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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Barrera, LA; Vedenko, A; Kurland, JV; Rogers, JM; Gisselbrecht, SS; Rossin, EJ; Woodard, J; Mariani, L; Kock, KH; Inukai, S; Siggers, T; Shokri, L; Gordân, R; Sahni, N; Cotsapas, C; Hao, T; Yi, S; Kellis, M; Daly, MJ; Vidal, M; Hill, DE; Bulyk, ML

Published Date

  • March 25, 2016

Published In

Volume / Issue

  • 351 / 6280

Start / End Page

  • 1450 - 1454

PubMed ID

  • 27013732

Pubmed Central ID

  • PMC4825693

Electronic International Standard Serial Number (EISSN)

  • 1095-9203

Digital Object Identifier (DOI)

  • 10.1126/science.aad2257


  • eng

Conference Location

  • United States