Abstract
The SPATA31 (alias FAM75A) gene family belongs to the core duplicon families that are thought to have contributed significantly to hominoid evolution. It is also among the gene families with the strongest signal of positive selection in hominoids. It has acquired new protein domains in the primate lineage and a previous study has suggested that the gene family has expanded its function into UV response and DNA repair. Here we show that over-expression of SPATA31A1 in fibroblast cells leads to premature senescence due to interference with aging-related transcription pathways. We show that there are considerable copy number differences for this gene family in human populations and we ask whether this could influence mutation rates and longevity in humans. We find no evidence for an influence on germline mutation rates, but an analysis of long-lived individuals (> 96 years) shows that they carry significantly fewer SPATA31 copies in their genomes than younger individuals in a control group. We propose that the evolution of SPATA31 copy number is an example for antagonistic pleiotropy by providing a fitness benefit during the reproductive phase of life, but negatively influencing the overall life span.
Highlights
Expansion of gene families with the concomitant acquisition of new functions can be a driving force for the evolutionary differentiation of species
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
We found that SPATA31A1 overexpressing cultures produced relatively fewer cells in each of the replication rounds than the controls transformed with the vector only (Fig. 1A)
Summary
Expansion of gene families with the concomitant acquisition of new functions can be a driving force for the evolutionary differentiation of species. Primate and human genomes include many interspersed segmental duplications, which may have been of special relevance for the evolution of the primate lineage [1]. These segmental duplications range between one to several hundred kilobases, and are characterized by a mosaic of repeat structures. About 430 blocks of the human genome have been identified as having been subject to multiple duplications during hominoid evolution [1] 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 [2, 3].
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