Department of Biology, Faculty of Science and Engineering, York University, Toronto, Ontario, Canada.
Mutat Res. 2009 Nov 2;670(1-2):68-73. doi: 10.1016/j.mrfmmm.2009.07.008. Epub 2009 Jul 25.
Much attention has been paid to polymorphisms, germline mutations, copy number variations and other inherited forms of genetic disparity among individuals. Less attention, except in the area of tumor formation, has been given to somatic changes to the genome -- changes which have the potential to affect all areas of human health. Discussions of somatic mutations in disease must begin with an understanding of the underlying spontaneous mutation rate/frequency. Previous assays of spontaneous mutant frequency relied on peptide display or function -- a selective step that limits the type of mutations detected. In order to obtain mutation frequencies through unbiased means we used a purely genetic approach to quantitate spontaneous in vivo mutant frequency from human blood cells. Using the constitutively expressed, essential gene Dihydrolipoamide dehydrogenase (DLD) we found mutational frequencies on the order of one mutation per kilobasepair. This is 10-1000x higher than previously reported spontaneous mutant frequencies which depended on a selective step. Our genomic based methods also revealed a role for transcription levels in somatic mutation generation and/or accumulation.
人们非常关注个体间的多态性、种系突变、拷贝数变异和其他遗传形式的遗传差异。除了在肿瘤形成领域，人们对基因组的体细胞变化（有可能影响人类健康的所有领域）关注较少。在讨论疾病中的体细胞突变时，必须首先了解潜在的自发突变率/频率。先前对自发突变频率的检测依赖于肽展示或功能——这是一个限制检测到的突变类型的选择步骤。为了通过无偏的方法获得突变频率，我们使用纯粹的遗传方法从人血细胞中定量自发的体内突变频率。使用组成型表达的必需基因二氢硫辛酰胺脱氢酶 (DLD)，我们发现突变频率约为每千碱基对一个突变。这比以前依赖选择步骤的报告的自发突变频率高 10-1000 倍。我们基于基因组的方法还揭示了转录水平在体细胞突变产生和/或积累中的作用。
