The influence of short indel heterozygosity on local nucleotide mutation rate

所有生物的基因组都会发生突变，但其中一些突变会比另一些更多吗？例如，在基因组的某一特定位置具有不同长度重复DNA的个体是否更有可能发生突变？为了研究这个问题，下一代DNA测序技术将被用来比较线虫实验种群中16个个体长度不同的基因组位置的突变特性。DNA测序信息将被用来测试1)DNA短片段不同的位点是否比没有短片段的位点突变更多，2)长度不同的位点两侧的区域是否存在更多的单DNA碱基突变。了解物种之间和物种内突变特性的差异具有纯粹的学术兴趣以外的意义。生活在工业化社会的大多数人都会死于具有复杂遗传基础的疾病；例如，有许多微妙的基因原因导致癌症。如果一个物种内不同个体的基因组突变率显著不同，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，需要根据对稀有变种在人类群体中的作用的更多认识，重新评估对推动人类疾病关联研究的“罕见变种/常见变种”概念框架的理解。如果在某一特定位置具有不同长度重复DNA的个体容易发生突变，情况确实会是这样。

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.