Journal Article

Transversions have larger regulatory effects than transitions

Scholtens, Denise M., Lowe, William L., Reddy, Timothy E., Guo, Cong, McDowell, Ian C., Nodzenski, Michael, Allen, Andrew S.

2017

Overview

Background Transversions (Tv’s) are more likely to alter the amino acid sequence of proteins than transitions (Ts’s), and local deviations in the Ts:Tv ratio are indicative of evolutionary selection on genes. Whether the two different types of mutations have different effects in non-protein-coding sequences remains unknown. Genetic variants primarily impact gene expression by disrupting the binding of transcription factors (TFs) and other DNA-binding proteins. Because Tv’s cause larger changes in the shape of a DNA backbone, we hypothesized that Tv’s would have larger impacts on TF binding and gene expression. Results Here, we provide multiple lines of evidence demonstrating that Tv’s have larger impacts on regulatory DNA including analyses of TF binding motifs and allele-specific TF binding. In these analyses, we observed a depletion of Tv’s within TF binding motifs and TF binding sites. Using massively parallel population-scale reporter assays, we also provided empirical evidence that Tv’s have larger effects than Ts’s on the activity of human gene regulatory elements. Conclusions Tv’s are more likely to disrupt TF binding, resulting in larger changes in gene expression. Although the observed differences are small, these findings represent a novel, fundamental property of regulatory variation. Understanding the features of functional non-coding variation could be valuable for revealing the genetic underpinnings of complex traits and diseases in future studies.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Amino acid sequence / Amino acids / Animal Genetics and Genomics / Binding sites / Biological evolution / Biomedical and Life Sciences / Computational Biology / Deoxyribonucleic acid / Depletion / Disruption / DNA / DNA - chemistry / DNA - metabolism / DNA-binding protein / Empirical analysis / Gene expression / Gene sequencing / Genetic diversity / Genetic variance / Genomes / Genomics / Human and rodent genomics / Life Sciences / Massively parallel reporter assay / Microarrays / Microbial Genetics and Genomics / Mutation / Plant Genetics and Genomics / Protein Binding / Proteins / Proteomics / Regulatory sequences / Regulatory variation / Research Article / SNPs / Studies / Transcription factors / Transcription Factors - chemistry / Transcription Factors - metabolism / Transitions / Transversions