Christine Harmant

Maternal traces of deep common ancestry and asymmetric gene flow between Pygmy hunter–gatherers and Bantu-speaking farmers

Two groups of populations with completely different lifestyles—the Pygmy hunter–gatherers and the Bantu-speaking farmers—coexist in Central Africa. We investigated the origins of these two groups and the interactions between them, by analyzing mtDNA variation in 1,404 individuals from 20 farming populations and 9 Pygmy populations from Central Africa, with the aim of shedding light on one of the most fascinating cultural transitions in human evolution (the transition from hunting and gathering to agriculture). Our data indicate that this region was colonized gradually, with an initial L1c-rich ancestral population ultimately giving rise to current-day farmers, who display various L1c clades, and to Pygmies, in whom L1c1a is the only surviving clade. Detailed phylogenetic analysis of complete mtDNA sequences for L1c1a showed this clade to be autochthonous to Central Africa, with its most recent branches shared between farmers and Pygmies. Coalescence analyses revealed that these two groups arose through a complex evolutionary process characterized by (i) initial divergence of the ancestors of contemporary Pygmies from an ancestral Central African population no more than ≈70,000 years ago, (ii) a period of isolation between the two groups, accounting for their phenotypic differences, (iii) long-standing asymmetric maternal gene flow from Pygmies to the ancestors of the farming populations, beginning no more than ≈40,000 years ago and persisting until a few thousand years ago, and (iv) enrichment of the maternal gene pool of the ancestors of the farming populations by the arrival and/or subsequent demographic expansion of L0a, L2, and L3 carriers.

Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations

Summary Humans differ in the outcome that follows exposure to life-threatening pathogens, yet the extent of population differences in immune responses and their genetic and evolutionary determinants remain undefined. Here, we characterized, using RNA sequencing, the transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli—ligands activating Toll-like receptor pathways (TLR1/2, TLR4, and TLR7/8) and influenza virus—and mapped expression quantitative trait loci (eQTLs). We identify numerous cis-eQTLs that contribute to the marked differences in immune responses detected within and between populations and a strong trans-eQTL hotspot at TLR1 that decreases expression of pro-inflammatory genes in Europeans only. We find that immune-responsive regulatory variants are enriched in population-specific signals of natural selection and show that admixture with Neandertals introduced regulatory variants into European genomes, affecting preferentially responses to viral challenges. Together, our study uncovers evolutionarily important determinants of differences in host immune responsiveness between human populations.

The Basque Paradigm: Genetic Evidence of a Maternal Continuity in the Franco-Cantabrian Region since Pre-Neolithic Times

Different lines of evidence point to the resettlement of much of western and central Europe by populations from the Franco-Cantabrian region during the Late Glacial and Postglacial periods. In this context, the study of the genetic diversity of contemporary Basques, a population located at the epicenter of the Franco-Cantabrian region, is particularly useful because they speak a non-Indo-European language that is considered to be a linguistic isolate. In contrast with genome-wide analysis and Y chromosome data, where the problem of poor time estimates remains, a new timescale has been established for the human mtDNA and makes this genome the most informative marker for studying European prehistory. Here, we aim to increase knowledge of the origins of the Basque people and, more generally, of the role of the Franco-Cantabrian refuge in the postglacial repopulation of Europe. We thus characterize the maternal ancestry of 908 Basque and non-Basque individuals from the Basque Country and immediate adjacent regions and, by sequencing 420 complete mtDNA genomes, we focused on haplogroup H. We identified six mtDNA haplogroups, H1j1, H1t1, H2a5a1, H1av1, H3c2a, and H1e1a1, which are autochthonous to the Franco-Cantabrian region and, more specifically, to Basque-speaking populations. We detected signals of the expansion of these haplogroups at ∼4,000 years before present (YBP) and estimated their separation from the pan-European gene pool at ∼8,000 YBP, antedating the Indo-European arrival to the region. Our results clearly support the hypothesis of a partial genetic continuity of contemporary Basques with the preceding Paleolithic/Mesolithic settlers of their homeland.

