DYNAMICS OF DNA REPEAT POLYMORPHISMS AND HUMAN DISEASE

在过去的两年中，通过我们自己以及其他人的工作，在了解以扩大形式引起疾病的三联体重复位点的遗传流行病学和发病机制方面取得了相当大的进展。然而，这种扩张的启动机制尚不清楚。我们自己的研究表明，正常大小范围内的等位基因突变对“预突变”阶段的等位基因库有重要贡献，这种突变机制通常可以用广义逐步突变模型（GSMM）来表述。此外，我们表明，三胞胎重复疾病的自然历史取决于人群相关因素。我们的研究产生了一个数学工具，马尔可夫突变凝聚（CMM），它能够模拟这种现象。我们建议研究CMM\的分析和计算特性，用于分析致病三联体重复多态性的等位基因大小分布数据，在正常个体以及携带者和受影响个体中。具体来说，我们的模型将纳入过去人口变化和人类种群进化史的影响。我们的目标是：(i)检测正常大小范围内等位基因的等位基因大小扩增/收缩突变偏倚的存在，如果存在偏倚，则检查其对这些位点上“预突变”等位基因频率的影响，（ii）检测突变率对等位基因大小的依赖，（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：（四）研究与人口有关的因素的影响；（五）设计统计检验并为检验假设进行幂次计算。最后，我们将评估这些因素对“突变前”等位基因用于疾病频率估计的预测效用的影响，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提供对致病突变的祖先以及疾病流行可以维持的条件的见解。这些改进的模型及其在全球数据中的应用也应该解释三联体重复序列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.