Abstract
We performed a whole-genome scan of genetic variants in splicing regulatory elements (SREs) and evaluated the extent to which natural selection has shaped extant patterns of variation in SREs. We investigated the degree of differentiation of single nucleotide polymorphisms (SNPs) in SREs among human populations and applied long-range haplotype- and multilocus allelic differentiation-based methods to detect selection signatures. We describe an approach, sampling a large number of loci across the genome from functional classes and using the consensus from multiple tests, for identifying candidates for selection signals. SRE SNPs in various SNP functional classes show different patterns of population differentiation compared with their non-SRE counterparts. Intronic regions display a greater enrichment for extreme population differentiation among the potentially tissue-dependent transcript ratio quantitative trait loci (trQTLs) than SRE SNPs in general and includ outlier trQTLs for cross-population composite likelihood ratio, suggesting that incorporation of context annotation for regulatory variation may lead to improved detection of signature of selection on these loci. The proportion of extremely rare SNPs disrupting SREs is significantly higher in European than in African samples. The approach developed here will be broadly useful for studies of function and disease-associated variation in the human genome.
Highlights
Alternative splicing (AS) increases human proteomic diversity by enabling multiple, distinct transcripts to be generated from the same precursor gene[1]
To gain further insights into the selective forces acting on splicing regulation and into the pattern of population differentiation observed at the splicing regulatory elements (SREs) single nucleotide polymorphisms (SNPs), we evaluated whether disruption or generation of the splicing motif by the derived allele is under selection in the various SNP classes
We investigated the pathogenicity of SRE variants as well as tested for signatures of selection at these loci using multiple approaches, such as those that consider haplotype diversity and structure as well as multi-locus differentiation
Summary
Alternative splicing (AS) increases human proteomic diversity by enabling multiple, distinct transcripts to be generated from the same precursor gene[1]. Nearly 90% of protein-coding genes may generate multiple transcript isoforms[2]. SREs are cis-acting elements and exert their regulatory function via recruitment of sequence-dependent RNA-binding factors, to activate or repress adjacent splice sites. A single change at any position within an SRE may turn off its regulatory function and disrupt the binding accuracy of the spliceosome to exon-intron boundaries, possibly generating a defective, disease-causing www.nature.com/scientificreports/. In a comparison of transcript levels obtained from lymphoblastoid cells derived from individuals of European and African descent, ~10% of the investigated genes showed population-specific splicing ratios[24]. Splicing-associated variants in the insulin gene that are more common or unique in individuals of African descent raised the hypothesis of the influence of selection resulting from the transition of an out-of-Africa ancestral population to primitive agriculture[26]. To investigate the genetic basis underlying differences in splicing in human populations, we performed comprehensive analyses of genetic variants in SREs, including the degree of population differentiation in SRE variants among continental populations using whole-genome sequence data, and of the extent to which the observed patterns of differentiation at these genomic loci are consistent with the action of selection using long-range haplotype- and multilocus allelic differentiation- based methods
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