DYNAMICS OF DNA REPEAT POLYMORPHISMS AND DISEASE

现在已知有几种人类疾病是由串联的 三核苷酸序列的重复。在基因组的所有这些区域 在正常人中发现了广泛的重复序列多态性， 个体描述这些多态性的文献越来越多 然而，这种重复的机制 如何在人群中维持疾病频率 目前还不清楚目前的实验数据表明， 重复大小的几种替代分子机制的可能性 扩张，但其后果方面的人口动态 基因型频率和疾病频率的变化， 种群之间的差异并不为人所知。该项目的主要目标是 为了解决这些问题， 重复扩增模型，根据基因型数据 频率和等位基因大小分布将在正常情况下进行研究， 以及受影响的个人。该小组所做的初步工作 研究人员指出，有限维马尔可夫突变模型， 分支过程理论和聚结理论可以提供很好的 重复的各种“突变”机制的数学描述 因此可以解释观察到的基因型分布 在这样的基因座和等位基因大小差异之间的过渡 在易患病家庭中的后代和父母。这些模型将在 使用分析和计算机模拟进行更详细的研究 方法，并将应用于人口数据，通过我们的 合作者这项研究的预期结果将是重要的 在提供深入了解疾病基因的祖先，以及 疾病流行的条件。 该项目的成果也将有助于了解 串联重复三核苷酸序列的分子异质性 通过重复大小扩增影响疾病进展。

Several human diseases are now known to be caused by expansion of tandem repeat of trinucleotide sequences. At all such regions of the genome extensive polymorphisms of repeat sizes are found among normal individuals. The literature characterizing these polymorphisms is growing at a rapid pace; however, the mechanism through which such repeat expansion occurs and how disease frequencies are maintained in populations is not yet known precisely. Current experimental data imply the possibility of several alternative molecular mechanisms of repeat size expansion, but their consequences with respect to the population dynamics of genotype frequencies and to disease frequency variation within and between populations are not well known. The broad aim of this project is to address these questions by providing mathematical population genetic models of repeat expansions, in light of which data on genotype frequencies and allele size distributions will be studied in normal as well as affected individuals. Preliminary work done by this group of researchers indicates that finite dimensional Markovian mutation models, the theory of branching processes and coalescence theory can provide good mathematical descriptions of various "mutational" mechanisms of repeat size expansions and can thus explain the observed genotype distributions at such loci and the transition of allele size differences between offspring and parents in disease-prone families. These models will be pursued in greater detail using analytical as well as computer simulation methods, and will be applied to population data available through our collaborators. The anticipated results of this study will be significant in providing insight into the ancestry of the disease genes as well as into the conditions under which disease prevalence can be maintained. Outcomes of this project will also be relevant for understanding how molecular heterogeneity at tandemly repeating trinucleotide sequences affects disease progression through repeat size expansions.