Transversions have larger regulatory effects than transitions

BMC Genomics
Cong GuoTimothy E Reddy

Abstract

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. 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. 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, fundame...Continue Reading

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Citations

Sep 29, 2020·PLoS Computational Biology·Alejandro V Cano, Joshua L Payne
Mar 8, 2019·Frontiers in Plant Science·Zinan LuoHussein Abdel-Haleem
Jul 22, 2020·Nature Biotechnology·Ibrahim C KurtJ Keith Joung
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Aug 17, 2020·BMC Genomics·Ahasanul HoqueMukhlesur Rahman
Nov 21, 2020·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Adria-Jaume RouraBozena Kaminska
Jun 4, 2021·Genetics·Juraj Bergman, Mikkel Heide Schierup
Sep 30, 2021·Archives of Microbiology·Aarti S KakatkarRavindranath Shashidhar
Nov 11, 2021·Omics : a Journal of Integrative Biology·Muliyar Krishna RajeshThottethodi Subrahmanya Keshava Prasad
Dec 17, 2021·Antioxidants & Redox Signaling·Joel R DrevetRobert John Aitken

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Datasets Mentioned

BETA
GM12878

Methods Mentioned

BETA
ChIP-seq
PCR
transfections

Software Mentioned

Genome Analysis Toolkit ( GATK )
STARR
DNAshapeR
POP
R
JASPAR
BioPython

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