Involvement of SPATA31 genes in aging and lifespan in humans

The SPATA31 (alias FAM75A) gene has gained new domains and became segmentally duplicated in the primate lineage, with humans harboring the relatively largest number of copies. It belongs to the core duplicons that are thought to have significantly contributed to hominoid evolution1 and is among the gene families with the strongest signal of positive selection in hominoids2. The newly acquired protein domains, as well experimental evidence have suggested that it has a function in UV response and DNA repair3. We have here over-expressed SPATA31A1, a representative member of the gene family, in human fibroblast cells and find that this leads to premature senescence. Gene expression analysis in these cells shows that this is mediated through changes in the regulation of cell cycle and extra-cellular matrix pathways, as well as senescence and DNA repair associated genes. Cells that express SPATA31A for a prolonged time period develop more de novo mutations than control cells. Given that SPATA31 genes are copy-number variable in humans, this could lead to differential effects on live span, with long-lived individuals to be predicted to have fewer copies on average. We find that this is indeed the case. Analysis of a large human panel of long-lived individuals (> 98 years) shows that they carry significantly fewer copies of SPATA31 in their genomes than individuals in a control panel. Our results suggest that an apparent evolutionary beneficial effect of more SPATA31 copies in protecting against UV-induced DNA damage has led to a secondary effect on aging related processes, including DNA repair induced mutations.