Science. 2016 Mar 25;351(6280):1450-1454. doi: 10.1126/science.aad2257. Epub 2016 Mar 24.

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

Barrera LA^1,^2,^3,⁴, Vedenko A^#¹, Kurland JV^#¹, Rogers JM^1,², Gisselbrecht SS¹, Rossin EJ^3,^5,⁶, Woodard J^1,², Mariani L¹, Kock KH^1,⁷, Inukai S¹, Siggers T¹, Shokri L¹, Gordân R¹, Sahni N^8,⁹, Cotsapas C^5,⁶, Hao T^8,⁹, Yi S^8,⁹, Kellis M^4,⁶, Daly MJ^5,^6,¹⁰, Vidal M^8,⁹, Hill DE^8,⁹, Bulyk ML^1,^2,^3,^6,^7,^8,¹¹.

Author information

1: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
2: Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA.
3: Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA.
4: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
5: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
6: Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
7: Program in Biological and Biomedical Sciences, Harvard University, Cambridge, MA 02138, USA.
8: Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
9: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
10: Center for Human Genetics Research and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
11: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
#: Contributed equally

Abstract

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.