Abstract

In human lymphoblastoid cell lines, 8,902 loci were identified at which genetic variation is significantly associated with local DNase I sensitivity; these variants are responsible for a large fraction of expression quantitative trait loci. Expression quantitative trait loci (eQTLs) are stretches of DNA that regulate gene transcription and expression and contribute to a particular phenotypic trait. eQTL mapping is an important tool for linking genetic variation to changes in gene regulation, but identifying the causal variants underlying eQTLs and the regulatory mechanisms involved remains a challenge. Degner et al. used DNaseI sequencing to measure genome-wide chromatin accessibility in 70 Yoruba lymphoblastoid cell lines to produce genome-wide maps of chromatin accessibility for each individual. They identify variants that they call DNaseI sensitivity quantitative trait loci (dsQTLs). The implication is that changes in chromatin accessibility or transcription-factor binding occur at many gene loci and are likely to be important contributors to phenotypic variation. The mapping of expression quantitative trait loci (eQTLs) has emerged as an important tool for linking genetic variation to changes in gene regulation1,2,3,4,5. However, it remains difficult to identify the causal variants underlying eQTLs, and little is known about the regulatory mechanisms by which they act. Here we show that genetic variants that modify chromatin accessibility and transcription factor binding are a major mechanism through which genetic variation leads to gene expression differences among humans. We used DNase I sequencing to measure chromatin accessibility in 70 Yoruba lymphoblastoid cell lines, for which genome-wide genotypes and estimates of gene expression levels are also available6,7,8. We obtained a total of 2.7 billion uniquely mapped DNase I-sequencing (DNase-seq) reads, which allowed us to produce genome-wide maps of chromatin accessibility for each individual. We identified 8,902 locations at which the DNase-seq read depth correlated significantly with genotype at a nearby single nucleotide polymorphism or insertion/deletion (false discovery rate = 10%). We call such variants ‘DNase I sensitivity quantitative trait loci’ (dsQTLs). We found that dsQTLs are strongly enriched within inferred transcription factor binding sites and are frequently associated with allele-specific changes in transcription factor binding. A substantial fraction (16%) of dsQTLs are also associated with variation in the expression levels of nearby genes (that is, these loci are also classified as eQTLs). Conversely, we estimate that as many as 55% of eQTL single nucleotide polymorphisms are also dsQTLs. Our observations indicate that dsQTLs are highly abundant in the human genome and are likely to be important contributors to phenotypic variation.