mutations of different molecular origins exhibit contrasting patterns of regional substitution rate variation突变不同分子起源的展览区域替代率变化的对比模式.pdfVIP

Mutations of Different Molecular Origins Exhibit Contrasting Patterns of Regional Substitution Rate Variation 1. 1.¤ 2 3 1 Navin Elango , Seong-Ho Kim , NISC Comparative Sequencing Program , Eric Vigoda , Soojin V. Yi * 1 School of Biology, Georgia Institute of Technology, Atlanta, Georgia, United States of America, 2 Genome Technology Branch and NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America, 3 College of Computing, Georgia Institute of Technology, Atlanta, Georgia, United States of America Abstract Transitions at CpG dinucleotides, referred to as ‘‘CpG substitutions’’, are a major mutational input into vertebrate genomes and a leading cause of human genetic disease. The prevalence of CpG substitutions is due to their mutational origin, which is dependent on DNA methylation. In comparison, other single nucleotide substitutions (for example those occurring at GpC dinucleotides) mainly arise from errors during DNA replication. Here we analyzed high quality BAC-based data from human, chimpanzee, and baboon to investigate regional variation of CpG substitution rates. We show that CpG substitutions occur approximately 15 times more frequently than other single nucleotide substitutions in primate genomes, and that they exhibit substantial regional variation. Patterns of CpG rate variation are consistent with differences in methylation level and susceptibility to subsequent deamination. In particular, we propose a ‘‘distance-decaying’’ hypothesis, positing that due to the molecular mechanism of a CpG substitution, rates are correlated with the stability of double-stranded DNA surrounding