DYNAMICS OF DNA REPEAT POLYMORPHISMS AND DISEASE

现在已知有几种人类疾病是由串联扩大引起的。 三核苷酸序列的重复。在基因组的所有这样的区域 在正常人群中发现了广泛的重复大小多态 个人。描述这些多态现象的文献越来越多 以快速的步伐；然而，这种重复的机制 疾病扩大的发生以及人群中疾病频率如何保持 目前还不能确切地知道。目前的实验数据表明， 重复大小的几种可供选择的分子机制的可能性 扩张，但它们对人口动态的影响 基因频率和疾病频率的变化 种群之间的差异并不为人所知。这个项目的总体目标是 通过提供数学种群遗传学来解决这些问题 重复扩展的模型，根据这些模型，关于基因的数据 频率和等位基因大小分布将在正常AS中进行研究 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 并因此可以解释观察到的基因分布 在这样的基因座上与转换后的等位基因大小存在差异 在易患疾病的家庭中的子女和父母。这些模型将是 使用分析和计算机模拟进行更详细的研究 方法，并将应用于通过我们的 合作者。这项研究的预期结果将是重要的。 提供对疾病基因起源的洞察以及 在何种条件下才能维持疾病流行。 该项目的结果也将与理解如何 重复三核苷酸序列的分子异质性 通过重复的大小扩张影响疾病的进展。

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.