Survey of variation in human transcription factors reveals prevalent DNA binding changes

Science  25 Mar 2016:
Vol. 351, Issue 6280, pp. 1450-1454
DOI: 10.1126/science.aad2257

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Variation and transcription factor binding

Little is known about the phenotypic and functional effects of genetic variants that result in amino acid changes within functional proteins. Barrera et al. investigated whether amino acid variants changed the DNA binding specificity or affinity of transcription factors. Predictive analyses identified changes in the proteins, and protein-binding microarrays verified changes that affected transcription factor function, including those associated with disease. Thus, within-human protein sequence variation can affect transcriptional regulatory networks, which, depending on the genetic variant, may confer robustness and buffer against amino acid changes and could explain phenotypic variation among individuals.

Science, this issue p. 1450


Sequencing of exomes and genomes has revealed abundant genetic variation affecting the coding sequences of human transcription factors (TFs), but the consequences of such variation remain largely unexplored. We developed a computational, structure-based approach to evaluate TF variants for their impact on DNA binding activity and used universal protein-binding microarrays to assay sequence-specific DNA binding activity across 41 reference and 117 variant alleles found in individuals of diverse ancestries and families with Mendelian diseases. We found 77 variants in 28 genes that affect DNA binding affinity or specificity and identified thousands of rare alleles likely to alter the DNA binding activity of human sequence-specific TFs. Our results suggest that most individuals have unique repertoires of TF DNA binding activities, which may contribute to phenotypic variation.

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