MODELS OF COMPLEX GENETIC SYSTEMS

拟议研究的总体目标是发展数学和 可用于解释人类基因数据的统计模型 和非人类群体。这样的模特。有必要提供 对不同遗传过程的定量预测，并允许 对有关基因变化机制的假设进行统计检验。 拟议的研究将集中在五个与 要分析的数据类型和数学模型的类型 将使用的方法。这些区域是(A)等位基因的地理模式 频率和DNA序列，(B)随机重复的多基因家族， (C)对细胞核中鸟嘌呤和细胞素含量的自然选择 基因组，(D)核苷酸位置之间的替换率差异，以及 (E)克隆繁殖物种的遗传学。将会有特别的 强调由突变、基因漂移、自然引起的基因变化 基因内紧密连锁位置的选择和基因流动 紧密连锁的微卫星基因座。微卫星基因座之间存在关联 人类至少有三种遗传性疾病(脆性X综合征， 强直性肌营养不良和肯尼迪病)，所以它特别重要 为了了解控制等位基因大小分布的过程 这样的基因座存在于高等植物的核基因组中 动物。 分析方法和计算机模拟方法的结合将用于 建议的研究。分析理论将提供全面的 用于理解在每种情况下建模的流程的框架和 计算机模拟模型将允许探索 从分析模型获得的结果的稳健性和将 提供了一种方法来测试所开发方法的统计能力。为 选择性中性等位基因的模型，大多数分析理论将是 基于合并的方法，在这种方法中，基因的祖先或 对样本中的站点进行建模。中性点的计算机仿真模型 等位基因也将基于合并的方法。

The overall goal of the proposed research is to develop mathematical and statistical models that can be used to interpret genetic data from human and nonhuman populations. Such models. are necessary to provided quantitative predictions of different genetic processes and to permit the statistical testing of hypotheses concerning mechanisms of genetic change. The proposed research will focus on five areas that are closely related in the kinds of data that will be analyzed and the kinds of mathematical methods that will be used. The areas are (a) geographic patterns in allele frequencies and DNA sequences, (b) tandemly repeated multigene families, (c) natural selection on guanine and cytocine content in the nuclear genome, (d) variation among nucleotide sites in substitution rates, and (e) genetics of clonally reproducing species. There will be particular emphasis on genetic changes caused by mutation, genetic drift, natural selection and gene flow at closely linked sites within a gene and at closely linked microsatellite loci. Microsatellite loci are associated with at least three genetic diseases in humans (fragile X syndrome, myotonic dystrophy, and Kennedy's disease) so it is especially important to understand the processes governing the distribution of allele sizes at such loci, which are found throughout the nuclear genomes of higher animals. A combination of analytic and computer simulation methods will be used in the proposed research. The analytic theory will provide the overall framework for understanding the processes modeled in each case and the computer simulation models will allow for the exploration of the robustness of the results obtained from the analytic models and will provide a way to test the statistical power of the methods developed. For models of selectively neutral alleles, most of the analytic theory will be based on the method of coalescents, in which the ancestry of genes or sites in a sample is modeled. Computer simulation models of neutral alleles will also be based on the coalescent approach.