Journal
GENOME BIOLOGY
Volume 8, Issue 10, Pages -Publisher
BMC
DOI: 10.1186/gb-2007-8-10-r225
Keywords
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Funding
- NATIONAL CANCER INSTITUTE [U54CA112952, R01CA104663, R01CA106520] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [R01HG004065] Funding Source: NIH RePORTER
- NCI NIH HHS [R01 CA106520, U54 CA112952, R01 CA104663, 1-R01-CA106520-03, 5-U54-CA112952-03, 1-R01-CA104663-05] Funding Source: Medline
- NHGRI NIH HHS [R01 HG004065, 1-R01-HG004065] Funding Source: Medline
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Background: The phenomenon of functional site turnover has important implications for the study of regulatory region evolution, such as for promoter sequence alignments and transcription factor binding site (TFBS) identification. At present, it remains difficult to estimate TFBS turnover rates on real genomic sequences, as reliable mappings of functional sites across related species are often not available. As an alternative, we introduce a flexible new simulation system, Phylogenetic Simulation of Promoter Evolution (PSPE), designed to study functional site turnovers in regulatory sequences. Results: Using PSPE, we study replacement turnover rates of different individual TFBSs and simple modules of two sites under neutral evolutionary functional constraints. We find that TFBS replacement turnover can happen rapidly in promoters, and turnover rates vary significantly among different TFBSs and modules. We assess the influence of different constraints such as insertion/ deletion rate and translocation distances. Complementing the simulations, we give simple but effective mathematical models for TFBS turnover rate prediction. As one important application of PSPE, we also present a first systematic evaluation of multiple sequence aligners regarding their capability of detecting TFBSs in promoters with site turnovers. Conclusion: PSPE allows researchers for the first time to investigate TFBS replacement turnovers in promoters systematically. The assessment of alignment tools points out the limitations of current approaches to identify TFBSs in non-coding sequences, where turnover events of functional sites may happen frequently, and where we are interested in assessing the similarity on the functional level. PSPE is freely available at the authors' website.
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