Theoretical Population Genetics

描述(由申请者提供)：该项目致力于开发新的人口遗传数据统计方法。将重点关注与等位基因之间的相关性有关的三个主要领域：群体结构的特征，遗传标记内部和之间以及沿单倍型的关联模式的特征，以及个体的亲缘关系和近亲繁殖的特征。理论的发展至少部分是为了应对当前人类SNP大规模调查的需要，以及对全基因组序列数据集的预期。这项工作是由华盛顿大学生物统计学系的一组研究人员提出的。他们提议继续与爱丁堡大学的W.G.希尔和昆士兰医学研究所的P.M.Visscher合作。正如一套40份出版物所证明的那样，这个扩大的小组在前一个授标期间成功地进行了互动。S.R.和B.L.Browning的Beagle方法将被应用于通过血统检测身份的区域。由此产生的相关性测量将用于改进标记与疾病关联的测试，并估计复杂人类特征的遗传力。由B.S.Weir和W.G.Hill描述的种群结构的特定于种群的措施将应用于最近发表的全基因组SNP数据集和全基因组序列数据集。将寻求改进对这些量进行推断的方法。通过血统和种群结构衡量身份，有可能确定人类基因组中受自然选择影响的区域，在进行这些分析时将注意到进化过程造成的巨大变异和偏斜。C.C.Laurie和B.S.Weir通过检查单个SNPs与来自大量SNPs的主成分的相关性来检测染色体特征(如倒位)的工作将得到扩展。引入的QTL定位的偏回归方法将应用于这一问题。不依赖于基因阶段的连锁不平衡方法被引入，并且以前已经被这些研究人员使用过。它们现在将扩展到当每个基因都有几个SNPs分型时，两个座位对之间不平衡的情况。关联作图继续引起人类遗传学家的极大兴趣，并将解决考虑(即使是低水平的)关联的问题。例如，在一项病例对照研究中，忽视至少有一个亲属的个人可能会导致权力的丧失。Y.Choi和B.S.Weir之前对简单等位基因关联检验的改进工作将扩展到更合适的Logistic回归方法。

DESCRIPTION (provided by applicant): This project is concerned with developing new statistical methodology for population genetic data. Attention will be focused on three main areas concerned with dependencies among sets of alleles: the characterization of population structure, the characterization of the association patterns within and between genetic markers and along haplotypes, and the characterization of relatedness and inbreeding for individuals. Theory will be developed at least in part in response to the needs of current large-scale SNP surveys for humans and in anticipation of whole-genome sequence data sets. The work is proposed by a group of investigators in the Department of Biostatistics at the University of Washington. They propose to continue collaboration with W.G. Hill at the University of Edinburgh and P.M. Visscher at the Queensland Institute of Medical Research. This extended group has interacted successfully over the previous award period, as evidenced by a set of 40 publications. The Beagle approach of S.R. and B.L. Browning will be applied to the detection of tracts of identity by descent. The resulting measures of relationship will be used to refine tests for marker-disease association and to estimate heritability of complex human traits. The population-specific measures of population structure described by B.S. Weir and W.G. Hill will be applied to recently published whole-genome SNP data sets and whole-genome sequence data sets. Methods will be sought to improve methods of drawing inferences about these quantities. Measures of identity by descent and of population structure have the potential to identify regions of the human genome that have been subject to natural selection, and these analyses will be conducted with attention to the large variation and skewness imposed by the evolutionary process. The work of C.C. Laurie and B.S. Weir on detecting chromosomal features, such as inversions, by examining correlations of individual SNPs with principal components derived from large sets of SNPs will be extended. The partial regression approach introduced for QTL mapping will be applied to this problem. Measures of linkage disequilibrium that do not depend on genotypic phase were introduced and have been used previously by these investigators. They will now be extended to the situation of disequilibrium between pairs of loci when several SNPs typed for each gene. Association mapping continues to be of considerable interest to human geneticists and the problem of accounting for (even low level) relatedness will be addressed. Ignoring individuals with at least one relative in a case-control study, for example, can lead to a loss of power. Previous work of Y. Choi and B.S. Weir that modified simple allelic association tests will be extended to the more appropriate logistic regression methods.