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G3 (Bethesda). 2014 Jun 26;4(9):1647-55. doi: 10.1534/g3.114.012195.

The functional significance of common polymorphisms in zinc finger transcription factors.

Author information

1
Genome Center and Department of Biochemistry and Molecular Medicine, University of California, Davis, California 95616.
2
Genome Center and Department of Evolution and Ecology, University of California, Davis, California 95616.
3
Genome Center and Department of Biochemistry and Molecular Medicine, University of California, Davis, California 95616 Genome Center and Department of Molecular and Cellular Biology, University of California, Davis, California 95616.
4
Genome Center and Department of Molecular and Cellular Biology, University of California, Davis, California 95616.
5
Genome Center and Department of Evolution and Ecology, University of California, Davis, California 95616 brannala@ucdavis.edu djsegal@ucdavis.edu.
6
Genome Center and Department of Biochemistry and Molecular Medicine, University of California, Davis, California 95616 brannala@ucdavis.edu djsegal@ucdavis.edu.

Abstract

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 with non-DNA-contacting residues (P = 0.00006), consistent with possible functional selection against SNPs at DNA-contacting positions. Functional predictions based on zinc finger transcription factor (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 or evidence of a different 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 factor binding sites.

KEYWORDS:

Hardy-Weinberg Equilibrium; nonsynonymous SNPs; trans-expression quantitative trait loci; transcription factors; zinc finger proteins

PMID:
24970883
PMCID:
PMC4169156
DOI:
10.1534/g3.114.012195
[Indexed for MEDLINE]
Free PMC Article

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