Dataset Information

Involvement of SPATA31 copy number variable genes in human lifespan.

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.

SUBMITTER: Bekpen C

PROVIDER: S-EPMC5940121 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Involvement of SPATA31 copy number variable genes in human lifespan.

Bekpen Cemalettin C Xie Chen C Nebel Almut A Tautz Diethard D

Aging 20180401 4

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 fibrobl ...[more]

PMID: 29676996

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Project description:Recent large-scale genomic studies within human populations have identified numerous genomic regions as copy number variant (CNV). As these CNV regions often overlap coding regions of the genome, large lists of potentially copy number polymorphic genes have been produced that are candidates for disease association. Most of the current data regarding normal genic variation, however, has been generated using BAC or SNP microarrays, which lack precision especially with respect to exons. To address this, we assessed 2,790 candidate CNV genes defined from available studies in nine well-characterized HapMap individuals by designing a customized oligonucleotide microarray targeted specifically to exons. Using exon array comparative genomic hybridization (aCGH), we detected 255 (9%) of the candidates as true CNVs including 134 with evidence of variation over the entire gene. Individuals differed in copy number from the control by an average of 100 gene loci. Both partial- and whole-gene CNVs were strongly associated with segmental duplications (55 and 71%, respectively) as well as regions of positive selection. We confirmed 37% of the whole-gene CNVs using the fosmid end sequence pair (ESP) structural variation map for these same individuals. If we modify the end sequence pair mapping strategy to include low-sequence identity ESPs (98-99.5%) and ESPs with an everted orientation, we can capture 82% of the missed genes leading to more complete ascertainment of structural variation within duplicated genes. Our results indicate that segmental duplications are the source of the majority of full-length copy number polymorphic genes, most of the variant genes are organized as tandem duplications, and a significant fraction of these genes will represent paralogs with levels of sequence diversity beyond thresholds of allelic variation. In addition, these data provide a targeted set of CNV genes enriched for regions likely to be associated with human phenotypic differences due to copy number changes and present a source of copy number responsive oligonucleotide probes for future association studies.

Dataset Information

Involvement of SPATA31 copy number variable genes in human lifespan.

Publications

Involvement of SPATA31 copy number variable genes in human lifespan.

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