The purpose of this project is the application of information theory to basic and clinical research on the relationships between DNA and protein sequences. We have collaborated with Dr. T. Schneider of NCI, et al, to perform DNA splice site analyses. This includes collaborative development of processing algorithms for the information content of macromolecular sequences. It also involves communication of data, processing methods, and results among researchers in diverse fields. The results of our extensive work on mutations of the Neurofibromatosis II (NF2) gene have been written up. Several previously unexplained mutational effects have been remarkably well explained by our information-theory based analysis. In particular, two point mutations that were thought to affect only the local amino acid translation were found to have very serious splicing effects, and thus very significant effects on the mRNA and subsequently encoded proteins. We are now preparing documents that describe this work involving collaboration across a wide range of disciplines. A set of analyses was done for Dr. Robert Nussbaum's group in NHGRI. The common feature of the sequences of interest was the expected presence of a """"""""G"""""""" at position IVS+4 in an intron. Using the generally accepted consensus sequence model, this should have no effect on splicing. According to our model, this base does make non-trivial contributions to the strength of the donor site. About 13 mutations and over 20 wild type sequences associated with 9 genes and several introns were analyzed. Some considerable effort was required to specify the genes and sequences that actually did allow the IVS+4 """"""""A"""""""" to """"""""G"""""""" change. In general, those donor sites with a """"""""G"""""""" at IVS+4 were stronger than average, and those mutations which generated an IVS+4 """"""""A"""""""" to """"""""G"""""""" change gave stronger donor sites at the beginning of the intron. However, the complexity of the cryptic sites associated with this set of point mutations seemed more important than the simple strengthening of the wild type (wt) donor site. An effort to analyze mutations associated with Duchenne muscular dystrophy sequences has been initiated with Dr. Therese Tuohy of the Department of Human Genetics of the University of Utah.
