Research Article: Involvement of SPATA31 copy number variable genes in human lifespan

Date Published: April 19, 2018

Publisher: Impact Journals

Author(s): Cemalettin Bekpen, Chen Xie, Almut Nebel, Diethard Tautz.


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.

Partial Text

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 [1]. These segmental duplications range between one to several hundred kilobases, and are characterized by a mosaic of repeat structures. They can be associated with rapid structural changes and chromosomal instability. 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]. Some of the most variable human CNV genes correspond to recently evolved gene families among the human core duplicons (e.g. NPIP and LRRC37A) [4].

Over-expression of SPATA31A1 in primary human fibroblast (HFF) cells was achieved using a mammalian expression vector with a CMV enhancer and promoter. Normal expression of SPATA31A1 is low in these cells, while the introduction of the expression vector resulted in a 2.7 fold increase. After the initial transformation, cells were re-cultured every three weeks for up to five additional rounds. We found that SPATA31A1 over-expressing cultures produced relatively fewer cells in each of the replication rounds than the controls transformed with the vector only (Fig. 1A). Based on the ß-galactosidase staining assay for cellular senescence, we observed about twice as many senescent cells in the SPATA31A1 over-expressing cultures than in the controls (Fig. 1B).

The segmentally duplicated genes in primates and humans have received special attention, since they may have significantly contributed to the evolution of these species [1]. However, only few of these genes have been studied in functional detail so far. Together with our previous analysis of the evolution of the SPATA31 gene family [6], the present data suggest that SPATA31 genes are involved in sensing and repairing UV-induced DNA damage, but also in the induction of pathways causing the premature aging of cells. Further, we show that long lived individuals have on average lower numbers of SPATA31 genes in their genome.




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