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How old is this mutation? - a study of three Ashkenazi Jewish founder mutations

Celia MT Greenwood12, Shuying Sun3, Justin Veenstra4, Nancy Hamel5, Bethany Niell6, Stephen Gruber7 and William D Foulkes589*

Author Affiliations

1 Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada

2 Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

3 General Medical Sciences (Oncology), Case Comprehensive Cancer Center, Cleveland, Ohio, USA

4 Department of Statistics and Actuarial Science, University of Western Ontario, London, Ontario, Canada

5 Department of Medical Genetics, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada

6 Diagnostic Radiology, Massachusetts General Hospital, Boston, MA, USA

7 University of Michigan School of Public Health, Ann Arbor, Michigan, USA

8 Cancer Genetics, Departments of Oncology and Human Genetics, Gerald Bronfman Centre for Clinical Research in Oncology, McGill University, Montreal, QC, Canada

9 Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada

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BMC Genetics 2010, 11:39  doi:10.1186/1471-2156-11-39

Published: 14 May 2010



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 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.


All 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).


For 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.