title: Alternative splice variants encoding unstable protein domains exist in the human brain.
abstract: Alternative splicing has been recognized as a major mechanism by which protein diversity is increased without significantly increasing genome size in animals and has crucial medical implications, as many alternative splice variants are known to cause diseases. Despite the importance of knowing what structural changes alternative splicing introduces to the encoded proteins for the consideration of its significance, the problem has not been adequately explored. Therefore, we systematically examined the structures of the proteins encoded by the alternative splice variants in the HUGE protein database derived from long (>4 kb) human brain cDNAs. Limiting our analyses to reliable alternative splice junctions, we found alternative splice junctions to have a slight tendency to avoid the interior of SCOP domains and a strong statistically significant tendency to coincide with SCOP domain boundaries. These findings reflect the occurrence of some alternative splicing events that utilize protein structural units as a cassette. However, 50 cases were identified in which SCOP domains are disrupted in the middle by alternative splicing. In six of the cases, insertions are introduced at the molecular surface, presumably affecting protein functions, while in 11 of the cases alternatively spliced variants were found to encode pairs of stable and unstable proteins. The mRNAs encoding such unstable proteins are much less abundant than those encoding stable proteins and tend not to have corresponding mRNAs in non-primate species. We propose that most unstable proteins encoded by alternative splice variants lack normal functions and are an evolutionary dead-end.
authors.affiliation: Laboratory of Gene-Product Informatics, Center for Information Biology-DNA Data Bank of Japan, National Institute of Genetics, Research Organization of Information and Systems, Shizuoka 411-8540, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Homma
authors.forename: Reiko F
authors.initials: RF
authors.lastname: Kikuno
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nagase
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.forename: Ken
authors.initials: K
authors.lastname: Nishikawa
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001921:Brain / Q000378:metabolism*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012313:RNA / Q000235:genetics / Q000378:metabolism; D022821:RNA Splice Sites; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D017386:Sequence Homology, Amino Acid
chemical_list: D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D022821:RNA Splice Sites; D012313:RNA