Uniparental markers in Italy reveal a sex-biased genetic structure and different historical strata

Located in the center of the Mediterranean landscape and with an extensive coastal line, the territory of what is today Italy has played an important role in the history of human settlements and movements of Southern Europe and the Mediterranean Basin. Populated since Paleolithic times, the complexity of human movements during the Neolithic, the Metal Ages and the most recent history of the two last millennia (involving the overlapping of different cultural and demic strata) has shaped the pattern of the modern Italian genetic structure. With the aim of disentangling this pattern and understanding which processes more importantly shaped the distribution of diversity, we have analyzed the uniparentally-inherited markers in ∼900 individuals from an extensive sampling across the Italian peninsula, Sardinia and Sicily. Spatial PCAs and DAPCs revealed a sex-biased pattern indicating different demographic histories for males and females. Besides the genetic outlier position of Sardinians, a North West–South East Y-chromosome structure is found in continental Italy. Such structure is in agreement with recent archeological syntheses indicating two independent and parallel processes of Neolithisation. In addition, date estimates pinpoint the importance of the cultural and demographic events during the late Neolithic and Metal Ages. On the other hand, mitochondrial diversity is distributed more homogeneously in agreement with older population events that might be related to the presence of an Italian Refugium during the last glacial period in Europe.

The epigenomic landscape of African rainforest hunter-gatherers and farmers

The genetic history of African populations is increasingly well documented, yet their patterns of epigenomic variation remain uncharacterized. Moreover, the relative impacts of DNA sequence variation and temporal changes in lifestyle and habitat on the human epigenome remain unknown. Here we generate genome-wide genotype and DNA methylation profiles for 362 rainforest hunter-gatherers and sedentary farmers. We find that the current habitat and historical lifestyle of a population have similarly critical impacts on the methylome, but the biological functions affected strongly differ. Specifically, methylation variation associated with recent changes in habitat mostly concerns immune and cellular functions, whereas that associated with historical lifestyle affects developmental processes. Furthermore, methylation variation—particularly that correlated with historical lifestyle—shows strong associations with nearby genetic variants that, moreover, are enriched in signals of natural selection. Our work provides new insight into the genetic and environmental factors affecting the epigenomic landscape of human populations over time.

Dispersals and genetic adaptation of Bantu-speaking populations in Africa and North America

Genetic analysis reveals the complex history of sub-Saharan Africans and African Americans. On the history of Bantu speakers Africans are underrepresented in many surveys of genetic diversity, which hinders our ability to study human evolution and the health of modern populations. Patin et al. examined the genetic diversity of Bantu speakers, who account for one-third of sub-Saharan Africans. They then modeled the timing of migration and admixture during the Bantu expansion. The analysis revealed adaptive introgression of genes that likely originated in other African populations, including specific immune-related genes. Applying this information to African Americans suggests that gene flow from Africa into the Americas was more complex than previously thought. Science, this issue p. 543 Bantu languages are spoken by about 310 million Africans, yet the genetic history of Bantu-speaking populations remains largely unexplored. We generated genomic data for 1318 individuals from 35 populations in western central Africa, where Bantu languages originated. We found that early Bantu speakers first moved southward, through the equatorial rainforest, before spreading toward eastern and southern Africa. We also found that genetic adaptation of Bantu speakers was facilitated by admixture with local populations, particularly for the HLA and LCT loci. Finally, we identified a major contribution of western central African Bantu speakers to the ancestry of African Americans, whose genomes present no strong signals of natural selection. Together, these results highlight the contribution of Bantu-speaking peoples to the complex genetic history of Africans and African Americans.

Identification of strains of Alcaligenes and Agrobacterium by a polyphasic approach.

ABSTRACT The number of stable discriminant biochemical characters is limited in the genera Alcaligenes andAgrobacterium, whose species are consequently difficult to distinguish from one another by conventional tests. Moreover, genomic studies have recently drastically modified the nomenclature of these genera; for example, Alcaligenes xylosoxidans was transferred to the genus Achromobacter in 1998. Twenty-five strains of Achromobacter xylosoxidans, three strains of an Agrobacterium sp., five strains of anAlcaligenes sp., and four unnamed strains belonging to the Centers for Disease Control and Prevention group IVc-2 were examined. These strains were characterized by conventional tests, including biochemical tests. The assimilation of 99 carbohydrates, organic acids, and amino acids was studied by using Biotype-100 strips, and rRNA gene restriction patterns were obtained with the automated Riboprinter microbial characterization system after cleavage of total DNA with EcoRI or PstI restriction endonuclease. This polyphasic approach allowed the two subspecies ofA. xylosoxidans to be clearly separated. Relationships between five strains and the Ralstonia paucula type strain were demonstrated. Likewise, three strains were found to be related to the Ochrobactrum anthropi type strain. We showed that substrate assimilation tests and automated ribotyping provide a simple, rapid, and reliable means of identifying A. xylosoxidans subspecies and that these two methods can be used as alternative methods to characterize unidentified strains rapidly when discriminant biochemical characters are missing.

