Haplotype analysis of the 185delAG BRCA1 mutation in ethnically diverse populations

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 B2500 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 B5 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) B650 years ago, and into the Iraqi-Jewish community B450 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.

The spectrum of BRCA1 and BRCA2 pathogenic sequence variants in Middle Eastern, North African, and South European countries

“…Using haplotype analysis of individuals from diverse and unlikely related ethnicities may allow for distinguishing some of these possibilities. Indeed, haplotype analysis of the c.66_67del BRCA1 PSV has shown that among Ashkenazi Jews, non‐Ashkenazi Jews, and non‐Jewish Hispanics, the PSV has a common haplotype, whereas the haplotype in Malaysians and English non‐Jews is distinct (Laitman et al, ).…”

BRCA1andBRCA2pathogenic sequence variants in women of African origin or ancestry

“…Despite the availability of substantial information regarding cancer risks in BRCA1/2 PSV carriers, the amount of information available to suggest that this PSV arose no more than 1500 years ago, suggesting that it was transmitted from the middle east to Africa, and did not arise there before the original migration of individuals out of Africa (Laitman et al, 2013). However, this PSV has been reported in native Africans (Zoure et al, 2018) and has arisen in multiple populations independently, so it is not known whether this PSV is a new PSV at a locus that demonstrates high mutation rates, or if it is the common Jewish founder PSV, which has been observed in Middle Eastern or North African populations (Laitman et al, 2013;Slaoui et al, 2014;Zoure et al, 2018).…”

Genomic Disparities in Breast Cancer among Latinas

“…43,45–47,50,56–58 One of the 3 Jewish founder mutations, BRCA1 185delAG is estimated to have arisen about 800 years ago or earlier and is believed to have been introduced into Latin America about 650 years ago. 59 When this mutation is identified in Latinos, haplotype analysis supports that this mutation is of the same origin as the Jewish founder mutation, rather than a separate genetic event. 60,61 Pooled mutation estimates performed by Porchia et al 55 found that BRCA1 185delAG is the second most prevalent BRCA1 mutation and its frequency is not significantly different between Mexico and other Latin American countries ( P = .70).…”