Relaxed Selection Shapes Species Lifespan and Ageing

A new study has discovered a fundamental mechanism by which mutations accumulate in key life-history modulating genes.

Lifespan varies massively between species, from mayflies that complete their life cycle within 24 hours to Bowhead whales that have an average lifespan of 200 years. To investigate how different lifespan strategies have evolved in nature, researchers at the Max Planck Institute for Biology of Ageing turned to studying African killfish.

"African killifishes live in a wide range of habitats, from rainforests to arid savanna woodlands. Based on the water availability in the environment, they live long or short. This great diversification constitutes a natural experiment of different lifespan strategies, making killifish a unique system for studying life history evolution," explains Dario Riccardo Valenzano, a senior author of this paper.

The researchers sequenced and analysed the genomes of 45 different species of African killfish to find the genomic basis underlying their adaptations to seasonal droughts. In annual (short-lived) species there is strong positive selection for genes involved in embryonic development and growth. Annual species also have a significantly larger proportion of candidate genes under relaxed (i.e. decreased strength of) selection, and this relaxation of selection causes genome expansion and the accumulation of detrimental mutations in key genes involved in ageing regulation, including mitochondrial RNA metabolism and insulin binding, which provides a mechanistic basis for the short lifespans that characterise annual killfish species. This is consistent with the theory that selection is stronger for genes expressed in early life and that selection relaxes for genes that are expressed in later stages of life.

The authors noted in the study that “relaxed selection on aging-related genes is unlikely a peculiar feature of annual killifishes, but rather a general phenomenon occurring during transitions of life-history strategies and changes of demography”.

Interestingly, even though humans are long-lived species, there is also significant relaxation of selection in the ageing and mitochondrial pathways. Out of 26 human populations, 21 were found to have significantly down-shifted DoS scores for genes related to ageing, and all populations have down-shifted DoS scores in mitochondrial genes. This supports the association between relaxed selection and aging-related phenotypic dysfunction.

Valenzano concluded that “ natural selection simply does not work as efficiently for genes important in late life. It doesn’t matter if a mutation makes you a little bit sick when you are old, because you have reproduced already and transmitted that mutation to your offspring. We found that this basic principle explains the expanded genome and the accumulation of detrimental mutations in short-lived killifish."

Further investigation of genes that are under relaxed selection may help to uncover novel genetic risk variants for ageing-related diseases.