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

BMC Genetics

Research Article

Nancy Hamel¹  William D Foulkes²  Justin Veenstra³  Bethany Niell⁴  Shuying Sun⁵  Celia MT Greenwood⁶  Stephen Gruber⁷ 

[1] Department of Medical Genetics, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada;Department of Medical Genetics, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada;Cancer Genetics, Departments of Oncology and Human Genetics, Gerald Bronfman Centre for Clinical Research in Oncology, McGill University, Montreal, QC, Canada;Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada;Department of Statistics and Actuarial Science, University of Western Ontario, London, Ontario, Canada;Diagnostic Radiology, Massachusetts General Hospital, Boston, MA, USA;General Medical Sciences (Oncology), Case Comprehensive Cancer Center, Cleveland, Ohio, USA;Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada;Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada;University of Michigan School of Public Health, Ann Arbor, Michigan, USA;

关键词: Credible Interval;    Founder Mutation;    Recent Common Ancestor;    Gene Genealogy;    Coalescent Time;   

DOI  :  10.1186/1471-2156-11-39

 received in 2009-11-12, accepted in 2010-05-14,  发布年份 2010

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Greenwood et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.