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Recent population genetic studies have provided valuable insights on the demographic history of our species. However, some issues such as the dating of the first demographic expansions in human populations remain puzzling. Indeed, although a few genetic studies argued that the first human expansions were concomitant with the Neolithic transition, many others found signals of expansion events starting during the Palaeolithic. Here we performed a simulation study to show that these contradictory findings may result from the differences in the genetic markers used, especially if two successive expansion events occurred. For a large majority of replicates for each scenario tested, microsatellite data allow only detecting the recent expansion event in that case, whereas sequence data allow only detecting the ancient expansion. Combined with previous real data analyses, our results bring support to the ideas that (i) a first human expansions started during the Palaeolithic period, (ii) a second expansion event occurred later, concomitantly with the Neolithic transition.

Two variants (c.[301_302delAG];[301_302delAG] and c.[150delA];[150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG];[301_302delAG] or c.[150delA];[150delA] or c.[301_302delAG];[ 150delA]. They originated from 21 different countries worldwide. We genotyped 21 single-nucleotide variant markers flanking the 9.6-Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations--a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated the ancestral origin of both variants--c.[301_302delAG] was carried on 0.2 Mb-long haplotype in a majority of European patients arising ~101 generations ago (confidence interval 90.1-116.4). Patients from the Iberian Peninsula displayed a different haplotype, which was estimated to have emerged 23.3 (20.1-29.1) generations ago. Subsequently, the data indicated that both the haplotypes were transmitted to Latin American patients ~13.8 (12.2-17.0) and 16.4 (14.4-20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3 Mb was estimated to appear 43.7 (38.4-52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot spots as previously assumed, but are founder variants.

The transition from hunting and gathering to plant and animal domestication was one of the most important cultural and technological revolutions in human history. According to archeologists and paleoanthropologists, this transition triggered major demographic expansions. However, few genetic studies have found traces of Neolithic expansions in the current repartition of genetic polymorphism, pointing rather toward Paleolithic expansions. Here, we used microsatellite autosomal data to investigate the past demographic history of 87 African and Eurasian human populations with contrasted lifestyles (nomadic hunter-gatherers, semi-nomadic herders and sedentary farmers). Likely due to the combination of a higher mutation rate and the possibility to analyze several loci as independent replicates of the coalescent process, the analysis of microsatellite data allowed us to infer more recent expansions than previous genetic studies, potentially resulting from the Neolithic transition. Despite the variability in their location and environment, we found consistent expansions for all sedentary farmers, while we inferred constant population sizes for all hunter-gatherers and most herders that could result from constraints linked to a nomadic or semi-nomadic lifestyle and/or competition for land between herders and farmers. As an exception, we inferred expansions for Central Asian herders. This might be linked with the arid environment of this area that may have been more favorable to nomadic herders than to sedentary farmers. Alternatively, current Central Asian herders may descent from populations who have first experienced a transition from hunter-gathering to sedentary agropastoralism, and then a second transition to nomadic herding.

The high prevalence of type 2 diabetes and its uneven distribution among human populations is both a major public health concern and a puzzle in evolutionary biology. Why is this deleterious disease so common, while the associated genetic variants should be removed by natural selection? The 'thrifty genotype' hypothesis proposed that the causal genetic variants were advantageous and selected for during the majority of human evolution. It remains, however, unclear whether genetic data support this scenario. In this study, we characterized patterns of selection at 10 variants associated with type 2 diabetes, contrasting one herder and one farmer population from Central Asia. We aimed at identifying which alleles (risk or protective) are under selection, dating the timing of selective events, and investigating the effect of lifestyle on selective patterns. We did not find any evidence of selection on risk variants, as predicted by the thrifty genotype hypothesis. Instead, we identified clear signatures of selection on protective variants, in both populations, dating from the beginning of the Neolithic, which suggests that this major transition was accompanied by a selective advantage for non-thrifty variants. Combining our results with worldwide data further suggests that East Asia was particularly prone to such recent selection of protective haplotypes. As much effort has been devoted so far to searching for thrifty variants, we argue that more attention should be paid to the evolution of non-thrifty variants.

The c.1544+1G>A substitution at the 5' splice donor site of intron 15 of the ITGA2B gene, called the French Gypsy mutation, causes Glanzmann thrombasthenia, an inherited hemorrhagic disorder transmitted as an autosomal recessive trait and characterized by an altered synthesis of the platelet αIIbβ3 integrin. So far, this mutation has only been found in affected individuals originating from French Manouche families, strongly suggesting a founder effect. Our goal was to investigate the origin of the French Gypsy mutation. We estimated the age of the mutation by a likelihood-based method that uses the length of the shared haplotypes among a set of patients. For this, we genotyped 23 individuals of Manouche origin; consisting of 9 Glanzmann thrombasthenia patients homozygous for the French Gypsy mutation, 6 heterozygous carriers and 8 homozygous wild-type individuals. They were genotyped for four single-nucleotide polymorphisms using high-resolution melting curve analysis, and for two CA repeats in the BRCA1 and THRA genes at chromosome 17, using fragment analysis gels. We found that a haplotype of five polymorphic loci covering a 4-cM region was strongly associated with the French Gypsy mutation, suggesting a founder effect. The estimated age of this founder mutation was 300-400 years (range 255-552 years). Thus, all carriers of the French Gypsy mutation c.1544+1G>A at intron 15 descended from a common ancestor 300-400 years ago.