Origins, admixture and founder lineages in European Roma

The Roma, also known as ‘Gypsies’, represent the largest and the most widespread ethnic minority of Europe. There is increasing evidence, based on linguistic, anthropological and genetic data, to suggest that they originated from the Indian subcontinent, with subsequent bottlenecks and undetermined gene flow from/to hosting populations during their diaspora. Further support comes from the presence of Indian uniparentally inherited lineages, such as mitochondrial DNA M and Y-chromosome H haplogroups, in a significant number of Roma individuals. However, the limited resolution of most genetic studies so far, together with the restriction of the samples used, have prevented the detection of other non-Indian founder lineages that might have been present in the proto-Roma population. We performed a high-resolution study of the uniparental genomes of 753 Roma and 984 non-Roma hosting European individuals. Roma groups show lower genetic diversity and high heterogeneity compared with non-Roma samples as a result of lower effective population size and extensive drift, consistent with a series of bottlenecks during their diaspora. We found a set of founder lineages, present in the Roma and virtually absent in the non-Roma, for the maternal (H7, J1b3, J1c1, M18, M35b, M5a1, U3, and X2d) and paternal (I-P259, J-M92, and J-M67) genomes. This lineage classification allows us to identify extensive gene flow from non-Roma to Roma groups, whereas the opposite pattern, although not negligible, is substantially lower (up to 6.3%). Finally, the exact haplotype matching analysis of both uniparental lineages consistently points to a Northwestern origin of the proto-Roma population within the Indian subcontinent.

Human herpesvirus 8, Southern Siberia.

