Dissertation Research: Tempo and Mode of HLA Evolution in the Americas

欧洲传染病传入美洲，造成土著居民灾难性的生命损失。虽然这场悲剧在整个美洲都很普遍，但亚利桑那州北部讲尤曼语的部落哈瓦苏派人的历史可以证明这一点。哈瓦苏派人居住在大峡谷的一个偏远的侧面峡谷，生活在相对孤立的环境中。在1897年至1905年期间，哈瓦苏派人遭受了一系列流感和麻疹的流行；只有四分之一的人口幸存下来。以前的研究表明，这些流行病导致了对两个主要组织相容性复合体(MHC)基因杂合子的选择，这两个基因是抵御病原体的免疫防御的关键组成部分。为了确定哈瓦苏派人MHC基因的变异模式是否是病原体抗性选择的结果，我们打算对微卫星座位进行全基因组调查，这是高度突变的标记，不受自然选择的影响。由于这些标记不受选择的影响，它们的变异模式将只反映哈瓦苏派人的人口历史。我们将检查分布在所有22个常染色体上的106个基因座，其中3个与MHC基因有关，15对相互关联。遗传、群体变异和连锁对之间的关联模式将最终决定自然选择是否导致在这个代表性群体的MHC基因上观察到的变异。这项研究有望深入了解与欧洲人殖民美洲有关的美洲原住民人口下降的遗传后果。

The introduction of European infectious diseases to the Americas resulted in a catastrophic loss of life among the indigenous populations. While this tragedy was widespread throughout the Americas, it can be exemplified by the history of the Havasupai, a Yuman-speaking tribe of northern Arizona. The Havasupai inhabit a remote side canyon of the Grand Canyon and live in relative isolation. Between 1897 and 1905, the Havasupai suffered serial epidemics of introduced influenza and measles; only one-quarter of the population survived. Previous research suggests that these epidemics resulted in selection for individuals who were heterozygous at two major histocompatibility complex (MHC) genes, which are critical components of immunological defense against pathogens.To determine whether the pattern of variation at MHC genes in the Havasupai is the result of selection for pathogen resistance, we intend to perform a genome-wide survey of microsatellite loci, which are highly mutable markers that are not subject to natural selection. Because these markers are not subject to selection, their pattern of variation will reflect only the demographic history of the Havasupai. We will examine 106 loci spread over all 22 autosomes, three of which are linked to the MHC genes and 15 pairs are linked to one another. The patterns of inheritance, population variation, and association between linked pairs will determine conclusively if natural selection is responsible for the variation observed at the MHC genes of this representative population. This research promises to yield insight into the genetic consequences of the Native American population declines associated with colonization of the Americas by Europeans.