title: Survey of variation in human transcription factors reveals prevalent DNA binding changes.
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.
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.|Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA.|Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA.|Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Barrera
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Vedenko
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jesse V
authors.initials: JV
authors.lastname: Kurland
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.|Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Rogers
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Gisselbrecht
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA.|Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.|Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Rossin
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.|Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Jaie
authors.initials: J
authors.lastname: Woodard
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Mariani
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.|Program in Biological and Biomedical Sciences, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Kian Hong
authors.initials: KH
authors.lastname: Kock
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sachi
authors.initials: S
authors.lastname: Inukai
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Trevor
authors.initials: T
authors.lastname: Siggers
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Leila
authors.initials: L
authors.lastname: Shokri
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Raluca
authors.initials: R
authors.lastname: Gordân
authors.affiliation: Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Sahni
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.|Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Cotsapas
authors.affiliation: Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Hao
authors.affiliation: Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Yi
authors.affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.|Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.
authors.forename: Manolis
authors.initials: M
authors.lastname: Kellis
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.|Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.|Center for Human Genetics Research and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.affiliation: Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Vidal
authors.affiliation: Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Hill
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.|Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA.|Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA.|Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA.|Program in Biological and Biomedical Sciences, Harvard University, Cambridge, MA 02138, USA.|Center for Cancer Systems Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.|Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Martha L
authors.initials: ML
authors.lastname: Bulyk
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D003198:Computer Simulation; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D059472:Exome / Q000235:genetics; D005786:Gene Expression Regulation; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D040081:Protein Array Analysis; D011485:Protein Binding; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; D004247:DNA