2 December 2016
Martha Bulyk
Division of Genetics
Brigham & Women's Hospital and
Harvard Medical School
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 are developing a computational, structure-based approach to evaluate TF variants for their impact on DNA-binding activity. We are using universal protein binding microarrays to assay sequence-specific DNA-binding activity across reference and variant alleles found in individuals of diverse ancestries and families with Mendelian diseases. We have found variants 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.