Genetics and Historical Demography of the Ashkenazim

描述（由申请人提供）：本研究的目的是测试长期存在的对立假设，这些假设为为什么在德系犹太人中存在如此高的导致疾病表型的突变提供了解释。该方法结合了理论和实证方法。首先，根据历史记录构建了德系犹太人人口历史的计算机模型。模拟了遗传进化，并利用蒙特卡罗程序对获得的观测遗传数据的概率进行了评估。一种似然方法将用于区分相互竞争的假设和模型的参数化。实证方法包括调查大量的微卫星位点，以及被认为代表欧洲德系犹太人殖民的不同阶段的几个人群的主要组织相容性复合体序列变异。这两个基因数据集将测试遗传瓶颈的可能性。如果发现了瓶颈，并且其他数据与低长期有效规模的人口模型相一致，这表明选择在从小种群中去除有害突变方面可能是低效的。然而，如果没有证据表明存在瓶颈，这表明最近的人口扩张可以大大增加有害突变的频率。

DESCRIPTION (provided by applicant): The purpose of this research is to test long-standing rival hypotheses that offer explanations for why there is such a high prevalence of mutations that cause disease phenotypes among the Ashkenazi Jews. The approach integrates a theoretical and empirical approach. First a computer model of Ashkenazi demographic history is constructed from historical records. Genetical evolution is simulated and probabilities of obtained observed genetic data are evaluated with a Monte Carlo procedure. A likelihood method will used to distinguish among competing hypotheses and parameterizations of models. The empirical approach consists of surveying a large number of microsatellite loci, as well as major histocompatibility complex sequence variation in several populations thought to represent the various stages of Ashkenazi colonization of Europe. These two genetic datasets will be tested for the possibility of a genetic bottleneck. If a bottleneck is found and other data are consistent with a demographic model of low long-term effective size, this suggests that selection can be inefficient at removing deleterious mutations from small populations. However, should there be no evidence for a bottleneck, this suggests that recent population's expansion can greatly increase the frequency of deleterious mutations.