A genome wide exploration of the pleiotropic theory of senescence, are human disease and senescence the result of natural selection?

Abstract

The increasing global ageing of the World’s population, has spurred the interest on the causes and mechanisms of senescence, the physical decay of organisms with age. Se- nescence has long been a mystery and, as of today, there is no single universally accep- ted theory that accounts for the ultimate evolutionary purpose of senescence (if indeed there is one). Perhaps the most popular of the evolutionary explanations proposed so far is the pleiotropic theory of senescence, suggested by G. Williams in 1957¹. This theory states that mutations conferring risk for traits that are damaging for the organism late in life (e.g. after the fertile stage) might be maintained in a population if they are advanta- geous early in life, when they can result in an increased reproductive success. In humans, this theory is consistent with evidence coming from certain genes ( mTOR , from specific conditions (haemochromatosis) or from the life-long reproductive patterns of a few animal models (swans and the fruit fly). Interestingly, recent genome wide asso- ciation studies (GWAS) show that pleiotropy is common², with at least 17% of the genes and 4.6% of SNPs associated to a given disease being involved in 2 or more conditions. However, an exhaustive assessment of the impact of all these pleiotropic effects in the senescence of our species has not yet been carried out.

Using public metadata from Genome-Wide Association Studies (GWAS)³ we quantified the global extent and evolutionary implications of the kind of early-late age antagonistic pleiotropy defined in our species. Disease conditions were split in early or late onset conditions, based on several age thresholds. Pleiotropies were computed among the SNPs reported associated to the diseases. To gather data on SNPs, we used strategies based in its LD properties to increase sample size.

Our preliminary results are two-fold. First, they revealed some non-trivial antagonistic pleiotropies such as between bipolar disorder and osteoarthritis, or glioma and glauco- ma, that may be relevant to diagnosis and treatment of age-related disease. Second, and more interestingly in evolutionary terms, we observed a significant excess of ear-ly-late antagonistic pleiotropy in our genomes.

At the time of this submission, we are examining the ancestral or derived state of the alleles involved in these pleiotropies and studying the potential signature of natural se- lection in the genomic regions harbouring these SNPs.