Schematic presentation of iterative hybridizations, composed of two steps: forward (left) and subtractive hybridizations (right)

<p><b>Copyright information:</b></p><p>Taken from "An selection scheme for oligonucleotide probes to discriminate between closely related DNA sequences"</p><p></p><p>Nucleic Acids Research 2007;35(9):e66-e66.</p><p>Published online 10 Apr 2007</p><p>PMCID:PMC1888810.</p><p>© 2007 The Author(s)</p> Intended and non-intended targets, probes and complexes between them are drowned in the legend (down). Note that intended targets are attached to the solid support, while non-intended targets are free in solution

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

Proportion of significant SNPs separated from regulatory region by a recombination hotspot (as in Figure 4).

<p>A hotspot has been simulated between the transcript locus and the regulatory rSNP as illustrated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038667#pone-0038667-g004" target="_blank">Figure 4</a>.</p

Manhattan plots of <i>p</i>-values from the contingency test.

<p>(<b>A</b>) for all autosomes using HapMap2 polymorphisms and AI data for LRRIQ3; (<b>B</b>) using HapMap3 polymorphisms and AI data for TAPBP; and (<b>C</b>) using 1000 genomes sequences for chromosome 6 and the same AI data for TAPBP.</p

Empirical False Positive Rate estimates.

<p>Percent of SNPs showing <i>p</i>-values below 0.01, after randomly assigning AI to 5, 10, 15, 20 and 29 individuals out of the 54 considered (based on the set of Ge et al.). Based on 20 whole genome scans for 10, 15 and 20 AI individuals and on 20 scans of chromosomes 1 to 4 for 5 and 29 AI individuals.</p

Four possible mutational pathways creating three distinct sets of three haplotypes.

<p>Depending on the sequence of mutations starting with the ancestral haplotype on the left, we obtain three sets of haplotypes, referred to as below, parallel and above to reflect the position of the <i>A</i>-site vs. <i>R</i>-site mutation on the genealogy shown on the right. These genealogical positions can be modified by recombination. We assume no recurrent mutations.</p