DYNAMICS OF DNA REPEAT POLYMORPHISMS AND HUMAN DISEASE

在过去的两年里，通过我们自己的工作以及其他人的工作，在理解三重重复基因座的遗传流行病学和致病机制方面取得了相当大的进展，这些重复基因座导致疾病的扩大形式。然而，这种扩张的启动机制还不是很清楚。我们自己的工作表明，正常大小范围内的等位基因突变对“前突变”阶段的等位基因库有很大贡献，这种突变机制(S)通常可以用广义逐步突变模型来描述。此外，我们还表明，三联体重复疾病的自然历史取决于与人口相关的因素。我们的研究产生了一个数学工具，结合马尔可夫突变(CMM)，它能够模拟这种现象。我们建议研究CMM在分析致病三重重复多态的等位基因大小分布数据时，在正常个体以及携带者和患病个体中的分析和计算特性。具体地说，我们的模型将纳入过去人口变化和人类人口进化史的影响。我们的目标是：(I)检测正常大小范围内的等位基因是否存在等位基因大小扩展/收缩突变偏差，如果存在偏差，则检查其对这些基因座“前突变”等位基因频率的影响；(Ii)检测突变率的等位基因大小依赖关系；(Iii)检查自然选择在维持等位基因“正常”重复大小变异中的作用。根据这些目标开发的模型将用于以下方面：(4)研究与人口有关的因素的影响；(5)设计统计检验和进行假设检验的能力计算。最后，(Vi)我们将评估这些因素对用于疾病频率估计的“预突变”等位基因的预测效用的影响，以及对疾病筛查的样本量要求的影响。这项研究的预期结果应该能洞察致病突变的起源，以及疾病流行能够维持的条件。这些精细化的模型及其对全球数据的应用也应该解释三联体重复的分子异质性如何影响疾病进展。

During the past two years, through our own work as well as by others, considerable progress has been made in understanding the genetic epidemiology and pathogenesis of triplet repeat loci which cause disease in expanded form. However, the mechanism of initiation of this expansion is not well understood. Our own work indicates that mutation at alleles in the normal size range contribute significantly to allele pools of the "premutation" stage, and that such mutation mechanism(s) can, in general, be formulated as a Generalized Stepwise Mutation Model (GSMM). Further, we showed that the natural history of triplet repeat diseases depends on population-related factors. Our study produced a mathematical tool, the Coalescent with Markov Mutations (CMM), which is capable of modeling this phenomenon. We propose to study the analytical and computational properties of the CMM\ when used to analyze data on allele size distributions at disease-causing triplet repeat polymorphisms, in normal individuals as well as in carrier and affected individuals. Specifically, our models will incorporate the impact of past demographic changes and the evolutionary history of human populations. Our aims are: (i) to detect the presence of allele-size expansion/contraction mutation bias for alleles in the normal size range and, if bias exists, to examine its affect on the frequency of "premutation" alleles at these loci, (ii) to detect allele size dependence of mutation rates, and (iii) to examine the role of natural selection in the maintenance of "normal" repeat-size variation of alleles. Models developed under these aims will be used as follows: (iv) to study the impact of population-related factors and (v) to design statistical tests and to conduct power computations for hypotheses testing. Finally, (vi) we will assess the impact of these factors on the predictive utility of "premutation" alleles for disease frequency estimation and on sample size requirements for disease screening. The anticipated results of this study should provide insight into the ancestry of disease-causing mutations as well as into the conditions under which disease prevalence can be maintained. These refined models and their applications to world-wide data should also explain how the molecular heterogeneity of triplet repeats affects disease progression.