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，在了解导致疾病扩展形式的三联体重复基因座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。 我们自己的工作表明，正常大小范围内等位基因的突变对“前突变”阶段的等位基因库有显着贡献，并且这种突变机制通常可以表述为广义逐步突变模型（GSMM）。此外，我们表明三联体重复疾病的自然史取决于与人群相关的因素。 我们的研究产生了一种数学工具，即马尔可夫突变合并（CMM），它能够对这种现象进行建模。我们建议研究 CMM 在用于分析正常个体以及携带者和受影响个体中致病三联体重复多态性的等位基因大小分布数据时的分析和计算特性。 具体来说，我们的模型将纳入过去人口变化和人类进化历史的影响。 我们的目标是：（i）检测正常大小范围内等位基因是否存在等位基因大小扩张/收缩突变偏差，如果存在偏差，则检查其对这些位点上“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性，以及（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用途：（iv）研究人口相关因素的影响，以及（v）设计统计检验并进行假设检验的功效计算。 最后，（vi）我们将评估这些因素对疾病频率估计的“前突变”等位基因的预测效用以及疾病筛查的样本量要求的影响。 这项研究的预期结果应有助于深入了解致病突变的起源以及疾病流行得以维持的条件。 这些改进的模型及其在全球数据中的应用还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.