A genetic approach to quantifying human in vivo mutation frequency uncovers transcription level effects

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 10–1000× 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.