Regulatory SNPs: Altered Transcription Factor Binding Sites Implicated in Complex Traits and Diseases

Abstract

The vast majority of the genetic variants (mainly SNPs) associated with various human traits and diseases map to a noncoding part of the genome and are enriched in its regulatory compartment, suggesting that many causal variants may affect gene expression. The leading mechanism of action of these SNPs consists in the alterations in the transcription factor binding via creation or disruption of transcription factor binding sites (TFBSs) or some change in the affinity of these regulatory proteins to their cognate sites. In this review, we first focus on the history of the discovery of regulatory SNPs (rSNPs) and systematized description of the existing methodical approaches to their study. Then, we brief the recent comprehensive examples of rSNPs studied from the discovery of the changes in the TFBS sequence as a result of a nucleotide substitution to identification of its effect on the target gene expression and, eventually, to phenotype. We also describe state-of-the-art genome-wide approaches to identification of regulatory variants, including both making molecular sense of genome-wide association studies (GWAS) and the alternative approaches the primary goal of which is to determine the functionality of genetic variants. Among these approaches, special attention is paid to expression quantitative trait loci (eQTLs) analysis and the search for allele-specific events in RNA-seq (ASE events) as well as in ChIP-seq, DNase-seq, and ATAC-seq (ASB events) data.

agReg-SNPdb: A Database of Regulatory SNPs for Agricultural Animal Species

“…However, the identification of causal variants and the elucidation of their regulatory roles is proceeding at a slow rate [ 4 , 5 ]. Today, it is well known that most disease- and trait-associated SNPs are not located within the coding regions of genes but in non-coding regions [ 6 , 7 , 8 , 9 ]. SNPs that are located in regulatory regions can alter TFBSs leading to a change in the binding affinity of TFs and, in extreme cases, even result in the disruption of a TFBS or the creation of a new TFBS ( Figure 1 ) and, thus, affect gene expression.…”

“…The importance of rSNPs has been studied extensively in humans and they are found to have a causal role for numerous traits and diseases [ 13 , 14 , 15 , 16 ]. A recent review on human rSNPs summarizes different rSNP studies [ 6 ]. Due to the great interest in rSNPs, several tools and databases for the analysis of the effects of SNPs on regulatory elements, e.g., TFBSs, have been developed for humans or certain model organisms.…”

Genome‐wide discovery ofDNApolymorphisms via resequencing of chickpea cultivars with contrasting response to drought stress

“…However, overexpression of both DREB1A and PIF4 showed enhanced drought stress tolerance without growth retardation (Kudo et al, 2017). The DNA polymorphisms in TFBSs may lead to the altered expression of the underlying genes due to alteration of TF binding affinity and/or elimination of natural binding sites or creation of new binding sites, which consequently impacts the response to environmental stress (Buroker, 2016; Degtyareva et al, 2021). For instance, DNA polymorphisms in promoter region of HSP70 differentiated heat stress sensitive and tolerant genotypes in Paralichthys olivaceus (Qi et al, 2014).…”

Expression quantitative trait locus rs6356 is associated with the susceptibility of heroin addiction by potentially influencing the TH gene expression in the hippocampus and nucleus accumbens

“…Genetic variants can be associated with the methylation and expression level of the gene. These variants are known as the methylation quantitative trait locus (mQTL) (Villicaña & Bell, 2021) or expression quantitative trait locus (eQTL) (Degtyareva, Antontseva, & Merkulova, 2021).…”