Breast cancer, consanguinity, and lethal tumor genes: simulation of BRCA1/2 prevalence over 40 generations

Marriage between biological relatives is a social custom with a long history in many parts of the world. Today, hundreds of millions of individuals live in consanguineous families. The offspring of consanguineous parents are more likely to have the same two alleles (homozygosity) by descent. In consanguineous family with BRCA1/2 gene mutations, an offspring is more likely to be BRCA1/2 homozygous. The consequences of BRCA1/2 mutation homozygosity in humans are unknown. In knockout mice, BRCA1 or BRCA2 homozygotes die as embryos. Because tumor suppressor genes are conserved and less species-specific than other genes, human BRCA1/2 homozygotes are likely to be biologically non-viable and are unknown to exist. Among the conceptuses of consanguineous couples, there are excess deaths (abortions, stillbirths, perinatal and early-childhood deaths) as well as a decreased risk of breast cancer, especially in younger females. It has been suggested that, in part, the excess deaths are due to BRCA1/2 and other still undiscovered tumor gene homozygotes. To examine the consequences of the long-term practice of consanguineous marriage on the prevalence of lethal cancer genes, we simulated, by computer, the mating of non-consanguineous and consanguineous populations over 40 generations. The program was developed in Basic for a Macintosh computer. The input comprised the rates of consanguineous marriage types and the output parameter was the rate of heterozygotes (carriers) in each generation. The combined prevalence of BRCA1/2 mutation of 1% was used as a starting reference point. Absence of spontaneous mutations and gene flow were assumed. In a randomly mating population, the BRCA1/2 carrier rate decreases on average 0.0035% every 25 years. In a highly consanguineous population, the carrier rate decreases on average 0.022% every 25 years, or six times faster than in a non-consanguineous population. There is a worldwide trend of decreasing breast cancer incidence with an increasing consanguinity rate. In conclusion, the BRCA1/2 and possibly other undiscovered tumor gene carrier rates are significantly lower in consanguineous than in non-consanguineous populations. Gene frequency in a population depends on the rate of inbreeding and length of consanguineous practices. A drift phenomenon may exert a major effect on the carrier rate. Consanguinity may explain part of the worldwide variation of breast cancer incidence.