PMID: 8940269Dec 1, 1996Paper

Age and origin of two common MLH1 mutations predisposing to hereditary colon cancer

American Journal of Human Genetics
A L MoisioP Peltomäki

Abstract

Two mutations in the DNA mismatch repair gene MLH1, referred to as mutations 1 and 2, are frequent among Finnish kindreds with hereditary nonpolyposis colorectal cancer (HNPCC). In order to assess the ages and origins of these mutations, we constructed a map of 15 microsatellite markers around MLH1 and used this information in haplotype analyses of 19 kindreds with mutation 1 and 6 kindreds with mutation 2. All kindreds with mutation 1 showed a single allele for the intragenic marker D3S1611 that was not observed on any unaffected chromosome. They also shared portions of a haplotype of 4-15 markers encompassing 2.0-19.0 cM around MLH1. All kindreds with mutation 2 shared another allele for D3S1611 and a conserved haplotype of 5-14 markers spanning 2.0-15.0 cM around MLH1. The degree of haplotype conservation was used to estimate the ages of these two mutations. While some recessive disease genes have been estimated to have existed and spread for as long as thousands of generations worldwide and hundreds of generations in the Finnish population, our analyses suggest that the spread of mutation 1 started 16-43 generations (400-1,075 years) ago and that of mutation 2 some 5-21 generations (125-525 years) ago. These datings are com...Continue Reading

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