hypermutable non-synonymous sites are under stronger negative selectionhypermutable非同义网站受到更强的负选择.pdfVIP

Hypermutable Non-Synonymous Sites Are under Stronger Negative Selection 1,2. 3,4. 5 1 Steffen Schmidt , Anna Gerasimova , Fyodor A. Kondrashov , Ivan A. Adzuhbei , Alexey S. 3,4 1 Kondrashov *, Shamil Sunyaev * 1 Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America, 2 Department of Biochemistry, Max ¨ Planck Institute for Developmental Biology, Tubingen, Germany, 3 Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, United States of America, 4 Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan, United States of America, 5 Section on Ecology, Behavior, and Evolution, Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America Abstract Mutation rate varies greatly between nucleotide sites of the human genome and depends both on the global genomic location and the local sequence context of a site. In particular, CpG context elevates the mutation rate by an order of magnitude. Mutations also vary widely in their effect on the molecular function, phenotype, and fitness. Independence of the probability of occurrence of a new mutation’s effect has been a fundamental premise in genetics. However, highly mutable contexts may be preserved by negative selection at important sites but destroyed by mutation at sites under no selection. Thus, there may be a positive correlation between the rate of mutations at a nucleotide site and the magnitude of their effect on fitness. We studied the impact of CpG context