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The Functional Significance of Common Polymorphisms in Zinc Finger Transcription Factors
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2014 (English)In: G3 (Bethesda, Md.), ISSN 2160-1836, Vol. 4, 1647-1655 p.Article in journal (Refereed) Published
Abstract [en]

Variants that alter the DNA-binding specificity of transcription factors could affect the specificity for and expression of potentially many target genes, as has been observed in several tumor-derived mutations. Here we examined if such trans expression quantitative trait loci (trans-eQTLs) could similarly result from common genetic variants. We chose to focus on the Cys2-His2 class of zinc finger transcription factors because they are the most abundant superfamily of transcription factors in human and have well-characterized DNA binding interactions. We identified 430 SNPs that cause missense substitutions in the DNA-contacting residues. Fewer common missense SNPs were found at DNA-contacting residues compared to non-DNA-contacting residues (P = 0.00006), consistent with possible functional selection against SNPs at DNA-contacting positions. Functional predictions based on ZNF DNA binding preferences also suggested that many common substitutions could potentially alter binding specificity. However, Hardy-Weinberg Equilibrium analysis and examination of seven orthologs within the primate lineage failed to find evidence of trans-eQTLs associated with the DNA-contacting positions, nor evidence of a difference selection pressure on a contemporary and evolutionary timescales. The overall conclusion was that common SNPs that alter the DNA-contacting residues of these factors are unlikely to produce strong trans-eQTLs, consistent with the observations by others that trans-eQTLs in humans tend to be few and weak. Some rare SNPs might alter specificity, and remained rare due to purifying selection. The study also underscores the need for large-scale eQTLs mapping efforts that might provide experimental evidence for SNPs that alter the choice of transcription factors binding sites.

Place, publisher, year, edition, pages
2014. Vol. 4, 1647-1655 p.
National Category
Natural Sciences Biological Sciences
Research subject
Diversity of life
Identifiers
URN: urn:nbn:se:nrm:diva-623DOI: 10.1534/g3.114.012195PubMedID: 24970883OAI: oai:DiVA.org:nrm-623DiVA: diva2:745121
Available from: 2014-09-09 Created: 2014-09-09 Last updated: 2015-02-02

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CiteExportLink to record
Permanent link

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Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
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  • de-DE
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  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
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  • Other locale
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Output format
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