J. Hashemi et al., Haplotype analysis and age estimation of the 113insR CDKN2A founder mutation in Swedish melanoma families, GENE CHROM, 31(2), 2001, pp. 107-116
Germline mutations in the CDKN2A tumor suppressor gene located on 9p21 have
been linked to development of melanomas in some families. A germline 3-bp
insertion in exon 2 of CDKN2A, leading to an extra arginine at codon 113 (1
13insR), has been identified in 17 Swedish melanoma families. Analysis of 1
0 microsatellite markers, spanning approximately I Mbp in the 9p21 region,
showed that all families share a common allele for at least one of the mark
ers closest to the CDKN2A gene, suggesting that the 113insR mutation is an
ancestral founder mutation. Differences in the segregating haplotypes, due
to meiotic recombinations and/or mutations in the short-tandem-repeat marke
rs, were analyzed further to estimate the age of the mutation. Statistical
analysis using a maximum likelihood approach indicated that the mutation ar
ose 98 generations (90% confidence interval: 52-167 generations), or approx
imately 2,000 years, ago. Thus, 113insR would be expected to have a more wi
despread geographic distribution in European and North American regions wit
h ancestral connections to Sweden. Alternatively, CDKN2A may lie in a recom
bination hot spot region, as suggested by the many meiotic recombinations i
n this narrow similar to1-cM region an 9p21. (C) 2001 Wiley-Liss, Inc.