groups and non-model organisms.

Demogenomic inference from spatially and temporally heterogeneous samples.

Modern and ancient genomes are not necessarily drawn from homogeneous populations, as they may have been collected from different places and at different times. This heterogeneous sampling can be an issue for demographic inferences and results in biased demographic parameters and incorrect model choice if not properly considered. When explicitly accounted for, it can result in very complex models and high data dimensionality that are difficult to analyse. In this paper, we formally study the impact of such spatial and temporal sampling heterogeneity on demographic inference, and we introduce a way to circumvent this problem. To deal with structured samples without increasing the dimensionality of the site frequency spectrum (SFS), we introduce a new structured approach to the existing program fastsimcoal2. We assess the efficiency and relevance of this methodological update with simulated and modern human genomic data. We particularly focus on spatial and temporal heterogeneities to evidence the interest of this new SFS-based approach, which can be especially useful when handling scattered and ancient DNA samples, as in conservation genetics or archaeogenetics.

Genetic analysis of a bronze age individual from Ulug-depe (Turkmenistan).

The Oxus Civilisation (or Bactrio-Margian Archaeological Complex, BMAC) was the main archaeological culture of the Bronze Age in southern Central Asia. Paleogenetic analyses were previously conducted mainly on samples from the eastern part of BMAC. The population associated with BMAC descends from local Chalcolithic populations, with some outliers of steppe or South-Asian descent. Here, we present new genome-wide data for one individual from Ulug-depe (Turkmenistan), one of the main BMAC sites, located at the southwestern edge of the BMAC. We demonstrate that this individual genetically belongs to the BMAC cluster. Using this genome, we confirm that modern Indo-Iranian-speaking populations from Central Asia derive their ancestry from BMAC populations, with additional gene flow from the western and the Altai steppes in higher proportions among the Tajiks than the Yagnobi ethnic group.

Codiversification of gut microbiota with humans.

The gut microbiomes of human populations worldwide have many core microbial species in common. However, within a species, some strains can show remarkable population specificity. The question is whether such specificity arises from a shared evolutionary history (codiversification) between humans and their microbes. To test for codiversification of host and microbiota, we analyzed paired gut metagenomes and human genomes for 1225 individuals in Europe, Asia, and Africa, including mothers and their children. Between and within countries, a parallel evolutionary history was evident for humans and their gut microbes. Moreover, species displaying the strongest codiversification independently evolved traits characteristic of host dependency, including reduced genomes and oxygen and temperature sensitivity. These findings all point to the importance of understanding the potential role of population-specific microbial strains in microbiome-mediated disease phenotypes.

The genomic origins of the world's first farmers.

The precise genetic origins of the first Neolithic farming populations in Europe and Southwest Asia, as well as the processes and the timing of their differentiation, remain largely unknown. Demogenomic modeling of high-quality ancient genomes reveals that the early farmers of Anatolia and Europe emerged from a multiphase mixing of a Southwest Asian population with a strongly bottlenecked western hunter-gatherer population after the last glacial maximum. Moreover, the ancestors of the first farmers of Europe and Anatolia went through a period of extreme genetic drift during their westward range expansion, contributing highly to their genetic distinctiveness. This modeling elucidates the demographic processes at the root of the Neolithic transition and leads to a spatial interpretation of the population history of Southwest Asia and Europe during the late Pleistocene and early Holocene.

Genetic continuity of Indo-Iranian speakers since the Iron Age in southern Central Asia.

Since prehistoric times, southern Central Asia has been at the crossroads of the movement of people, culture, and goods. Today, the Central Asian populations are divided into two cultural and linguistic groups: the Indo-Iranian and the Turko-Mongolian groups. Previous genetic studies unveiled that migrations from East Asia contributed to the spread of Turko-Mongolian populations in Central Asia and the partial replacement of the Indo-Iranian populations. However, little is known about the origin of the latters. To shed light on this, we compare the genetic data on two current-day Indo-Iranian populations - Yaghnobis and Tajiks - with genome-wide data from published ancient individuals. The present Indo-Iranian populations from Central Asia display a strong genetic continuity with Iron Age samples from Turkmenistan and Tajikistan. We model Yaghnobis as a mixture of 93% Iron Age individual from Turkmenistan and 7% from Baikal. For the Tajiks, we observe a higher Baikal ancestry and an additional admixture event with a South Asian population. Our results, therefore, suggest that in addition to a complex history, Central Asia shows a remarkable genetic continuity since the Iron Age, with only limited gene flow.

