As I write this, many of my colleagues are in Vienna, gathering for the 15th Annual International Conference on Intelligent Systems for Molecular Biology (ISMB)<\/a> & 6th European Conference on Computational Biology (ECCB).<\/p>\n I\u2019m not going to attend ISMB this year, unfortunately\u2014a confluence of new job and busy schedule. Next year, ISMB will be closer to home in Toronto. I\u2019m looking forward to it, because it will also give me a good reason to stop by and visit a scientist I know, Professor Laurence (Larry) Moran<\/a> up at U of Toronto.<\/p>\n Dr. Moran is interested in many things, including the molecular-level effects of evolutionary processes. If you read the Usenet newsgroup talk.origins<\/a> you\u2019ll find some very good posts by Larry on many topics, including neutral selection. His website linked above has other interesting sites he\u2019s authored, I recommend them. He also blogs at Sandwalk: strolling with a skeptical biochemist<\/a><\/p>\n Over the past few years, I\u2019ve had some interesting discussions (sometimes heated) online with Larry on neutral selection, biological \u201cnoise\u201d, and alternative splicing. For example, in the past discussions Larry\u2019s viewpoint was that the majority of alternative splicing was noise with some functional exceptions. My viewpoint at the time, back in 2003 or so, was that there was a definite use for alternative splicing with specific examples, and we discussed the possibility that many of the alternative forms were in fact nonfunctional noise that yet provided a selectable background of protein forms for evolution.<\/p>\n Until recently, I had been working at a biopharma company that was interested in alternative splice products\u2026like many other biopharmas at the time. The idea was that the discovery of an alternative splice product would be a chance to get some intellectual property rights on a protein and its use. I had seen countless examples of such alternative splicing products when combing through EST databases. Some genes had a plethora of alternatively spliced forms. In fact, we published a paper on the complexity of a particular GPCR family, the LGR receptors, in Molecular Human Reproduction<\/a> in which we found several alternatively spliced variants of the receptor that seemed to have expressed protein products that had a functional activity in vivo<\/em>.<\/p>\n There is other evidence for the complexity and functionality of splice variants, see for example this excellent open access review, Benjamin J. Blencowe Cell, Vol 126, 37-47, 14 July 2006<\/a> . The review is complex and detailed and I can only suggest you read it if you\u2019re interested, as I can\u2019t hope to do it justice here. One of its subsections gives a discussion of the global consequence of alternative splicing. Acknowledging the stochastic nature of splicing, and that many transcripts may in fact have no apparent biological function, the author proposes a new level of regulatory complexity: an alternative splicing \u201cnetwork\u201d which may further regulate cellular proceses by providing different isoforms in different contexts\u2014essentially, for specific interaction coordination in different tissues. He writes, \u201cAn emerging model is that these subsets of genes may comprise \u201clayers\u201d of gene networks that coordinate specific cellular functions.\u201d<\/p>\n At ISMB\/ECCE this year will be several talks specifically discussing alternative splicing, both in evolutionary terms (primates), in humans (ENCODE), and in specific cases of certain proteins.<\/p>\n One such presentation will be by Michael Tress, who was the first author of many on a PNAS paper detailing analysis of manually annotated splice variants in the GENCODE project (Tress et. al, The implications of alternative splicing in the ENCODE protein complement. PNAS 2007 Mar 27;104(13):5495-5500<\/a> ) where the authors examined a small segment of the human compliment of alternative splicing: about 2600 annotated transcripts for 487 distinct loci, with an average of 2.53 transcripts per locus. Supporting the papers mentioned in the Blencowe review, the Tress publication finds that in the loci they examined, that \u201d…these functional alternative isoforms appear to be the exception rather than the rule.\u201d They also conclude that many isoforms may be deleterious based on detailed structural analysis of the protein products, but they note \u201cIf alternative transcripts in low numbers do not adversely affect the organism, the selection pressure against exon loss or substitution will be reduced, and the new variants will be tolerated, making large evolutionary changes possible.\u201d<\/p>\n So, where is work on alternative splicing going to lead in the future? Blencowe\u2019s review mentioned that there is a significant number of human SNPs that may cause disease phenotypes by affecting splicing. These diseases may result in aberrant splicing in the affected gene, causing loss of a transcript by nonsense-mediated RNA decay (NMD) or causing loss of a protein domain or protein interaction region, thereby disrupting the operating characteristics of the protein. There will likely be future work in discovering these SNPs and variations leading to alternative splicing. Additionally (also in Blencowe) there will likely be further work in examining patterns of alternative splicing between species, between tissues, and between specific developmental and biochemical contexts.<\/p>\n There is a lot of room for new research on alternative splicing. I recently attended a Gordon conference on Bioinformatics<\/a> which I cannot discuss in detail as many results were not yet published. However, I can mention that I saw some good talks by Boston labs on alternative splicing: \u201cCooperative, Compensatory and Context Effects in Pre-mRNA Splicing\u201d by Chris Burge at MIT<\/a> , and \u201cPolymorphic Splicing in Humans\u201d by Hunter Fraser at the Broad Institute.<\/p>\n