Specific modelling of regulatory units in DNA sequences

Transcriptional control regions are usually composed of a complex arrangement of individual transcriptional elements like protein binding sites. This modular structure allows generation of enormous functional diversity of regulatory regions with a limited set of individual elements. We implemented simple formal representations of these general features of regulatory regions into an algorithm capable of developing complex models reflecting both the element composition and the functional organization of individual elements. Our method (ModelGenerator) requires a training set of at least 10 sequences containing the regulatory regions to be modelled and a very simple initial model which may consist of just two characteristic transcription factor binding sites. We show the capability of our algorithm to expand the initial model solely by comparative sequence analysis leading to complex, biologically meaningful models. A second program (ModelInspector) is capable to scan new sequence data for matches to models defined by ModelGenerator. We show two models for retroviral transcriptional control regions to be highly specific. A search against GenBank using one of the models is shown to be free of false negatives and to produce less than 2 false positives/million nucleotides. Thus, our algorithms appear to be useful tools for the analysis of extremely long genomic sequences which are now becoming available as results of various genome sequencing projects.