Abundant contribution of short tandem repeats to gene expression variation in humans

Abstract

Expression quantitative trait loci (eQTLs) are a key tool to dissect cellular processes mediating complex diseases. However, little is known about the role of repetitive elements as eQTLs. We report a genome-wide survey of the contribution of Short Tandem Repeats (STRs), one of the most polymorphic and abundant repeat classes, to gene expression in humans. Our survey identified 2,060 significant expression STRs (eSTRs). These eSTRs were replicable in orthogonal populations and expression assays. We used variance partitioning to disentangle the contribution of eSTRs from linked SNPs and indels and found that eSTRs contribute 10%-15% of the cisheritability mediated by all common variants. Functional genomic analyses showed that eSTRs are enriched in conserved regions, co-localize with regulatory elements, and are predicted to modulate histone modifications. Our results show that eSTRs provide a novel set of regulatory variants and highlight the contribution of repeats to the genetic architecture of quantitative human traits.

Direct Identification of Hundreds of Expression-Modulating Variants using a Multiplexed Reporter Assay

“…Conservative estimates suggest that in 34-41% of eQTL peaks (dependent on the population tested), the causal variant will be the top associated allele. Second, only a subset of the true variants responsible for eQTLs (23-64%, according to recent estimates) will act on enhancers or promoters, which are the functional classes that will be detected in the MPRA assay (Farh et al, 2015;Gymrek et al, 2015;Lappalainen et al, 2013). Variants that work by other processes, such as microsatellites or post-transcriptional regulation, would not be expected to score.…”

Beyond SNPs and CNV: Pharmacogenomics of Polymorphic Tandem Repeats

“…Next, polymorphic promoters STR are associated with increased variance in local gene expression and DNA methylation, suggesting functional role for STR [18]. Finally, recent studies revealed contribution of STR alleles to gene expression levels and phenotypes [9]. The functional role of STR has been demonstrated by effects on gene expression, splicing, protein sequence, and association with pathogenic effects [18].…”

“…Inherently hypervariable microsatellites modulate gene expression through several possible mechanisms, e.g. direct addition of functional DNA motifs, modification of local DNA or RNA structure, epigenetic modification of the local region, altered spacing or orientation of regulatory molecules, and alteration of nucleosome positioning [9,18].…”

“…About 19% of human genes contain at least one STR in their upstream regulatory region [6,8]. Recent studies demonstrated that STR in the human genome contributes to variation in gene expression [9]. Statistical analysis of tandem repeat distribution showed a sharp increase around Transcription Start Site (TSS), spanning several kilobases up-and downstream from the TSS [7].…”

Magnitude of Human Genetic Variations: A Mini Review

“…STRs significantly contribute to the genetic architecture of quantitative human traits and various clinically relevant conditions. 56 Dinucleotide Repeats-The most common of the microsatellite tandem repeats dispersed in the euchromatic arms of chromosomes. They consist of two nucleotides repeated in tandem; guanine and thymine, (GT)n, or (CA)n is the most frequently seen which is present at an estimated 50 000-100 000 sites per genome.…”