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Analysis of variation at transcription factor binding sites in Drosophila and humans

Mikhail Spivakov12*, Junaid Akhtar2, Pouya Kheradpour34, Kathryn Beal1, Charles Girardot2, Gautier Koscielny1, Javier Herrero1, Manolis Kellis34, Eileen EM Furlong2 and Ewan Birney1*

Author Affiliations

1 European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, CB10 1SD, UK

2 Genome Biol Unit, European Molecular Biology Laboratory, D-69117 Heidelberg, Germany

3 MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA 02139, USA

4 Broad Institute, Cambridge, MA 02142, USA

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Genome Biology 2012, 13:R49  doi:10.1186/gb-2012-13-9-r49

Published: 5 September 2012



Advances in sequencing technology have boosted population genomics and made it possible to map the positions of transcription factor binding sites (TFBSs) with high precision. Here we investigate TFBS variability by combining transcription factor binding maps generated by ENCODE, modENCODE, our previously published data and other sources with genomic variation data for human individuals and Drosophila isogenic lines.


We introduce a metric of TFBS variability that takes into account changes in motif match associated with mutation and makes it possible to investigate TFBS functional constraints instance-by-instance as well as in sets that share common biological properties. We also take advantage of the emerging per-individual transcription factor binding data to show evidence that TFBS mutations, particularly at evolutionarily conserved sites, can be efficiently buffered to ensure coherent levels of transcription factor binding.


Our analyses provide insights into the relationship between individual and interspecies variation and show evidence for the functional buffering of TFBS mutations in both humans and flies. In a broad perspective, these results demonstrate the potential of combining functional genomics and population genetics approaches for understanding gene regulation.