The effects of deleterious mutations on ageing

Sammanfattning: Ageing is defined as the deterioration of an individual's physiological performance with advancing age, which leads to a decrease in reproduction and/or survival. The question why most organisms age has preoccupied humans for millennia and, over the last decades, resulted in an ever-increasing research effort to understand this phenomenon. The full explanation for why we age has, however, remained elusive. Evolutionary theories of ageing are based on two assumptions, which together inevitably result in organismal ageing, that the strength of selection declines with age and that mutations have age-specific effects. While a declining strength of selection with age naturally follows from external sources of death, the age-specific properties of mutations is a topic we only have a rudimentary understanding of. Established theories of ageing predict that mutations either have a beneficial or neutral effect early in life, and a deleterious effect later in life. New theory suggests that mutations with a small negative effect already early in life can also contribute to the evolution of ageing, a possibility that potentially explains empirical results that have been difficult to reconcile with current theories. Deleterious mutations may also directly or indirectly explain the sex differences in ageing and lifespan that are observed in many species.In this thesis, I investigate the age-specificity of deleterious mutations and test if they contribute to sex differences in ageing and lifespan. In paper I and II, I investigate the age-specificity of a set of supposedly deleterious mutations, by estimating their effect on fecundity in young, middle-aged and moderately old Drosophila melanogaster females. The majority of tested mutations show age-specific effects, with a detrimental effect that gradually increases with advancing age. These results thus support that mutations expressing a small negative effect already at an early age also can contribute to the evolution of ageing.In paper III, I manipulate the expression of autosomal deleterious mutations in D. melanogaster through inbreeding, and test if this has different effects on male and female ageing as predicted if sexual selection has shaped sex differences in ageing through condition-dependent investment in current reproduction. I find a sex difference in ageing in high condition, but not in low condition flies, suggesting that sexual selection indeed has shaped how resources are allocated between reproduction and somatic maintenance in relation to condition. I did not find a corresponding response for lifespan.In paper IV, I investigate if sex differences in lifespan are partly explained by the unconditional expression of recessive deleterious mutations on the single X-chromosome in males (the Unguarded X hypothesis). I test this hypothesis by forcing D. melanogaster females to express recessive mutations on the X-chromosome to the same extent as males do and assess their effect on female lifespan. This direct test did not show the expected reduction in female lifespan and thus fails to support the Unguarded X hypothesis as a major explanation of sex differences in lifespan.