Y CHROMOSOME EVOLUTION AND MODERN HUMAN ORIGINS

这项拟议的研究将比较Y染色体(NRY)、线粒体DNA(MtDNA)和X染色体非重组部分的全球变异模式，以研究影响人类基因组变异的因素，并检验有关人类种群历史和人口统计学的假说。这项研究的动机是需要增加我们对我们物种历史的了解，以及使某些种群更容易患上更高遗传病的进化力量。总体设计将筛选NRY上16kb的核苷酸变异，3kb的非D-loop mtDNA，以及来自11个人类群体的550条染色体样本中两个X染色体座位(一个低重组基因和一个高重组基因)每个3-5kb的核苷酸变异，以及来自全球26个群体的50个男性样本。这种嵌套抽样设计将允许直接比较具有不同确定偏差的两种抽样战略，并将为检验有关人口历史和人口结构、非洲和非非洲遗传变异的不同模式以及男性和女性迁移率的若干假设提供一个健全的框架。通过分析具有不同突变率、重组率和/或有效大小的基因座，理清特定于基因座的因素和各种群体水平力量塑造人类基因组多样性的相对影响是可行的。这项研究还将侧重于区域规模的问题，特别强调最近人口扩散的遗传后果。具体地说，它将把散居海外的犹太人作为一个模型系统，并将测试有关创始人事件的数量和时间的假设，这些事件导致德系犹太人人口中隐性疾病的频率增加。

The proposed research will compare global patterns of variation on the non-recombining portion of the Y chromosome (NRY), mitochondrial DNA (mtDNA), and the X chromosome in order to study the forces shaping human genome variation, and to test hypotheses about the history and demography of human populations. This research is motivated by the need to increase our knowledge of the history of our species and of the evolutionary forces predisposing certain populations to higher rates of genetic disease. The overall design will be to screen for nucleotide variation in 16 kilobases (kb) on the NRY, 3 kb of non-D- loop mtDNA, and 3 to 5 kb from each of two X chromosome loci (one low and one high recombination gene) in a sample of 550 chromosomes from 11 human populations, as well as a global sample of 50 males drawn from 26 worldwide populations. This nested sampling design will allow the direct comparison of two sampling strategies with different ascertainment biases, and will provide a sound framework for testing of a number of hypotheses pertaining to the demographic history and structure of human populations, different patterns of African versus non- African genetic variation, and male versus female migration rates. By analyzing loci with different mutation rates, recombination rates, and/or effective sizes, it should be feasible to disentangle the relative influences of locus-specific factors and a variety of population-level forces shaping human genome diversity. This research will also focus on regional-scale questions, with special emphasis on the genetic consequences of recent population dispersals. Specifically, it will develop the Jewish Diaspora as a model system, and will test hypotheses concerning the number and timing of founder events leading to increased frequencies of recessive diseases in Ashkenazi Jewish populations.