Origins and architecture of human genomic variation

人类基因组变异的起源和结构

• 批准号: RGPIN-2014-06317
• 负责人: Labuda, Damian
• 金额: $ 1.75万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=567731
• 关键词: Origins; architecture; human; genomic; variation

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.

我们的节目是关于识别、理解和解释人类群体中的遗传变异模式。进化史包括两个部分。首先是过去的人口学，它可以由所讨论的基因组片段的谱系来代表；这些谱系是通过迁徙、创始人效应、遗传漂移、近亲交配、混合以及自然选择来雕刻的。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，这些标记可以在样本个体携带的染色体中找到，作为标记来推断潜在的家谱，从而推断种群和基因组进化历史。我们想要检验的假设在很大程度上是从我们之前的研究中得出的。我们建议解决三组问题，涉及(I)智人起源的时间、其在非洲的早期历史、走出非洲的扩张(S)及其之后，重点分析携带古混合物信息的单倍型的DNA片段，(Ii)识别携带古混合物的假定特征的基因组片段(用于在(I)寻找与参考古代基因组共享衍生等位基因并且也受到地理限制(例如，仅在非洲内外)的SNPs簇，以及(Iii)使用通过突变和重组记录的过去人口统计事件的差异签名。关于重组，我们使用了两种方法，基于连锁不平衡系数R2和前面描述的四配子检验。由于第一次“看到”只交换(CO)和第二次基因转换(GC)，我们建议研究两者的影响，这是非常新的：第一，在基因组水平上区分CO和GC的影响，第二，这也可以用于研究种群的历史。我们建立在我们早期工作的基础上，包括在世界范围内的样本中调查X连锁片段的遗传多样性。这些研究使我们能够提出非正统的假设，关于非洲祖先人口的结构，非洲以外瓶颈的时间和地点，关于后来被证实起源于尼安德特人的非非洲基因贡献，以及创始人效应在大陆特别是美洲的人口形成中的作用。为了探索这些问题，我们对我们收集的样本(10,000条X染色体)进行了重新测序和基因分型，并从现有的数据库中添加了信息。我们依赖于我们扩展的合作者网络。我们开发了新的计算工具来更好、更多地从遗传记录中读取数据(例如，时间创始人效应、研究适应性选择、估计重组率、寻找调控变量或区分CO和GC等-参见CV)。目前，越来越需要将实验室能力与计算技能和统计遗传学知识相结合的进化基因组学专家。通过连接不同的学科，我们的研究计划促进了跨学科倡议，并成为培养新一代受过基础和应用科学培训的专家的温床，如生物信息学和人口基因组学。为了填补这些领域的教学空白，我在2006年发起了一项教学计划，从那时起，这项计划继续作为蒙特利尔春季学校的年度版本。我们研究项目的基因组学(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一个很好的培训环境。这是尽管我们关注我们物种的历史、其种群和遗传学，本身就很有趣，但方法、途径和应用是普遍使用的。