title: Rare and common regulatory variation in population-scale sequenced human genomes.
abstract: Population-scale genome sequencing allows the characterization of functional effects of a broad spectrum of genetic variants underlying human phenotypic variation. Here, we investigate the influence of rare and common genetic variants on gene expression patterns, using variants identified from sequencing data from the 1000 genomes project in an African and European population sample and gene expression data from lymphoblastoid cell lines. We detect comparable numbers of expression quantitative trait loci (eQTLs) when compared to genotypes obtained from HapMap 3, but as many as 80% of the top expression quantitative trait variants (eQTVs) discovered from 1000 genomes data are novel. The properties of the newly discovered variants suggest that mapping common causal regulatory variants is challenging even with full resequencing data; however, we observe significant enrichment of regulatory effects in splice-site and nonsense variants. Using RNA sequencing data, we show that 46.2% of nonsynonymous variants are differentially expressed in at least one individual in our sample, creating widespread potential for interactions between functional protein-coding and regulatory variants. We also use allele-specific expression to identify putative rare causal regulatory variants. Furthermore, we demonstrate that outlier expression values can be due to rare variant effects, and we approximate the number of such effects harboured in an individual by effect size. Our results demonstrate that integration of genomic and RNA sequencing analyses allows for the joint assessment of genome sequence and genome function.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland. stephen.montgomery@unige.ch
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Montgomery
authors.forename: Tuuli
authors.initials: T
authors.lastname: Lappalainen
authors.forename: Maria
authors.initials: M
authors.lastname: Gutierrez-Arcelus
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
mesh_terms: D017398:Alternative Splicing; D044383:Black People / Q000235:genetics; D020869:Gene Expression Profiling; D014644:Genetic Variation; D005828:Genetics, Population; D015894:Genome, Human / Q000235:genetics*; D060148:HapMap Project; D006239:Haplotypes; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D044465:White People / Q000235:genetics