Abstract
The 185delAG* BRCA1 mutation is encountered primarily in Jewish Ashkenazi and Iraqi individuals, and sporadically in non-Jews. Previous studies estimated that this is a founder mutation in Jewish mutation carriers that arose before the dispersion of Jews in the Diaspora ∼2500 years ago. The aim of this study was to assess the haplotype in ethnically diverse 185delAG* BRCA1 mutation carriers, and to estimate the age at which the mutation arose. Ethnically diverse Jewish and non-Jewish 185delAG*BRCA1 mutation carriers and their relatives were genotyped using 15 microsatellite markers and three SNPs spanning 12.5 MB, encompassing the BRCA1 gene locus. Estimation of mutation age was based on a subset of 11 markers spanning a region of ∼5 MB, using a previously developed algorithm applying the maximum likelihood method. Overall, 188 participants (154 carriers and 34 noncarriers) from 115 families were included: Ashkenazi, Iraq, Kuchin-Indians, Syria, Turkey, Iran, Tunisia, Bulgaria, non-Jewish English, non-Jewish Malaysian, and Hispanics. Haplotype analysis indicated that the 185delAG mutation arose 750–1500 years ago. In Ashkenazim, it is a founder mutation that arose 61 generations ago, and with a small group of founder mutations was introduced into the Hispanic population (conversos) ∼650 years ago, and into the Iraqi–Jewish community ∼450 years ago. The 185delAG mutation in the non-Jewish populations in Malaysia and the UK arose at least twice independently. We conclude that the 185delAG* BRCA1 mutation resides on a common haplotype among Ashkenazi Jews, and arose about 61 generations ago and arose independently at least twice in non-Jews.
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Acknowledgements
The work at City of Hope was supported in part by American Cancer Society Award #RSGT-00–263–01, and awards #1R03CA139588 and #1RC4CA153828 from the United States National Cancer Institute (PI: JNW). AL was supported by an award from Genesis UK. DGE and WGN are supported by the Manchester NIHR BRC. The Malaysian Breast cancer Genetic Study (MyBrCa) is supported by grants from the Malaysian Ministry of Science, Technology and Innovation, the Ministry of Higher Education (HIR Grant UM.C/HlR/MOHE/06) and charitable funding through Cancer Research Initiatives Foundation (CARIF).
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Laitman, Y., Feng, BJ., Zamir, I. et al. Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations. Eur J Hum Genet 21, 212–216 (2013). https://doi.org/10.1038/ejhg.2012.124
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DOI: https://doi.org/10.1038/ejhg.2012.124
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