Genome-wide inference of natural selection on human transcription factor binding sites

Arbiza, L., Gronau, I., Aksoy, B. A., Hubisz, M. J., Gulko, B., Keinan, A., Siepel, A. (2013) Genome-wide inference of natural selection on human transcription factor binding sites. Nat Genet, 45 (7). pp. 723-9. ISSN 1061-4036

URL: http://www.ncbi.nlm.nih.gov/pubmed/23749186
DOI: 10.1038/ng.2658

Abstract

For decades, it has been hypothesized that gene regulation has had a central role in human evolution, yet much remains unknown about the genome-wide impact of regulatory mutations. Here we use whole-genome sequences and genome-wide chromatin immunoprecipitation and sequencing data to demonstrate that natural selection has profoundly influenced human transcription factor binding sites since the divergence of humans from chimpanzees 4-6 million years ago. Our analysis uses a new probabilistic method, called INSIGHT, for measuring the influence of selection on collections of short, interspersed noncoding elements. We find that, on average, transcription factor binding sites have experienced somewhat weaker selection than protein-coding genes. However, the binding sites of several transcription factors show clear evidence of adaptation. Several measures of selection are strongly correlated with predicted binding affinity. Overall, regulatory elements seem to contribute substantially to both adaptive substitutions and deleterious polymorphisms with key implications for human evolution and disease.

Item Type: Paper
Uncontrolled Keywords: Animals Base Sequence Binding Sites/genetics Chromosome Mapping Computer Simulation *Genome, Human/genetics Genome-Wide Association Study Humans Models, Genetic Models, Statistical Mutation/physiology Regulatory Sequences, Nucleic Acid/genetics Selection, Genetic/*genetics Substrate Specificity Transcription Factors/*metabolism
Subjects: bioinformatics
bioinformatics > genomics and proteomics
bioinformatics > computational biology
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:
Communities: CSHL labs > Siepel lab
Depositing User: Matt Covey
Date Deposited: 15 Jan 2015 21:00
Last Modified: 15 Jan 2015 21:00
PMCID: PMC3932982
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31045

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