Population Mixture Effects on Genetic Variation

随着该项目进入第14个年头，总体目标仍然是描述种群混合对遗传变异的影响，并将其与遗传连锁和过去的人口变化区分开来。随着基因组研究中新的实验室和计算方法的引入，现在人们普遍认为，基因及其与环境/生活方式风险因素的相互作用的映射可以成功地进行基于人群的关联研究设计，并适当考虑可能影响群体水平基因关联的进化因素。基于过去在这个项目中所做的工作和其他研究人员，我们建议解决的问题，人口混合物的影响：（一）单块大小和模式;（二）有效的选择标记和标记密度的策略;和（三）的方法调整的情况下和控制的隐藏的差异，使关联研究设计的成本效益，并不容易出现假阳性结果。使用分析以及基于聚结和扩散模型理论的计算机模拟方法，我们将研究基于SNP的研究对上述问题的推论的影响。最后，利用我们研究小组从五个选定人群中收集的匿名DNA库，（两个混血儿-美国非裔美国人和来自新莱昂的墨西哥混血儿;两个世界主义者-美国高加索人和中国人;和克罗地亚亚得里亚海群岛的一个小的孤立的人口），我们将产生关于单倍型特征的相似性/不相似性的经验数据，利用微卫星和SNP进行了一系列的理论和实证研究，以探讨群体混合对连锁不平衡特性的影响，并通过LD开发更好的关联作图策略。 标记。这些数据，除了分析和模拟工作，将规定界限的参数下，混合和/或非平衡人口可以用于复杂的疾病研究。该项目的结果将有助于（a）在不同混合历史的人群中使用重复和SNP标记制定基因定位策略，以及（B）了解复杂表型背后的突变的历史和全球传播。

As this project enters in its 14th year, the over-all objectives still remain the characterization of the effects of population mixtures on genetic variation, and differentiation of this from that of genetic linkage and past demographic changes. With introduction of newer laboratory and computational methods in genomic studies, it is now widely accepted that mapping of genes and their interactions with environmental/life style risk factors can be successfully conducted using population-based association study designs, with appropriate considerations of evolutionary factors that may affect association of genes at population level. Based on the past work done in this project and by other investigators, we propose to address the issues of effects of population mixtures on: (i) haploblock size and pattern; (ii) strategies for efficient choice of markers and marker densities; and (iii) methods of adjustments for cryptic differences of cases and controls, so as to make the association study designs cost-effective, and less prone to false positive results. Using analytical as well as computer simulations methods based on the theory of coalescence and diffusion models, we will examine the effects of SNP based studies on the inferences of the above issues. Finally, using the anonymous DNA repositories of our study team from five selected populations (two admixed - US African-Americans, and Mexican Mestizo from Nuevo Leon; two cosmopolitans - US Caucasians, and Chinese; and one small isolated population from Adriatic Islands of Croatia), we will generate empirical data on similarities/dissimilarities of the characteristics of haplotype/haploblocks and choice of markers for 2 to 3 selected regions of the genome, using both microsatellite and SNP a series of theoretical and empirical studies to investigate the effects of population admixture of properties of linkage disequilibrium and to develop better strategies for association mapping through LD. markers. Such data, in addition to the analytical and simulation work, will prescribe bounds for parameters under which mixed and/or non-equilibrium populations can be used for complex disease studies. The results of this project will aid (a) in developing strategies of mapping genes using repeat as well as SNP markers in populations of different mixture histories, and (b) in understanding the history and global spread of mutations underlying complex phenotypes.