Beyond the Identification of Transcribed Sequences:
Functional, Evolutionary and Expression Analysis
12th International Workshop
October 25-28, 2002
Washington, DC

List of Abstracts * Speakers * Organizers * Authors * Original Announcement

Point Mutations Occur at a Faster Rate in Exons than in Noncoding DNA in Primate Genomes

Subashchandran Sankarasubramanian and Sudhir Kumar
Arizona State University, Tempe, AZ 85281 USA
Telephone: 480-965-2091
Fax: 480-965-2519

Currently point mutation rate in exons and noncoding (introns and intergenic) regions are assumed to be the same. However, comparative sequence analyses of synonymous substitutions in exons and that of long fragments of human and chimpanzee genomes reveal up to a 50% higher mutation rate in exons than in noncoding DNA. We propose a differential CpG content hypothesis to explain this fundamental, and seemingly unintuitive, pattern. Expectations and predictions of this hypothesis are confirmed in an analysis using 151 protein coding genes, 42 pseudogenes, 25 introns and 202 kb of intergenic region between human and chimpanzee, gorilla, orangutan, macaque and baboon comparisons. We find that the mutation rate in non-CpG sites is the same in noncoding DNA and in the synonymous sites of exons; the increased exonic rate is the result of the overabundance of CpG dinucleotides. The rate of CpG decay is approximately constant over time in human, apes and old world monkey genomes. These results explain the excessive human single nucleotide polymorphisms in exons compared to noncoding regions observed in a study by Cargill et al. (1999), suggest an underlying mechanism for the higher mutation rate in GC-rich genes, and provide a new tool for estimating divergence times between human populations and closely related primates.

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