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染色体的非重组部分的全球变异模式，以研究塑造人类基因组变异的力量，并检验关于人类历史和人口统计学的假设。这项研究的动机是需要增加我们对人类历史和进化力量的了解，这些力量使某些人群易患遗传疾病。总体设计将筛选来自11个人群的550条染色体样本中NRY上的16千碱基（kb），非d环mtDNA上的3 kb，两个X染色体位点（一个低重组基因和一个高重组基因）各3至5 kb的核苷酸变异，以及来自世界26个人群的50名男性的全球样本。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策略，并将为测试与人口统计历史和人口结构、非洲与非非洲遗传变异的不同模式以及男性与女性迁移率有关的许多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，应该可以解开基因座特异性因素和各种种群水平力量形成的人类基因组多样性的相对影响。这项研究也将集中于区域尺度的问题，特别强调最近人口分散的遗传后果。具体来说，它将把犹太流散发展为一个模型系统，并将测试有关导致德系犹太人群体隐性疾病频率增加的创始人事件的数量和时间的假设。

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.