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- Lockwood, Sarah H, et al.
(author)
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The Functional Significance of Common Polymorphisms in Zinc Finger Transcription Factors
- 2014
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In: G3. - : Oxford University Press (OUP). - 2160-1836. ; 4, s. 1647-1655
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Journal article (peer-reviewed)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 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.
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| 3. |
- Zhang, Chi, et al.
(author)
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Robustness of compound Dirichlet priors for Bayesian inference of branch lengths
- 2012
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In: Systematic Biology. - : Oxford University Press (OUP). - 1063-5157 .- 1076-836X. ; 61:5, s. 779-784
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Journal article (peer-reviewed)abstract
- We modified the phylogenetic program MrBayes 3.1.2 to incorporate the compound Dirichlet priors for branch lengths proposed recently by Rannala, Zhu, and Yang (2012. Tail paradox, partial identifiability and influential priors in Bayesian branch length inference. Mol. Biol. Evol. 29:325-335.) as a solution to the problem of branch-length overestimation in Bayesian phylogenetic inference. The compound Dirichlet prior specifies a fairly diffuse prior on the tree length (the sum of branch lengths) and uses a Dirichlet distribution to partition the tree length into branch lengths. Six problematic data sets originally analyzed by Brown, Hedtke, Lemmon, and Lemmon (2010. When trees grow too long: investigating the causes of highly inaccurate Bayesian branch-length estimates. Syst. Biol. 59:145-161) are reanalyzed using the modified version of MrBayes to investigate properties of Bayesian branch-length estimation using the new priors. While the default exponential priors for branch lengths produced extremely long trees, the compound Dirichlet priors produced posterior estimates that are much closer to the maximum likelihood estimates. Furthermore, the posterior tree lengths were quite robust to changes in the parameter values in the compound Dirichlet priors, for example, when the prior mean of tree length changed over several orders of magnitude. Our results suggest that the compound Dirichlet priors may be useful for correcting branch-length overestimation in phylogenetic analyses of empirical data sets.
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