No evidence for female kin association, indications for extragroup paternity, and sex-biased dispersal patterns in wild western gorillas.

Characterizing animal dispersal patterns and the rational behind individuals' transfer choices is a long-standing question of interest in evolutionary biology. In wild western gorillas (Gorilla gorilla), a one-male polygynous species, previous genetic findings suggested that, when dispersing, females might favor groups with female kin to promote cooperation, resulting in higher-than-expected within-group female relatedness. The extent of male dispersal remains unclear with studies showing conflicting results. To investigate male and female dispersal patterns and extragroup paternity, we analyzed long-term field observations, including female spatial proximity data, together with genetic data (10 autosomal microsatellites) on individuals from a unique set of four habituated western gorilla groups, and four additional extragroup males (49 individuals in total). The majority of offspring (25 of 27) were sired by the group male. For two offspring, evidence for extragroup paternity was found. Contrarily to previous findings, adult females were not significantly more related within groups than across groups. Consistently, adult female relatedness within groups did not correlate with their spatial proximity inferred from behavioral data. Adult females were similarly related to adult males from their group than from other groups. Using R ST statistics, we found significant genetic structure and a pattern of isolation by distance, indicating limited dispersal in this species. Comparing relatedness among females and among males revealed that males disperse farer than females, as expected in a polygamous species. Our study on habituated western gorillas shed light on the dispersal dynamics and reproductive behavior of this polygynous species and challenge some of the previous results based on unhabituated groups.

fastsimcoal2: demographic inference under complex evolutionary scenarios.

MOTIVATION: fastsimcoal2 extends fastsimcoal, a continuous time coalescent-based genetic simulation program, by enabling the estimation of demographic parameters under very complex scenarios from the site frequency spectrum under a maximum-likelihood framework. RESULTS: Other improvements include multi-threading, handling of population inbreeding, extended input file syntax facilitating the description of complex demographic scenarios, and more efficient simulations of sparsely structured populations and of large chromosomes. AVAILABILITY AND IMPLEMENTATION: fastsimcoal2 is freely available on http://cmpg.unibe.ch/software/fastsimcoal2/. It includes console versions for Linux, Windows and MacOS, additional scripts for the analysis and visualization of simulated and estimated scenarios, as well as a detailed documentation and ready-to-use examples.

Demographic inference.

In the last ten years, the next generation sequencing revolution has multiplied the amount of genetic data for many organisms by orders of magnitude. This has not only led to evolutionary biologists having more data available but also to new and different types of data: from a handful of allozyme markers in the 70s, we got dozens of restriction fragment length polymorphisms (RFLPs) in the 80s, hundreds of microsatellites in the 90s, thousands to hundreds of thousands of single nucleotide polymorphisms (SNPs) in the 2000s, a few full genomes in the 2010s, and thousands of full genomes in the 2020s. These data have provided information not only on the genetic diversity and evolution of the organisms studied but also on genome-wide patterns of selection, linkage disequilibrium, as well as recombination and mutation processes. Below, we will describe how these new genomic data can be used to infer the past demographic history of populations.

Gene flow as a simple cause for an excess of high-frequency-derived alleles.

Most human populations exhibit an excess of high-frequency variants, leading to a U-shaped site-frequency spectrum (uSFS). This pattern has been generally interpreted as a signature of ongoing episodes of positive selection, or as evidence for a mis-assignment of ancestral/derived allelic states, but uSFS has also been observed in populations receiving gene flow from a ghost population, in structured populations, or after range expansions. In order to better explain the prevalence of high-frequency variants in humans and other populations, we describe here which patterns of gene flow and population demography can lead to uSFS by using extensive coalescent simulations. We find that uSFS can often be observed in a population if gene flow brings a few ancestral alleles from a well-differentiated population. Gene flow can either consist in single pulses of admixture or continuous immigration, but different demographic conditions are necessary to observe uSFS in these two scenarios. Indeed, an extremely low and recent gene flow is required in the case of single admixture events, while with continuous immigration, uSFS occurs only if gene flow started recently at a high rate or if it lasted for a long time at a low rate. Overall, we find that a neutral uSFS occurs under more restrictive conditions in populations having received single pulses of gene flow than in populations exposed to continuous gene flow. We also show that the uSFS observed in human populations from the 1000 Genomes Project can easily be explained by gene flow from surrounding populations without requiring past episodes of positive selection. These results imply that uSFS should be common in non-isolated populations, such as most wild or domesticated plants and animals.

