Evidence of selection on splicing-associated loci in human populations and relevance to disease loci mapping

• Published in: Scientific reports 2017-07, Vol.7 (1), p.5980-15, Article 5980
• Main Authors: Gamazon, Eric R., Konkashbaev, Anuar, Derks, Eske M., Cox, Nancy J., Lee, Younghee
• Format: Article
• Language: English
• Subjects: 45; 45/43; 631/114/2184; 631/208/457/649; Chromosome Mapping; Disease - genetics; Gene mapping; Genetic diversity; Genetic Loci; Genetic variance; Genetics, Population; Genome-Wide Association Study; Genomes; Genotype & phenotype; Haplotypes; Human populations; Humanities and Social Sciences; Humans; Introns - genetics; multidisciplinary; Natural selection; Nucleotide Motifs - genetics; Polymorphism, Single Nucleotide - genetics; Population differentiation; Quantitative trait loci; Regulatory sequences; RNA Splicing - genetics; Science; Science (multidisciplinary); Selection, Genetic; Single-nucleotide polymorphism; Splicing; Transcription
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-05744-9

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.