Abstract
BackgroundSeveral founder mutations leading to increased risk of cancer among Ashkenazi Jewish individuals have been identified, and some estimates of the age of the mutations have been published. A variety of different methods have been used previously to estimate the age of the mutations. Here three datasets containing genotype information near known founder mutations are reanalyzed in order to compare three approaches for estimating the age of a mutation. The methods are: (a) the single marker method used by Risch et al., (1995); (b) the intra-allelic coalescent model known as DMLE, and (c) the Goldgar method proposed in Neuhausen et al. (1996), and modified slightly by our group. The three mutations analyzed were MSH2*1906 G->C, APC*I1307K, and BRCA2*6174delT.ResultsAll methods depend on accurate estimates of inter-marker recombination rates. The modified Goldgar method allows for marker mutation as well as recombination, but requires prior estimates of the possible haplotypes carrying the mutation for each individual. It does not incorporate population growth rates. The DMLE method simultaneously estimates the haplotypes with the mutation age, and builds in the population growth rate. The single marker estimates, however, are more sensitive to the recombination rates and are unstable. Mutation age estimates based on DMLE are 16.8 generations for MSH2 (95% credible interval (13, 23)), 106 generations for I1037K (86-129), and 90 generations for 6174delT (71-114).ConclusionsFor recent founder mutations where marker mutations are unlikely to have occurred, both DMLE and the Goldgar method can give good results. Caution is necessary for older mutations, especially if the effective population size may have remained small for a long period of time.
Highlights
Several founder mutations leading to increased risk of cancer among Ashkenazi Jewish individuals have been identified, and some estimates of the age of the mutations have been published
The mutation MSH2*1906 G->C leads to increased risk of colorectal cancer among Ashkenazi Jewish individuals [4], and the colorectal cancer-susceptibility allele APC I1307K appears to confer a relative risk of 1.5-2.0 for colorectal cancer (CRC) on carriers [5]
Several quite different methods have been proposed for estimating mutation age, and here we evaluate and compare three approaches, and make recommendations as to when and where each method is preferable
Summary
Several founder mutations leading to increased risk of cancer among Ashkenazi Jewish individuals have been identified, and some estimates of the age of the mutations have been published. A simple model for gene genealogies is the star genealogy where all copies of the disease-causing mutation are assumed to have one common coalescent time Under this model, all the histories of each copy of the mutation are independent of one another; this assumption is quite reasonable for fast-growing populations where the probability of two lineages merging is small. Assuming a bifurcating genealogy where all lineages split at the same time, Labuda et al (1996) [11] showed that the estimate of Risch (1995) was likely to be biased downwards They developed a correction factor that increases the estimated age and accounts for the population growth rate (see Additional file 1, part A)
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