Transversions have larger regulatory effects than transitions

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

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Citations (Scopus)

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
Number of pages1
JournalBMC Genomics
Volume18
Issue number1
DOIs
StatePublished - May 19 2017

Fingerprint

Transcription Factors
Gene Expression
DNA
DNA-Binding Proteins
Regulator Genes
Human Activities
Amino Acid Sequence
Alleles
Binding Sites
Mutation
Population
Genes
Proteins

Keywords

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

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

Cite this

Guo, Cong ; McDowell, Ian C. ; Nodzenski, Michael ; Scholtens, Denise M ; Allen, Andrew S. ; Lowe Jr, William L ; Reddy, Timothy E. / Transversions have larger regulatory effects than transitions. In: BMC Genomics. 2017 ; Vol. 18, No. 1.
@article{70bc5601a4d443938741df2fc9e24972,
title = "Transversions have larger regulatory effects than transitions",
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.",
keywords = "Massively parallel reporter assay, Regulatory variation, SNPs, Transitions, Transversions",
author = "Cong Guo and McDowell, {Ian C.} and Michael Nodzenski and Scholtens, {Denise M} and Allen, {Andrew S.} and {Lowe Jr}, {William L} and Reddy, {Timothy E.}",
year = "2017",
month = "5",
day = "19",
doi = "10.1186/s12864-017-3785-4",
language = "English (US)",
volume = "18",
journal = "BMC Genomics",
issn = "1471-2164",
publisher = "BioMed Central",
number = "1",

}

Transversions have larger regulatory effects than transitions. / Guo, Cong; McDowell, Ian C.; Nodzenski, Michael; Scholtens, Denise M; Allen, Andrew S.; Lowe Jr, William L; Reddy, Timothy E.

In: BMC Genomics, Vol. 18, No. 1, 394, 19.05.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Transversions have larger regulatory effects than transitions

AU - Guo, Cong

AU - McDowell, Ian C.

AU - Nodzenski, Michael

AU - Scholtens, Denise M

AU - Allen, Andrew S.

AU - Lowe Jr, William L

AU - Reddy, Timothy E.

PY - 2017/5/19

Y1 - 2017/5/19

N2 - 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.

AB - 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.

KW - Massively parallel reporter assay

KW - Regulatory variation

KW - SNPs

KW - Transitions

KW - Transversions

UR - http://www.scopus.com/inward/record.url?scp=85019376313&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019376313&partnerID=8YFLogxK

U2 - 10.1186/s12864-017-3785-4

DO - 10.1186/s12864-017-3785-4

M3 - Article

C2 - 28525990

AN - SCOPUS:85019376313

VL - 18

JO - BMC Genomics

JF - BMC Genomics

SN - 1471-2164

IS - 1

M1 - 394

ER -