SPATA31 Gene Family Copy Numbers as a Human Example of Antagonistic Pleiotropy
Antagonistic pleiotropy is the name given to the phenomenon in which evolutionary processes select for a genetic variant that aids in evolutionary fitness when young, but then causes harm to the individual later in life. Many theorists consider aging as a whole to be antagonistic pleiotropy writ large, but one can pick out individual mechanisms in many species that are compelling candidates to be the result of such a process. In the open access paper noted here, the authors point out one plausibly pleiotropic set of genes in our species.
Expansion of gene families with the concomitant acquisition of new functions can be a driving force for the evolutionary differentiation of species. Compared to other mammals, primate and human genomes include many interspersed segmental duplications, which may have been of special relevance for the evolution of the primate lineage. About 430 blocks of the human genome have been identified as having been subject to multiple duplications during hominoid evolution. Clustering analysis of these segmentally duplicated regions in the human genome suggests that a part of the duplication blocks have formed around a "core" or "seed" duplicon.
The SPATA31 gene family belongs to the core duplicon gene families and it has been shown to be one of the fastest evolving gene families in the human lineage. It has expanded from a single copy in mouse to at least nine copies in humans, located at seven different sites on both arms of chromosome 9. Compared to the mouse gene, we found that the human SPATA31 genes are broadly expressed and have acquired new functional domains, among them a cryptochrome/photolyase domain, suggesting the acquisition of a function in UV damage repair.
Antibody staining showed that the protein is re-localized from the nucleolus to the whole nucleus upon UV irradiation, a pattern known for proteins involved in UV damage sensing and repair. Based on CRISPR/Cas mediated knockouts of members of the gene family in fibroblast cell cultures, we found that the reduction of copy number in cells leads to enhanced sensitivity towards UV-irradiation. Given that increased UV-light resistance of the skin may have played a major role in human evolution, we proposed that the acquisition of an involvement in UV damage sensing or repair has lead to the adaptive evolution of SPATA31.
An interesting side effect of the SPATA31 gene knockouts was that the respective cells survived somewhat longer than normal primary fibroblast cell lines, although this was difficult to quantify. We have therefore used here the alternative approach, namely to over-express a representative member of the SPATA31 gene family, SPATA31A1, and study its effect on cell survival. We find that this over-expression results indeed in premature senescence of the cells, through interference with known aging related pathways. Based on these results, we asked whether natural copy number variation in humans correlates with senescence, in the sense that fewer SPATA31 copies should correlate with longer life span. We can indeed show this effect in a cohort of long-lived individuals. Humans that have reached an age of 95 or higher have on average fewer SPATA31 gene copies than a younger control population.
It has generally been suggested that there is a complex interaction between cellular senescence, tumor incidence due to somatic mutations, and aging. Our data imply that SPATA31 genes are part of this process and that their variation in copy number contributes via this effect to longevity in humans. Having more copies may lead to more somatic mutations, including some that cause cancer, while having fewer copies reduces this effect, thus allowing longer life spans.
The SPATA31 copy number effect on aging can be seen as an example for antagonistic pleiotropy. Higher copy numbers provide a benefit early in life, due to better protection of the skin against sunlight, allowing to spend more time during the day for foraging, social life, mate seeking and child care, all factors that should increase reproductive fitness. Hence, there would be positive selection for higher copy numbers. But more copies would also lead to a higher expression of SPATA31 and our cell-culture results show that such a higher expression induces DNA repair pathways. This could lead to a higher incidence of repair-induced damage in the cells and thus to cancer. If this becomes a problem during reproductive age, one would have a potential negative selection against high copy number. Hence, a balance in copy number should be maintained in the population, but with a certain variance. This variance has the effect that total lifetime beyond reproductive age is affected, with individuals with fewer copies having a higher probability to live longer.
Some years ago I came to think about that it humanity could start a "study" trying to extend life in humans as long as possible. We should find a female and sequencer genome and if she had enough of the beneficial alleles she should be included in the study. From day 1 after birth she should be injected or when she were able to eat get all supplements available no matter costs for her whole life. Then we will see over a century in the future where long she lived.