Microsatellites in the Eukaryotic DNA Mismatch Repair Genes as Modulators of Evolutionary Mutation Rate
- Dong Kyung Chang1,
- David Metzgar2,
- Christopher Wills2,3, and
- C. Richard Boland1,4
- 1Department of Medicine and Cancer Center, 2Department of Biology, and 3Center for Molecular Genetics, University of California San Diego, La Jolla, California 92093-0688, USA
This extract was created in the absence of an abstract.
All “minor” components of the human DNA mismatch repair (MMR) system—MSH3, MSH6, PMS2, and the recently discovered MLH3—contain mononucleotide microsatellites in their coding sequences. This intriguing finding contrasts with the situation found in the “major” components of the DNA MMR system—MSH2 and MLH1—and, in fact, most human genes. Although eukaryotic genomes are rich in microsatellites, nontriplet microsatellites are rare in coding regions. The recurring presence of exonal mononucleotide repeat sequences within a single family of human genes would therefore be considered exceptional.
A study of 10,000 random primate (primarily human) coding sequences (8.6 million base pairs) showed that the average-sized sequence coding for a human gene is expected to contain approximately 0.1, 0.03, and 0.006 mononucleotide runs of length 7 bp or more, 8 bp or more, and 9 bp or more, respectively (Metzgar et al. 2000). Together, the four minor MMR genes contain three 7-bp runs, four 8-bp runs, and one 9-bp run. By nature of their form and position within the genes, these runs do not appear to be evolutionarily homologous. The probability of finding this many mononucleotide microsatellites by chance in a group of four genes is 3.2 × 10−7(0.43 × 0.124 × 0.024). Controlling for gene length yields a probability of 1.3 × 10−6. Therefore, the human minor MMR genes contain a significant excess of mononucleotide repeats. The probability would be even lower if the calculation included the MED1 (MBD4) gene, considered by some to be another minor MMR gene, which has an exonal 10-bp polyadenosine sequence.
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