Models of Complex Genetic Systems

描述（由申请人提供）：提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和计算效率高的数据分析方法，揭示决定现有遗传变异模式的力量。本提案的重点是在单个位点上的等位基因频率的地理变异模式和在紧密相连的位点上的等位基因组（单倍型）。等位基因的地理分布可以揭示当代和过去的扩散模式，而在紧密相连的位点上的等位基因之间的联系强度可以揭示过去的种群增长、种群裂变和种群融合，并表明影响一个基因组区域的那种自然选择。拟议的研究将涉及对生物体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。该研究计划将依靠分析和计算机模拟方法。作为研究计划的一部分开发的计算机程序将在首席研究员的网站上提供。拟议的研究有几个实际目标。它将有助于绘制影响人类遗传疾病风险的等位基因位点，并表明这些等位基因是否受到自然选择的影响。(2)揭示自然选择对主要组织相容性复合体（MHC）基因座的影响程度，MHC在人类免疫应答中起着重要作用。(3)它将表明基因组区域（啮齿动物和人类之间）的长期保存能在多大程度上预测人类和黑猩猩内部和之间的DNA序列变异模式，从而有助于选择潜在人类遗传疾病和复杂表型性状的候选位点。(4)它将表明人类遗传变异的模式如何反映近代和古代人口的增长和迁移。

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.