Origins and architecture of human genomic variation

我们的项目是关于认识、理解和解释人类群体中基因变异的模式。进化史包括两个组成部分。首先是过去的人口统计，可以用所讨论的基因组片段的家谱来表示；这些谱系是由迁徙、奠基人效应、遗传漂变、近亲繁殖、混合以及自然选择塑造而成的。其次是过去的遗传事件、突变和重组，它们在基因组记录中留下了印记。反过来，这些可以在样本个体携带的染色体中发现的标记，作为推断潜在谱系的标记，从而推断种群和基因组进化史。我们想要检验的假设很大程度上来自于我们以前的研究。我们建议解决以下三组问题：(i)智人的起源时间，其在非洲的早期历史，非洲以外的扩张(s)和之后，我们的分析重点是携带单倍型的DNA片段，为古代混合提供信息；（ii）识别携带假定的古代混合特征的基因组片段(用于(i)项下的分析，通过寻找与参考古代基因组共享衍生等位基因的snp集群，并且也受到地理限制（例如仅在非洲境内或境外），以及（iii）使用通过突变和重组记录的过去人口事件的差异特征。在重组方面，我们采用了两种方法，一种是基于连锁不平衡系数r2，另一种是基于前面描述的四配子测试。由于第一种“只看到”杂交（CO）和第二种基因转换（GC），我们提出研究两者的影响，这是非常新的：首先，在基因组尺度上区分CO和GC的影响，其次，如何将其也用于研究种群的历史。我们建立在我们早期的工作，包括调查遗传多样性的x链片段在世界范围内的样本。这些研究让我们提出了一些非正统的假设，比如非洲祖先人口的结构、走出非洲瓶颈的时间和地点、后来被证实是尼安德特人起源的非非洲基因贡献，以及在大陆、特别是美洲的人类定居过程中奠基者效应的作用。为了解决这些问题，我们对我们收集的样本（X染色体）进行了重测序和基因分型，并添加了来自现有数据库的信息。我们依靠我们广泛的合作伙伴网络。我们开发了新的计算工具，以更好地从遗传记录中读取更多信息（如时间奠基者效应，研究适应性选择，估计重组率，寻找调节变异，或区分CO和GC等）。目前，进化基因组学专家的需求日益增长，他们将实验室能力与计算技能和统计遗传学知识相结合。通过连接不同学科，我们的研究项目促进了跨学科的倡议，并成为培养新一代在基础科学和应用科学（如生物信息学和人口基因组学）方面受过培训的专家的温床。为了填补这些领域的教学空白，我在2006年开始了一项教学倡议，从那时起一直延续到蒙特利尔春季学校的年度版本。我们研究计划的基因组学（计算和实验）和群体遗传学方向为未来的进化生物学学者提供了良好的培训环境。尽管我们关注的是我们物种的历史、种群和遗传学，这本身就很有趣，但这些方法、途径和应用都是通用的。

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.