Located in the Eurasian heartland, Central Asia has played a major role in both the early spread of modern humans out of Africa and the more recent settlements of differentiated populations across Eurasia. A detailed knowledge of the peopling in this vast region would therefore greatly improve our understanding of range expansions, colonizations and recurrent migrations, including the impact of the historical expansion of eastern nomadic groups that occurred in Central Asia. However, despite its presumable importance, little is known about the level and the distribution of genetic variation in this region. We genotyped 26 Indo-Iranian- and Turkic-speaking populations, belonging to six different ethnic groups, at 27 autosomal microsatellite loci. The analysis of genetic variation reveals that Central Asian diversity is mainly shaped by linguistic affiliation, with Turkic-speaking populations forming a cluster more closely related to East-Asian populations and Indo-Iranian speakers forming a cluster closer to Western Eurasians. The scattered position of Uzbeks across Turkic- and Indo-Iranian-speaking populations may reflect their origins from the union of different tribes. We propose that the complex genetic landscape of Central Asian populations results from the movements of eastern, Turkic-speaking groups during historical times, into a long-lasting group of settled populations, which may be represented nowadays by Tajiks and Turkmen. Contrary to what is generally thought, our results suggest that the recurrent expansions of eastern nomadic groups did not result in the complete replacement of local populations, but rather into partial admixture.

The arylamine N-acetyltransferase 2 (NAT2) enzyme detoxifies a wide spectrum of naturally occurring xenobiotics including carcinogens and drugs. Variation at the NAT2 gene has been linked to the human acetylation capacity, either 'slow' or 'fast', which modifies susceptibility to cancer and adverse drug reactions. We investigated the possible influence of natural selection in shaping the acetylation phenotype and the NAT2 gene variability in six Central Asian populations, who are either long-term sedentary agriculturalists (two Tajik populations), recent sedentary agriculturalists (Kazakhs, Uzbeks) or nomad pastoralists (two Kirghiz populations). To this end, we sequenced the entire NAT2 coding exon, as well as genotyping nine intergenic SNPs covering a 200-kb region. Our results revealed that the two Tajik populations exhibited significantly higher proportions of slow acetylators than the nomadic populations. In addition, sequence-based neutrality tests yielded significantly positive values in Central Asian populations following an agriculturalist lifestyle, due to an excess of haplotypes at intermediate frequencies. Taken together, our data suggest that balancing selection, and/or directional selection on standing low-frequency alleles, have shaped NAT2 genetic diversity and the human acetylation phenotype in Central Asian agriculturalists. These results further support the hypothesis that a major transition in human lifestyle, such as the emergence of farming has dramatically changed human chemical environments and the selective pressures they imposed.

Three coalescent-based methods allowed us to infer some aspects of the history of three Bulgarian Gypsies populations belonging to the Vlax linguistic group: the Lom, Rudari and Kalderas. We used several kinds of genetic markers: HV1 sequences of the maternally inherited mitochondrial genome and microsatellites of the paternally inherited Y chromosome and of the biparentally inherited chromosome 8. This allowed us to infer several parameters for men and women: the splitting order of the populations and the ages of the splitting events, the growth rate in each population and the migration rates between populations. Altogether, they enabled us to infer a demographic scenario that could explain the genetic diversity of Vlax Roma: recent splits occurring after the arrival in Europe, asymmetric migration flows especially for males and unequal growth rates. This represents a considerable contribution to the Vlax Roma history in comparison with the inferences from classical population genetics.

In a previous study, we showed that the observation of high frequencies of certain inherited disorders in the population of Saguenay Lac Saint Jean (SLSJ) in Quebec can be explained in terms of the variance and the auto-correlation of effective family size (EFS) across generations. Correlated EFS, across generations, allows alleles introduced as a single copy to reach very high frequencies in about 12 generations. Here, we investigate the impact of this same demographic process on allelic association between a disease locus and closely linked neutral markers. We model the fate of a disease allele, introduced as a single copy, and of its surrounding haplotype. We show that the auto-correlation of EFS across generations increases the expected proportion of individuals who carry the ancestral haplotype in the present generation. Thus, the length of a shared haplotype is longer, making this population useful for coarse mapping. But this autocorrelation decreases the estimated value; thus ignoring the auto-correlation in EFS leads to an underestimate of the recombination rate. This result is of importance, since socio-demographic processes such as auto-correlation of EFS across generations have been described in other human populations.