The influence of short indel heterozygosity on local nucleotide mutation rate

所有生物体的基因组都会发生突变，但是否有些生物体的突变比其他生物体更多？例如，在基因组中的给定位点上具有不同长度的重复DNA的个体是否更容易发生突变？为了研究这个问题，将使用下一代DNA测序技术来比较来自线虫实验种群的16个个体中长度不同的基因组位点的突变特性。DNA测序信息将被用于测试1）DNA短片段差异的位点是否比没有差异的位点突变更多，以及2）在长度不同的位点两侧的区域是否有更多的单DNA碱基突变。了解物种之间和物种内部突变特性的差异具有超越纯粹学术兴趣的意义。生活在工业化社会的大多数人会死于具有复杂遗传基础的疾病;例如，有许多微妙的遗传原因导致癌症。如果基因组突变率在一个物种内的个体之间存在显著差异，这将对如何最好地研究此类复杂疾病产生重大影响。特别是，需要根据对罕见变异在人群中的作用的更高认识，重新评估对激发人类疾病关联研究的“罕见变异/常见变异”概念框架的理解。如果个体在某一特定位点上具有不同长度的重复DNA，就容易发生突变，那么情况确实如此。

All organisms' genomes mutate, but do some mutate more than others? For example, are individuals with differing lengths of repetitive DNA at a given site in their genome more likely to mutate? To examine this question, next-generation DNA sequencing technology will be used to compare the mutational properties at genomic sites that differ in length in 16 individuals from an experimental population of nematode worms. The DNA sequencing information will be used to test whether 1) sites that differ by short stretches of DNA mutate more than sites that do not and 2) if there is a greater number of single DNA base mutations in the regions flanking the sites that differ in length.Understanding how differences in mutational properties differ between and within species has implications beyond pure academic interests. Most people who live in an industrialized society will die of diseases with a complex genetic basis; for example, there are a multitude of subtle genetic causes that lead to cancers. If genomic mutation rates differ significantly among individuals within a species, this would have a significant effect on how to best approach the study of such complex diseases. In particular, the understanding of the "rare variant/common variant" conceptual framework that motivates association studies of human diseases would need to be re-evaluated in light of a greater appreciation of the role of rare variants in the human population. If individuals with differing lengths of repetitive DNA at a given site are predisposed to mutation, this will indeed be the case.