Why and when was lactase persistence selected for? Insights from Central Asian herders and ancient DNA.

The genetic adaptation of humans to the consumption of milk from dairying animals is one of the most emblematic cases of recent human evolution. While the phenotypic change under selection, lactase persistence (LP), is known, the evolutionary advantage conferred to persistent individuals remains obscure. One informative but underappreciated observation is that not all populations whose ancestors had access to milk genetically adapted to become lactase persistent. Indeed, Central Asian herders are mostly lactase nonpersistent, despite their significant dietary reliance on dairy products. Investigating the temporal dynamic of the -13.910:C>T Eurasian mutation associated with LP, we found that, after its emergence in Ukraine 5,960 before present (BP), the T allele spread between 4,000 BP and 3,500 BP throughout Eurasia, from Spain to Kazakhstan. The timing and geographical progression of the mutation coincides well with the migration of steppe populations across and outside of Europe. After 3,000 BP, the mutation strongly increased in frequency in Europe, but not in Asia. We propose that Central Asian herders have adapted to milk consumption culturally, by fermentation, and/or by colonic adaptation, rather than genetically. Given the possibility of a nongenetic adaptation to avoid intestinal symptoms when consuming dairy products, the puzzle then becomes this: why has LP been selected for at all?

Author Correction: 137 ancient human genomes from across the Eurasian steppes.

with In this Article, Angela M. Taravella and Melissa A. Wilson Sayres have been added to the author list (associated with: School of Life Sciences, Center for Evolution and Medicine, The Biodesign Institute, Arizona State University, Tempe, AZ, USA). The author list and Author Information section have been corrected online.

Close inbreeding and low genetic diversity in Inner Asian human populations despite geographical exogamy.

When closely related individuals mate, they produce inbred offspring, which often have lower fitness than outbred ones. Geographical exogamy, by favouring matings between distant individuals, is thought to be an inbreeding avoidance mechanism; however, no data has clearly tested this prediction. Here, we took advantage of the diversity of matrimonial systems in humans to explore the impact of geographical exogamy on genetic diversity and inbreeding. We collected ethno-demographic data for 1,344 individuals in 16 populations from two Inner Asian cultural groups with contrasting dispersal behaviours (Turko-Mongols and Indo-Iranians) and genotyped genome-wide single nucleotide polymorphisms in 503 individuals. We estimated the population exogamy rate and confirmed the expected dispersal differences: Turko-Mongols are geographically more exogamous than Indo-Iranians. Unexpectedly, across populations, exogamy patterns correlated neither with the proportion of inbred individuals nor with their genetic diversity. Even more surprisingly, among Turko-Mongols, descendants from exogamous couples were significantly more inbred than descendants from endogamous couples, except for large distances (>40 km). Overall, 37% of the descendants from exogamous couples were closely inbred. This suggests that in Inner Asia, geographical exogamy is neither efficient in increasing genetic diversity nor in avoiding inbreeding, which might be due to kinship endogamy despite the occurrence of dispersal.

137 ancient human genomes from across the Eurasian steppes.

For thousands of years the Eurasian steppes have been a centre of human migrations and cultural change. Here we sequence the genomes of 137 ancient humans (about 1× average coverage), covering a period of 4,000 years, to understand the population history of the Eurasian steppes after the Bronze Age migrations. We find that the genetics of the Scythian groups that dominated the Eurasian steppes throughout the Iron Age were highly structured, with diverse origins comprising Late Bronze Age herders, European farmers and southern Siberian hunter-gatherers. Later, Scythians admixed with the eastern steppe nomads who formed the Xiongnu confederations, and moved westward in about the second or third century BC, forming the Hun traditions in the fourth-fifth century AD, and carrying with them plague that was basal to the Justinian plague. These nomads were further admixed with East Asian groups during several short-term khanates in the Medieval period. These historical events transformed the Eurasian steppes from being inhabited by Indo-European speakers of largely West Eurasian ancestry to the mostly Turkic-speaking groups of the present day, who are primarily of East Asian ancestry.

