STATISTICAL METHODS FOR STUDYING DISEASE GENE HISTORY

描述：（申请人摘要）人类基因组计划已经 产生了许多长的人类DNA序列 如此长的序列可能涵盖 一个完整的基因及其侧翼区域。 这一进步和 快速DNA测序技术的发展将使大规模DNA测序成为可能， 来自人类群体的样品的区域，特别是含有 致病突变 另一种方法是研究微卫星 与突变密切相关的标记。 该项目的目标是 发展群体遗传学理论、统计方法和计算机 算法研究的历史和机制的维护， 一个群体中的致病突变。 具体目标是：（1） 发展了一个DNA区域发生点突变的结合理论， 自然选择和重组，（2）发展一个联合理论， 微卫星位点经历逐步突变、自然选择和 重组 目前的聚结方法假设平衡群体， 并且不适合于研究最近的突变， 选择，如囊性纤维化的AF508突变。 我们建议 开发一种结合方法， 携带突变体的亚群的历史。 (3)开发方法， 估计年龄的疾病引起突变的DNA序列或从 微卫星标记 (4)开发评估选择的方法， 系数和用于检验关于选择系数的假设， 一种致病突变 我们将开发的方法之一是 每个位点的多态性数据，并且不需要确定 DNA单倍型序列。 因此，该方法将特别有用 当通过DNA对样品中的多态性进行大规模筛选时 “芯片”。 (5)为上述方法开发一套计算机程序， （6）应用理论和方法， 囊性纤维化的AF 508突变体的年龄和选择系数。

DESCRIPTION: (Applicant's abstract) The Human Genome Project has already produced numerous long human DNA sequences. Such a long sequence may cover an entire gene and also its flanking regions. This progress and the advent of rapid DNA sequencing techniques will allow the sequencing of large DNA regions of samples from human populations, especially regions containing a disease-causing mutation. Alternatively, one may study microsatellite markers closely linked to the mutation. The goal of this project is to develop population genetics theory, statistical methods and computer algorithms for studying the history and the mechanism of maintenance of a disease-causing mutation in a population. The specific aims are (1) to develop a coalescent theory for a DNA region subject to point mutation, natural selection and recombination, (2) to develop a coalescent theory for microsatellite loci subject to stepwise mutation, natural selection and recombination. Current coalescent methods assume an equilibrium population, and are not appropriate for studying a recent mutation subject to natural selection, such as the AF508 mutation of cystic fibrosis. We propose to develop a coalescent approach incorporating a method for simulating the history of the subpopulation bearing the mutant. (3) to develop methods for estimating the age of a disease causing mutation from DNA sequences or from microsatellite markers. (4) to develop methods for estimating the selection coefficients and for testing hypotheses about the selection coefficients of a disease-causing mutation. One of the methods we will develop is for site-by-site polymorphism data, and does not require the determination of DNA haplotype sequences. Therefore, the method will be particularly useful when large scale screening of polymorphisms in a sample is done by DNA "chips". (5) to develop a computer package for the above methods accessible on the World Wide Web, and (6) to apply the theory and methods to estimate the age and selection coefficients of the AF508 mutant of cystic fibrosis.