Fine-mapping cis-regulatory variants in diverse human populations

Abstract

Genome-wide association studies (GWAS) are a powerful approach for connecting genotype to phenotype. Most GWAS hits are located in cis-regulatory regions, but the underlying causal variants and their molecular mechanisms remain unknown. To better understand human cis-regulatory variation, we mapped quantitative trait loci for chromatin accessibility (caQTLs)—a key step in cis-regulation—in 1000 individuals from 10 diverse populations. Most caQTLs were shared across populations, allowing us to leverage the genetic diversity to fine-map candidate causal regulatory variants, several thousand of which have been previously implicated in GWAS. In addition, many caQTLs that affect the expression of distal genes also alter the landscape of long-range chromosomal interactions, suggesting a mechanism for long-range expression QTLs. In sum, our results show that molecular QTL mapping integrated across diverse populations provides a high-resolution view of how worldwide human genetic variation affects chromatin accessibility, gene expression, and phenotype.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that minor issues remain unresolved (see decision letter).

Mechanisms of Interplay between Transcription Factors and the 3D Genome

“…Even without covalent modifications, some TFs known as pioneer factors can establish open chromatin by binding nucleosomal DNA (Zhu et al, 2018) and either displacing nucleosomes directly or recruiting chromatin remodelers (Spitz and Furlong, 2012). Quantitative trait locus (QTL) analysis suggests that the resulting changes in chromatin accessibility contribute to TFs' influence on long-range 3D genome organization (Tehranchi et al, 2019). These indirect, chromatin-mediated effects may provide a means by which TFs with only transient binding to DNA can trigger more enduring changes to chromosome conformation and ultimately gene expression.…”

Molecular mechanisms of coronary disease revealed using quantitative trait loci for TCF21 binding, chromatin accessibility, and chromosomal looping

“…To call the TCF21 binding (bQTL), chromatin accessibility (caQTL), and chromosomal looping (clQTL) quantitative trait loci, we employed a published regressionbased approach which uses post-assay allele frequencies together with genotypes of each sample to infer the proportion of each sample in the pool [9,13]. Comparing the pre-assay vs. post-assay allele frequencies allows the identification of outlier SNPs where these frequencies are significantly different from one another, which indicates a cis-acting QTL variant.…”

“…The regulatory variants that modulate other genomic features have also been characterized. QTLs for histone modification and chromatin accessibility and more recently chromosomal looping have also been mapped [9][10][11][12]. Such efforts have provided important information regarding the regulatory structure of the non-coding sequence in the genome and identified how such variation may regulate the risk for complex human disease.…”

“…In general, these studies have required conducting time-consuming and costly assays for each of the large numbers of individuals that is required to reach relevant genome-wide levels of statistical association. Recently, we have developed an efficient approach for mapping molecular QTLs which employs sample pooling prior to sequencing, and employed this method to map QTLs for transcription factor binding [13], methylation [14], and chromatin accessibility [9]. This pooling minimizes experimental variability between samples (both within and between experimental "batches"), considerably reducing the cost and effort of QTL mapping when compared to standard individual-level approaches [13].…”

The Landscape of Chromatin Accessibility in Skeletal Muscle During Embryonic Development in Pigs

“…In addition, studies have shown that some TFs called pioneer factors can establish chromatin accessibility by replacing or binding nucleosome DNA or by recruiting chromatin-remodeling agents [13,14]. Quantitative trait locus (QTL) analysis and 3D genome assembly have shown that changes in chromatin accessibility ultimately alter the long-range effects of TFs [15]. Therefore, it is especially important to study the interaction mechanism between TFs and chromatin accessibility during muscle development.…”