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Abstract:
Evolutionary theory suggests that lifespan-associated alleles should be purged from the gene pool, and yet decades of GWAS and model organism studies have shown they persist. Here, we explore one possible explanation: alleles that regulate lifespan are context dependent. This idea is core to the “evolutionary mismatch” hypothesis. It predicts that previously adaptive or neutral alleles in human populations have become mismatched to our current lifestyle underlying the high incidence of non-communicable diseases that impact lifespan today. However, the lack of statistical power to identify genotype-by-environment interactions at a genome-wide scale have limited our ability to test these hypotheses. To address this problem, we exposed thousands of outbred Drosophila to a standard and a high sugar diet. We then
sequenced over 10,000 individuals and track genome-wide allele frequency changes over time, as these populations aged. We mapped thousands of lifespan-altering alleles whose frequency changed throughout the course of the population’s lifetime, and remarkably, a third of these lifespan-associated alleles appear cryptic in standard diet but play an
important role in high sugar conditions. The identification of such large number of SNPs allowed us for the first time to test key predictions of the evolutionary mismatch hypothesis at genome-wide level. Specifically, we find that alleles that are now detrimental (reducing lifespan) are most likely to be recently derived, have stronger effects on a high-sugar diet, and were positively selected during the evolutionary history of the fruit fly. Our observations provide a) strong evidence for the pervasive nature of cryptic genetic variation and the key role it plays in shaping phenotypic variation between individuals, and b) support the hypothesis that historically neutral or beneficial alleles can become detrimental in novel conditions.
