Models of Complex Genetic Systems

描述（由申请人提供）：拟议的研究将是数学和统计模型，可用于分析和解释人类和其他人群的遗传数据。总体目标是开发可靠的和计算效率高的数据分析方法，以揭示是什么力量决定了现有的遗传变异模式。在这个建议中，重点是在一个单一的基因座和等位基因（单倍型）在紧密连锁的基因座的频率的地理变异模式。等位基因的地理分布可以揭示当代和过去的扩散模式，紧密连锁的基因座上等位基因之间的关联强度可以揭示过去的人口增长、人口分裂和人口融合，并表明影响基因组区域的自然选择类型。拟议中的研究将涉及对生物体的适应性没有影响的等位基因和已知或怀疑具有适应性影响的等位基因。研究计划将依靠分析和计算机模拟方法。作为研究项目的一部分开发的计算机程序可从主要研究者的网站获得。拟议的研究有几个实际目标。它将有助于绘制具有影响人类遗传性疾病风险的等位基因的基因座，并表明这些等位基因是否受到自然选择的影响。(2)它将揭示自然选择影响主要组织相容性复合体（MHC）基因座的程度，这些基因座在人类免疫反应中起着重要作用，在人群中存在差异。(3)它将表明基因组区域（啮齿动物和人类之间）的长期保护可以预测人类和黑猩猩内部和之间的DNA序列变异模式的程度，从而帮助选择潜在的人类遗传疾病和复杂表型性状的候选基因座。(4)它将表明人类遗传变异的模式如何反映近代和古代的人口增长和运动。

DESCRIPTION (provided by applicant): The proposed research will be on mathematical and statistical models that can be used for the analysis and interpretation of genetic data from human and other populations. The overall goal is to develop reliable and computationally efficient methods of data analysis that will reveal what forces determine existing patterns of genetic variation. Emphasis in this proposal is on patterns of geographic variation in the frequencies of alleles at a single locus and to sets of alleles (haplotypes) at closely linked loci. The geographic distribution of alleles can reveal contemporary and past patterns of dispersal and the strength of association between alleles at closely linked loci can reveal past episodes of population growth, population fission and population fusion and indicate the kind of natural selection that has been affecting a genomic region. The proposed research will be concerned both with alleles that have no effect on the fitness of an organism and with alleles known or suspected to have fitness effects. The research program will rely on both analysis and computer simulation methods. Computer programs developed as part of the research program will be available from the Principal Investigator's web site. The proposed research has several practical goals. It will facilitate the mapping of loci with alleles affecting the risk of inherited diseases in humans and indicate whether those alleles have been affected by natural selection. (2) It will reveal the extent to which natural selection affecting loci in the major histocompatibility complex (MHC), which play an important role in the immune response in humans, varies among populations. (3) It will indicate the extent to which long term conservation of genomic regions (between rodents and humans) can predict patterns of DNA sequence variation within and between humans and chimpanzees, thereby helping with the choice of candidate loci underlying human genetic diseases and complex phenotypic traits. (4) It will indicate how patterns of genetic variation in humans reflect recent and ancient population growth and movement.