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，并将其与遗传联系和过去的人口变化区分开来。随着新的实验室和计算方法在基因组研究中的引入，现在人们普遍认为，利用基于群体的关联研究设计，在适当考虑可能影响种群水平上基因关联的进化因素的情况下，可以成功地进行基因图谱及其与环境/生活方式风险因素的相互作用。基于本项目和其他研究人员过去所做的工作，我们建议解决群体混合对以下方面的影响问题：(I)单倍区大小和模式；(Ii)有效选择标记和标记密度的策略；以及(Iii)调整病例和对照的隐蔽差异的方法，以使关联研究设计具有成本效益，并且不容易出现假阳性结果。利用基于合并和扩散模型理论的分析和计算机模拟方法，我们将检验基于SNP的研究对上述问题推论的影响。最后，利用我们研究团队来自五个选定群体(两个混杂的美国非裔美国人和来自新莱昂的墨西哥梅斯蒂佐；两个世界都会的美国高加索人和中国人；以及一个来自克罗地亚亚得里亚海群岛的小而孤立的群体)的匿名DNA储存库，我们将产生关于单倍型/单倍块特征的异同以及选择基因组2到3个选定区域的标记的经验数据，利用微卫星和SNP进行一系列理论和实证研究，以探讨群体混合对连锁不平衡特性的影响，并通过LD开发更好的关联图谱策略。记号笔。除了分析和模拟工作之外，这些数据还将规定可用于复杂疾病研究的混合和/或非平衡总体的参数范围。该项目的结果将有助于(A)开发利用重复和SNP标记在不同混合历史的人群中定位基因的策略，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.