Age and origin of two common MLH1 mutations predisposing to hereditary colon cancer.
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 compatible with our genealogical results identifying a common ancestor born in the 16th and 18th century, respectively. Overall, our results indicate that all Finnish kindreds studied to date showing either mutation 1 or mutation 2 are due to single ancestral founding mutations relatively recent in origin in the population. Alternatively, the mutations arose elsewhere earlier and were introduced in Finland more recently.
Moisio
A L
AL
Department of Medical Genetics, Haartman Institute, University of Helsinki, Finland.
Sistonen
P
P
Weissenbach
J
J
de la Chapelle
A
A
Peltomäki
P
P
D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D002874:Chromosome Mapping / Q000379:methods*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004276:DNA, Satellite / Q000235:genetics*; D005387:Finland; D005819:Genetic Markers; D005828:Genetics, Population; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D010375:Pedigree
D004276:DNA, Satellite; D005819:Genetic Markers