Transversions have larger regulatory effects than transitions

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number394
Pages (from-to)1
Number of pages1
JournalBMC Genomics
Volume18
Issue number1
DOIs
StatePublished - May 19 2017

Keywords

  • Massively parallel reporter assay
  • Regulatory variation
  • SNPs
  • Transitions
  • Transversions

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

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