To the Editor: Human herpesvirus 8 (HHV-8) is the etiologic agent of Kaposi sarcoma. Sequence analysis of the highly variable open reading frame (ORF)–K1 of HHV-8 has enabled the identification of 5 main molecular subtypes, A–E (1). A and C subtypes are prevalent in persons in Europe, Mediterranean countries, northwestern China, and the United States; subtype B, in persons in sub-Saharan Africa; subtype D, in persons in the Pacific Islands and Japan (2–6); and subtype E, in Native Americans in the United States. Considering that K1 gene polymorphisms of HHV-8–infected persons reflect the divergence accumulated during the early migrations of modern humans out of Africa (1), it is tempting to put the polymorphisms observed in the different subtypes into an evolutionary perspective with their geographic distribution. It is thought that Native Americans infected by subtype E and Pacific Islanders, including those infected by subtype D in the Japanese archipelago, originated from a common ancestral genetic stock in continental Asia. Because Siberia constitutes the geographic link between mainland Asia, North America, and the Pacific (Technical Appendix), it is likely that the Siberian region has served as a source or a corridor of human dispersals to these regions. Thus, we conducted a molecular epidemiology HHV-8 survey of the Buryat population, a major indigenous group in southern Siberia, to gain new insights into the origins, possibly common, of HHV-8 subtypes D and E. After consent of local authorities and participants, we collected 745 human blood samples in 1995 in 17 medicosocial structures (homes for elderly persons, veterans of the Russian army, hospitalized persons, blood donors) located near Lake Baikal and originating from Ulan Ude (344), Ust Orda (216), and Chita (185), Siberia, Russia (additional data can be obtained directly from the authors). The median age of those included was 52 years (range 25–98 years); 489 (66%) were women. Antibodies against HHV-8 latency–associated nuclear antigen were identified by immunofluorescent antibody assay by using the BC3 cell line (3). Punctuate nuclear staining of BC3 cells at a 1:160 dilution was observed for 187 (25.1%) patients with no difference according to investigated regions (p = 0.32 by χ2 test) or between men (25.8%) and women (24.7%) (p = 0.76 by χ2 test; Technical Appendix). However, HHV-8 seroprevalence increased with patient age, rising from 12.9% (25–43 years) to 46.4% (>61 years) (p = 1.8 × 10–13 by χ2 test for trend) (Figure; Technical Appendix). No significant difference was observed in antibody titers according to age (p = 0.45 by Fisher exact test). These results demonstrate that HHV-8 infection is highly prevalent in the Siberian adult population tested. Figure Age-dependent human herpesvirus 8 (HHV-8) seroprevalence rates for 745 persons in southern Siberia 25–98 years of age who lived in the Ust Orda, Ulan Ude, or Chita districts during 1995. Seropositivity was based on strict criteria; only samples ... HHV-8 infection was determined by nested PCR that amplified a 737-bp fragment of the ORFK1 in peripheral blood buffy coats of 85 HHV-8–seropositive and 10 HHV-8–seronegative persons (3). Amplification was positive in 19/85 (22.4%) samples; sequences were obtained for 18 of these samples (Technical Appendix). These sequences showed 0%–7.31% nucleotide divergence and 0%–3.55% amino acid divergence. Nevertheless, 17 strains were found to be closely related with <1.75% nucleotide differences for 684 nt, and only 1 sequence (1445 strain) displayed higher nucleotide divergence. A comparative sequence analysis, including 66 representatives of K1 gene sequences of the HHV-8 A/C subtypes/subgroups, and sequences obtained from persons originating from Russia, was performed (7–9). Seventeen of the 18 HHV-8 strains from Siberia belonged to the A subtype; 15 clustered in a newly identified specific subclade (Technical Appendix). Notably, the 1445-Siberian strain, which exhibits the typical 5 aa deletion at positions 201–205, belongs to subtype C and clustered with the 7848 strain previously described by Lacoste et al. (9). Furthermore, both strains originate from Chita. Our results indicate that HHV-8 infection is highly prevalent in the population tested in southern Siberia and extend current knowledge on the worldwide distribution of HHV-8 genotypes. The presence of a Siberian strain monophyletic subclade suggests the existence of HHV-8 strains preferentially spreading among this population in southern Siberia. To ascertain the maternal ancestry of these persons, we sequenced the hypervariable region I (HVS-I) of the maternally-inherited mitochondrial DNA (mtDNA) and assigned haplogroups on the basis of the HVS-I motifs. Our analyses showed that 17/18 persons analyzed showed a mtDNA motif of clear continental east Asian origin (e.g., A, D correspond to different mtDNA haplogroups). One person (1474-strain) had a lineage (i.e., HV1) that is thought to have a western Eurasian origin. Overall, these mtDNA analyses indicate that the maternal ancestry of the persons examined here can be unambiguously attributed to East Asia, and not to Western Eurasia. K1 subtype A sequences recently found in the Xinjiang Uygur region in China (10) do not correspond to the specific Siberian clade described in our study. Thus, we must now consider that the widely distributed HHV-8 A/C subtype, so far mainly observed in Europe and Mediterranean countries, is also largely predominant in continental Asia.

The demographic history and mutational load of African hunter-gatherers and farmers

Understanding how deleterious genetic variation is distributed across human populations is of key importance in evolutionary biology and medical genetics. However, the impact of population size changes and gene flow on the corresponding mutational load remains a controversial topic. Here, we report high-coverage exomes from 300 rainforest hunter-gatherers and farmers of central Africa, whose distinct subsistence strategies are expected to have impacted their demographic pasts. Detailed demographic inference indicates that hunter-gatherers and farmers recently experienced population collapses and expansions, respectively, accompanied by increased gene flow. We show that the distribution of deleterious alleles across these populations is compatible with a similar efficacy of selection to remove deleterious variants with additive effects, and predict with simulations that their present-day additive mutation load is almost identical. For recessive mutations, although an increased load is predicted for hunter-gatherers, this increase has probably been partially counteracted by strong gene flow from expanding farmers. Collectively, our predicted and empirical observations suggest that the impact of the recent population decline of African hunter-gatherers on their mutation load has been modest and more restrained than would be expected under a fully recessive model of dominance.High-coverage exomes from 300 central African hunter-gatherers and farmers reveal recent population trends and gene flow, as well as insight into the effects these trends have had on their respective mutational loads.