Sex-specific genetic diversity is shaped by cultural factors in Inner Asian human populations.

OBJECTIVES: Sex-specific genetic structures have been previously documented worldwide in humans, even though causal factors have not always clearly been identified. In this study, we investigated the impact of ethnicity, geography and social organization on the sex-specific genetic structure in Inner Asia. Furthermore, we explored the process of ethnogenesis in multiple ethnic groups. METHODS: We sampled DNA in Central and Northern Asia from 39 populations of Indo-Iranian and Turkic-Mongolic native speakers. We focused on genetic data of the Y chromosome and mitochondrial DNA. First, we compared the frequencies of haplogroups to South European and East Asian populations. Then, we investigated the genetic differentiation for eight Y-STRs and the HVS1 region, and tested for the effect of geography and ethnicity on such patterns. Finally, we reconstructed the male demographic history, inferred split times and effective population sizes of different ethnic groups. RESULTS: Based on the haplogroup data, we observed that the Indo-Iranian- and Turkic-Mongolic-speaking populations have distinct genetic backgrounds. However, each population showed consistent mtDNA and Y chromosome haplogroups patterns. As expected in patrilocal populations, we found that the Y-STRs were more structured than the HVS1. While ethnicity strongly influenced the genetic diversity on the Y chromosome, geography better explained that of the mtDNA. Furthermore, when looking at various ethnic groups, we systematically found a genetic split time older than historical records, suggesting a cultural rather than biological process of ethnogenesis. CONCLUSIONS: This study highlights that, in Inner Asia, specific cultural behaviors, especially patrilineality and patrilocality, leave a detectable signature on the sex-specific genetic structure.

Mitochondrial Genetic Diversity of Eurasian Red Squirrels (Sciurus vulgaris) from Denmark.

Melanistic Eurasian red squirrels Sciurus vulgaris are commonly found on the Danish island of Funen. They are thought to represent native Danish squirrel types and are presently under threat from admixture with introduced red squirrels. In response, a conservation program was started in 2009 that involves the translocation of melanistic squirrels from Funen to the squirrel-free island of Langeland. Using mitochondrial DNA of 101 historical and modern samples from throughout Denmark, we assess for the first time population structure and mitochondrial genetic diversity of Danish squirrels compared to its larger pan-Eurasian distribution. We find that Danish squirrels have low levels of genetic diversity, especially melanistic individuals. Bayesian skyline reconstructions show that Danish squirrels have most probably experienced a severe bottleneck within the last 200 years. Also, fine-scale genetic structure was found between squirrels from the regions of Funen, Zealand and Jutland, which mimics the insular geography of Denmark. Additional nuclear DNA analyses will be required to determine the precise admixture levels between original Danish and introduced squirrels and to locate unmixed candidate populations for specific conservation efforts.

Confirmation of a founder effect in a Northern European population of a new ß-globin variant: HBB:c.23_26dup (codons 8/9 (+AGAA)).

ß-Thalassemia is a genetic disease caused by a defect in the production of the ß-like globin chain. More than 200 known different variants can lead to the disease and are mainly found in populations that have been exposed to malaria parasites. We recently described a duplication of four nucleotides in the first exon of ß-globin gene in several families of patients living in Nord-Pas-de-Calais (France). Using the genotypes at 12 microsatellite markers surrounding the ß-globin gene of four unrelated variant carriers plus an additional one recently discovered, we found that they shared a common haplotype indicating a founder effect that was estimated to have taken place 225 years ago (nine generations). In order to determine whether this variant arose in this region of Northern Europe or was introduced by migrants from regions of the world where thalassemia is endemic, we genotyped the first 4 unrelated variant carriers and 32 controls from Nord-Pas-de-Calais for 97 European ancestry informative markers (EAIMs). Using these EAIMs and comparing with population reference panels, we demonstrated that the variant carriers were very similar to the controls and were closer to North European populations than to South European or Middle-East populations. Rare ß-thalassemia variants have already been described in patients sampled in non-endemic regions, but it is the first proof of a founder effect in Northern Europe.