Negative selection on BRCA1 susceptibility alleles sheds light on the population genetics of late-onset diseases and aging theory.

The magnitude of negative selection on alleles involved in age-specific mortality decreases with age. This is the foundation of the evolutionary theory of senescence. Because of this decrease in negative selection with age, and because of the absence of reproduction after menopause, alleles involved in women's late-onset diseases are generally considered evolutionarily neutral. Recently, genetic and epidemiological data on alleles involved in late onset-diseases have become available. It is therefore timely to estimate selection on these alleles. Here, we estimate selection on BRCA1 alleles leading to susceptibility to late-onset breast and ovarian cancer. For this, we integrate estimates of the risk of developing a cancer for BRCA1-carriers into population genetics frameworks, and calculate selection coefficients on BRCA1 alleles for different demographic scenarios varying across the extent of human demography. We then explore the magnitude of negative selection on alleles leading to a diverse range of risk patterns, to capture a variety of late-onset diseases. We show that BRCA1 alleles may have been under significant negative selection during human history. Although the mean age of onset of the disease is long after menopause, variance in age of onset means that there are always enough cases occurring before the end of reproductive life to compromise the selective value of women carrying a susceptibility allele in BRCA1. This seems to be the case for an extended range of risk of onset functions varying both in mean and variance. This finding may explain the distribution of BRCA1 alleles' frequency, and also why alleles for many late-onset diseases, like certain familial forms of cancer, coronary artery diseases and Alzheimer dementia, are typically recent and rare. Finally, we discuss why the two most popular evolutionary theories of aging, mutation accumulation and antagonistic pleiotropy, may underestimate the effect of selection on survival at old ages.