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人口变化的影响区分开来。随着基因组研究中更新的实验室和计算方法的引入，现在人们普遍认为，使用基于群体的关联研究设计，适当考虑可能影响群体水平基因关联的进化因素，可以成功地进行基因定位及其与环境/生活方式风险因素的相互作用。基于本项目和其他研究者过去所做的工作，我们建议解决种群混合对单倍体大小和模式的影响问题；（ii）有效选择标记物和标记物密度的策略；（iii）对病例和对照组的隐性差异进行调整的方法，以使关联研究设计具有成本效益，并且不易出现假阳性结果。利用基于聚结和扩散模型理论的分析方法和计算机模拟方法，我们将研究基于SNP的研究对上述问题推论的影响。最后，使用我们研究小组从五个精选人群中选取的匿名DNA库(两个混血儿——美国非洲裔美国人和来自新莱昂州的墨西哥混血儿；两个世界混血儿——美国高加索人和中国人；克罗地亚和一个小型孤立的人口从亚得里亚海岛屿),我们将生成经验数据相似性/单体型的特点的不同/ haploblocks的标记和选择2到3选择的基因组区域,使用微卫星和SNP的一系列理论和实证研究调查的影响人口外加剂的连锁不平衡的性质和开发协会更好的策略映射通过很标记。这些数据，除了分析和模拟工作之外，将规定参数的界限，在这个界限下，混合和/或非平衡种群可以用于复杂疾病的研究。该项目的结果将有助于(a)在不同混合历史的群体中使用重复和SNP标记制定基因定位策略，以及(b)了解复杂表型下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.