Biological and technological implications of gene splice variants

Splice variants are important in biological functions and are of great interest to scientists. They have an important biological role (e.g . functional diversity) as well as a technological role affecting molecular studies (e.g. hybridization to microarray probes). These two roles are connected in a subtle manner---both are dependent on the self-recognition of reverse-complementary sequences. The inter-relation of the biological and technological role of alternative splicing has profound implications for our interpretation of biological data, and access to information about alternatively spliced transcripts is of critical importance to the current state of biological inquiry. Alternative splicing of gene transcripts generates a greater diversity in the transcriptome than that encapsulated in the genome. Taking alternative splicing into account requires mapping of probe sequence to exons. A database of all known splice variants and their exons is required. None of the published splice variant databases permit explicit identification of microarray probes that distinguish splice variants. To assign probes to splice variants and to generate a consistent nomenclature, variants need to be delineated explicitly. Guidelines exist for naming splice variants, but these guidelines have been adopted by few researchers, and there are no explicit standards. There are no published large-scale computational studies in which the relationship between the number of splice variants and biological function of a gene have been studied in a global manner. The advent of the Gene Ontology and tools like GoMiner now makes it feasible to perform this determination. The hypothesis tested in this dissertation is that genes with a high (CPD 0.95) number of splice variants correlate with a small number of specific biological functions. The research presented here describes the implementation and results of three elements needed to test this hypothesis: (1) Creating a comprehensive collection of known alternative splice forms of human genes; (2) Constructing methods to name and delineate splice variants; (3) Establishing the relationship between the numbers of splice variants and biological functions of a gene. In aid of these goals the sub-exon level mapping of probes-to-target sequences in the context of splice variants has been performed to explicitly identify probes that distinguish splice variants.