X-Linked <i>MTMR8</i> Diversity and Evolutionary History of Sub-Saharan Populations

<div><p>The genetic diversity within an 11 kb segment of the <i>MTMR8</i> gene in a sample of 111 sub-Saharan and 49 non-African X chromosomes was investigated to assess the early evolutionary history of sub-Saharan Africans and the out-of-Africa expansion. The analyses revealed a complex genetic structure of the Africans that contributed to the emergence of modern humans. We observed partitioning of two thirds of old lineages among southern, west/central and east African populations indicating ancient population stratification predating the out of Africa migration. Age estimates of these lineages, older than coalescence times of uniparentally inherited markers, raise the question whether contemporary humans originated from a single population or as an amalgamation of different populations separated by years of independent evolution, thus suggesting a greater antiquity of our species than generally assumed. While the oldest sub-Saharan lineages, ∼500 thousand years, are found among Khoe-San from southern-Africa, a distinct haplotype found among Biaka is likely due to admixture from an even older population. An East African population that gave rise to non-Africans underwent a selective sweep affecting the subcentromeric region where <i>MTMR8</i> is located. This and similar sweeps in four other regions of the X chromosome, documented in the literature, effectively reduced genetic diversity of non-African chromosomes and therefore may have exacerbated the effect of the demographic bottleneck usually ascribed to the out of Africa migration. Our data is suggestive, however, that a bottleneck, occurred in Africa before range expansion.</p></div

<i>Genetree</i> and ρ-statistics time estimates of mutations marking MTMRC8 segment history (figs. 1 and 2) based on 111 sub-Saharan African chromosomes and a Lebanese haplotype 23 chromosome.

<p><i>Genetree</i> and ρ-statistics time estimates of mutations marking MTMRC8 segment history (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080710#pone-0080710-g001" target="_blank">figs. 1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080710#pone-0080710-g002" target="_blank">2</a>) based on 111 sub-Saharan African chromosomes and a Lebanese haplotype 23 chromosome.</p

<i>MTMR8</i> segment haplotypes.

<p>The haplotype spans 11 Kb of the <i>MTMR8</i> gene, starting in intron 3 and ending in intron 5; the location of its polymorphic sites within the hg 19 genome reference sequence are shown in the third line. New alleles appear on the background of ancestral (chimpanzee) alleles, which are also shared with Neandertal and Denisova sequences, except for the polymorphic site 6 (highlighted in grey) where the derived allele is the same as that found in the Neandertal genome. The polymorphic sites 25 and 31, involving CpG-dinucleotides, are assumed to have mutated twice, indicated by asterisk, to create separate haplotypes 5 and 2, respectively (both found among Khoe-San).</p

Coalesecent analysis of the MTMR8 tree in Sub-Saharan Africa.

<p>The time scale in thousands of years is calculated using 7.5 My (internal left scale) or 6 My (external left scale) of sequence divergence between human and chimpanzee lineages. Numbering of mutations and haplotypes is the same as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080710#pone-0080710-g001" target="_blank">fig. 1</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080710#pone-0080710-t001" target="_blank">table 1</a>. Note that a Levantine chromosome carrying haplotype 23 was included in this analysis.</p

Network of MTMR8 haplotypes.

<p>Haplotype frequencies are proportional to the surface of the circle (or to its single colored segment within a population group). Numbering of mutations and haplotypes is the same as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080710#pone-0080710-t001" target="_blank">table 1</a>. Asterisks indicate two mutations in the CpG-sites 25 and 31 that presumably represent independent substitutions leading to separate haplotypes 5 and 2, respectively (both found among Khoe-San). When a series of mutation occurs on a single branch their order of appearance is arbitrary as we cannot know which one was first or last based on the presented data.</p

Native American Admixture in the Quebec Founder Population

<div><p>For years, studies of founder populations and genetic isolates represented the mainstream of genetic mapping in the effort to target genetic defects causing Mendelian disorders. The genetic homogeneity of such populations as well as relatively homogeneous environmental exposures were also seen as primary advantages in studies of genetic susceptibility loci that underlie complex diseases. European colonization of the St-Lawrence Valley by a small number of settlers, mainly from France, resulted in a founder effect reflected by the appearance of a number of population-specific disease-causing mutations in Quebec. The purported genetic homogeneity of this population was recently challenged by genealogical and genetic analyses. We studied one of the contributing factors to genetic heterogeneity, early Native American admixture that was never investigated in this population before. Consistent admixture estimates, in the order of one per cent, were obtained from genome-wide autosomal data using the ADMIXTURE and HAPMIX software, as well as with the fastIBD software evaluating the degree of the identity-by-descent between Quebec individuals and Native American populations. These genomic results correlated well with the genealogical estimates. Correlations are imperfect most likely because of incomplete records of Native founders’ origin in genealogical data. Although the overall degree of admixture is modest, it contributed to the enrichment of the population diversity and to its demographic stratification. Because admixture greatly varies among regions of Quebec and among individuals, it could have significantly affected the homogeneity of the population, which is of importance in mapping studies, especially when rare genetic susceptibility variants are in play.</p></div

Native American ancestry proportions in the Quebec regions.

<p>Here Quebec regional/ethnocultural groups are presented with (number of individuals with genotype data; number of individuals with genealogical data). For each population, expected Native American genetic contribution was estimated using genealogical data. The Native American ancestry proportions in the Quebec subpopulations was estimated with 1) the ADMIXTURE software <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065507#pone.0065507-Alexander1" target="_blank">[43]</a> 2) the HAPMIX software <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065507#pone.0065507-Price1" target="_blank">[39]</a>, and 3) IBD sharing analysis using the fastIBD software <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065507#pone.0065507-Browning1" target="_blank">[41]</a>. For each measure, we tested for differences among subpopulations using a Kruskal-Wallis test (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0065507#pone.0065507.s008" target="_blank">Table S3</a>).</p

Scatter plots of correlations.

<p>Scatter plots showing the correlations between different Native American genetic ancestry estimates in the Quebec subpopulations (upper) and between genetic ancestry estimates and genealogical genetic contribution of Native American founders to the Quebec individuals (lower). The Pearson correlation coefficient (r) is shown on each plot.</p

Map of Quebec subpopulations.

<p>In colors are the 10 regions/subpopulations included in the analyses.</p

Native American ancestry proportions and age of admixture in the Quebec population sample by different methods and using different reference populations (see Table S2).

a<p>For ADMIXTURE, Siberians were used as a third reference population,. whereas IBD sharing and ALDER, used only Native Americans as a single reference population.</p>b<p>For HAPMIX, 50 samples were randomly selected from each of the reference populations to match the Native North American sample size.</p