title: The functional significance of common polymorphisms in zinc finger transcription factors.
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.
authors: Genome Center and Department of Biochemistry and Molecular Medicine, University of California, Davis, California 95616.
authors: Sarah H
authors: SH
authors: Lockwood
authors: Genome Center and Department of Evolution and Ecology, University of California, Davis, California 95616.
authors: Anna
authors: A
authors: Guan
authors: 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.
authors: Abigail S
authors: AS
authors: Yu
authors: Genome Center and Department of Evolution and Ecology, University of California, Davis, California 95616.
authors: Chi
authors: C
authors: Zhang
authors: 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.
authors: Artem
authors: A
authors: Zykovich
authors: Genome Center and Department of Molecular and Cellular Biology, University of California, Davis, California 95616.
authors: Ian
authors: I
authors: Korf
authors: Genome Center and Department of Evolution and Ecology, University of California, Davis, California 95616 brannala@ucdavis.edu djsegal@ucdavis.edu.
authors: Bruce
authors: B
authors: Rannala
authors: Genome Center and Department of Biochemistry and Molecular Medicine, University of California, Davis, California 95616 brannala@ucdavis.edu djsegal@ucdavis.edu.
authors: David J
authors: http://orcid.org/0000-0001-8962-3105
authors: DJ
authors: Segal
mesh_terms: D004247:DNA / Q000378:metabolism; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D040641:Quantitative Trait Loci; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D014157:Transcription Factors; D004247:DNA
keywords: Hardy-Weinberg Equilibrium; nonsynonymous SNPs; trans-expression quantitative trait loci; transcription factors; zinc finger proteins