Origins and architecture of human genomic variation

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Our program is about recognizing, understanding and explaining patterns of genetic variation among human populations. Evolutionary history involves two components. First is past demography that can be represented by genealogies of genomic segments in question; these genealogies were sculptured by migration, founder effects, genetic drift, inbreeding, admixture as well as natural selection. Second are past genetic events, mutations and recombinations that left marks in the genomic record. In turn, these marks, which can be found in the chromosomes carried by sampled individuals, serve as markers to infer the underlying genealogies and thus the populations and genomic evolutionary history. The hypotheses we want to examine largely grew from our previous studies. We propose to address three groups of questions concerning (i)the time of the origin of H.sapiens, its early history in Africa, the out of Africa expansion(s) and after, focusing our analyses on DNA segments carrying haplotypes informative for archaic admixture, (ii) the identification of genomic segments carrying putative signatures of archaic admixture (for analyses under (i) by looking for clusters of SNPs that share derived alleles with a reference archaic genome and are also geographically restricted (e.g. exclusively in or outside Africa), and (iii) the use of differential signatures of past demographic events recorded by mutation and by recombination. Concerning recombination, we use two methods, based on linkage disequilibrium coefficient-r2 and on four-gamete test, described earlier. Because the first “sees” only crossing over (CO)and the second gene conversion (GC) as well, we propose to study the effect of both, and this is very new: first, to distinguish between the effects of CO and GC at the genomic scale, and second, how this can be also used to study populations’ history. We build on our earlier work that includes investigations of genetic diversity of X-linked segments in world-wide sample. These studies allowed us to forward unorthodox hypotheses about the structured ancestral African population, the time and place of the out-of-Africa bottleneck, about the non-African genetic contribution subsequently confirmed to be of the Neanderthal origin and the role of founder effects in the peopling of continents and of the Americas in particular. To pursue these questions, we use resequencing and genotyping of samples from our collection (n>10,000 (of X chromosomes), adding information from available databases. We rely on our extended network of collaborators. We develop new computational tools to read better and more from the genetic record (such as to time founder effects, study adaptive selection, to estimate recombination rate, finding regulatory variants, or distinguishing between CO and GC, etc. –see CV). Currently, there is a growing need of specialists in evolutionary genomics integrating laboratory competence with computational skills and knowledge in statistical genetics. By bridging different disciplines, our research program promotes interdisciplinary initiatives and becomes a breeding ground of new generation of specialists trained in basic and applied sciences such as bioinformatics and population genomics. To fill a gap in teaching in these fields, in 2006 I started a teaching initiative, which continues since then as yearly editions of Montreal Spring School. The genomics (computational and experimental) and population genetics orientation of our research program provides an excellent training environment for future scholars in evolutionary biology at large. This is in spite of the fact that we focus on the history of our species, its populations and genetics, interesting by itself, but the methods, approaches and applications are of general use.