Nucleic Acids Research Advance Access published online on October 15, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn738
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Methods Online |
Evolutionary computation for discovery of composite transcription factor binding sites
1Natural Selection, Inc., 9330 Scranton Rd., Suite 150, San Diego, CA 92121 and 2Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
*To whom correspondence should be addressed. Tel: +1 317 277 9657; Fax: +1 317 276 6009; Email: chen_su{at}lilly.com
Received July 7, 2008. Revised September 5, 2008. Accepted October 2, 2008.
Previous research demonstrated the use of evolutionary computation for the discovery of transcription factor binding sites (TFBS) in promoter regions upstream of coexpressed genes. However, it remained unclear whether or not composite TFBS elements, commonly found in higher organisms where two or more TFBSs form functional complexes, could also be identified by using this approach. Here, we present an important refinement of our previous algorithm and test the identification of composite elements using NFAT/AP-1 as an example. We demonstrate that by using appropriate existing parameters such as window size, novel-scoring methods such as central bonusing and methods of self-adaptation to automatically adjust the variation operators during the evolutionary search, TFBSs of different sizes and complexity can be identified as top solutions. Some of these solutions have known experimental relationships with NFAT/AP-1. We also indicate that even after properly tuning the model parameters, the choice of the appropriate window size has a significant effect on algorithm performance. We believe that this improved algorithm will greatly augment TFBS discovery.