Transversions have larger regulatory effects than transitions.

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Guo, C; McDowell, IC; Nodzenski, M; Scholtens, DM; Allen, AS; Lowe, WL; Reddy, TE

Published Date

  • May 19, 2017

Published In

Volume / Issue

  • 18 / 1

Start / End Page

  • 394 -

PubMed ID

  • 28525990

Pubmed Central ID

  • 28525990

Electronic International Standard Serial Number (EISSN)

  • 1471-2164

Digital Object Identifier (DOI)

  • 10.1186/s12864-017-3785-4

Language

  • eng

Conference Location

  • England