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

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.

Potential regulatory SNPs in the ATXN7L3B and KRT15 genes are associated with gender-specific colorectal cancer risk.

Aim: According to the current data, a major factor for phenotypic variation of complex traits and disease susceptibility is the cis-acting effects of noncoding variants on gene expression. Our purpose was to evaluate the association between colorectal cancer (CRC) and six single nucleotide polymorphisms identified using our original bioinformatics approach as regulatory and putatively related to CRC. Materials: One hundred and sixty CRC patients and 185 healthy controls have been genotyped for rs590352, rs2072580, rs78317230, rs3829202, rs11542583 and rs4796672. Results: Genotypes and alleles distributions of rs590352 of ATXN7L3B gene were significantly different between the male CRC subjects and controls. Significant correlation of genotype with CRC is observable for women only for the rs4796672 of KRT15 gene. Analysis of haplotypes reveals that rs2072580 of the ISCU and SART3 genes can be also associated with CRC. Conclusion: We have identified three SNPs associated with CRC risk and demonstrated a gender specificity of rs590352 and rs4796672.

Novel approach to functional SNPs discovery from genome-wide data reveals promising variants for colon cancer risk.

In the majority of colorectal cancer (CRC) cases, the genetic basis of predisposition remains unexplained. The goal of the study was to assess the regulatory SNPs (rSNPs) in the human genome and to reveal СRC drivers based on the available chromatin immunoprecipitation sequencing (ChIP-Seq, ChIA-PET) and transcriptional profiling (RNA-Seq) data. We combined positional (locations within genome regulatory elements) and functional (associated with allele-specific binding and expression) criteria followed by an analysis using genome-wide association studies (GWAS) and minor allele frequency (MAF) datasets. DeSeq2 analysis through 70 CRC patients reinforced the regulatory potential. rSNPs (1,476) that were associated with significant (P < 0.01) allele-specific events resulting in thirty that exhibited a link with CRC according to the MAF and 27, with a risk of malignancy in general according to GWAS. Selected rSNPs may modify the expression of genes for tumor suppressors and the regulators of signaling pathways, including noncoding RNAs. However, the rSNPs from the most represented group affect the expression of genes related to splicing. Our findings strongly suggest that the identified variants might contribute to CRC susceptibility, which indicates that aberrant splicing is one of the key mechanisms for unraveling disease etiopathogenesis and provides useful inputs for interpreting how genotypic variation corresponds to phenotypic outcome.