Alternative splicing is a regulated process during gene expression that results in a single gene encoding two or more proteins. That is, the phenomenon whereby the same gene gives rise to multiple different transcripts, depending upon which combination of exons are incorporated in the mature mRNA transcript. For reasons that are so far unknown, the proportion of alternatively spliced genes vary according to each species. For example alternative splicing is rare in plants whereas in humans more than 70% of the genes are alternatively spliced. Alternative splice transcripts can be identified for almost every human gene. Due to the alternative splice approximately 30,000 human genes may encode 64,000 to 96,000 different proteins.[note 1] The average human gene contains between 10 and 15 exons and encodes three or more different proteins due to alternative splicing. Alternative splicing can be either constitutive or regulated. In the first case, more than one product is always produced from the transcribed gene and in the latter case different forms are generated at different times, under different conditions, or even in different cell or tissue types. In most cases the proteins synthesized from a gene by alternative splicing are identical along most of their length but differing in key regions that may affect important properties like their cellular location, the kinetics of their catalytic activity or the types of ligands they can bind.
Alternative splicing was first observed in the late 1970s while biochemists were studying the bacteriophage φX174. They discovered that the genome of this bacteriophage directed the production of more proteins than was expected based on the size of its DNA. They solved this paradox demonstrating that some of the φX174 genes, in fact, overlap.
Alternative splicing and introns
The introns make alternative splicing possible but they are not, apparently, just biologically inert spaces. There is growing evidence that they perform many functions, including the regulation of alternative splicing.[note 2] Proteins that regulate splicing bind to specific sites called exonic splicing enhancers (ESE) or intronic splicing enhancers (ISE) that enhance the splicing at nearby splice sites. These proteins can also bind to other kinds of specific sites called silencers. These sites are called exonic splicing silencers (ESS) or intronic splicing silencers (ISS) and they repress the splicing at nearby splice sites. In genes with various introns, some of these introns can be removed alone or in combination depending on how the machinery of recomposition interacts with the RNA.
Types of alternative splicing events
- Exon skipping or cassette exon: An exon may be either included or skipped (a cassete exon).
- Mutually exclusive exons: The mature mRNA includes either the exon in green or the exon in yellow, but not both.
- Alternative splice donor site: An alternative 5' splice junction (donor site) is used, changing the 3' boundary of the upstream exon.
- Alternative splice acceptor site: An alternative 3' splice junction (acceptor site) is used, changing the 5' boundary of the downstream exon.
- Intron retention: An intron is either retained or excluded.
- This number is an estimate and may vary. For example, another author provides the estimate that we, humans, have about 25,000 genes and these genes encode more than about 100,000 proteins, as in Griffiths, Anthony J. F.; Wessler, Susan R.; Lewontin, Richard C.; Carroll, Sean B. (2008). Introduction to Genetic Analysis (9th ed.). New York: W. H. Freeman and Company. p. 296. ISBN 978-0-7167-6887-6. .
- After a debate between Stephen Meyer, Stephen Matheson and Arthur Hunt at Biola University, a blog war occurred including Stephen Matheson, Richard Sternberg and Laurence Moran. Moran and Matheson tried to ridicule the statement of Stephen Meyer that many introns are not junk DNA, claiming that only a handful of introns have function. Richard Sternberg responded to Matheson calculating that a reasonable estimate for the number of human introns that undergo alternative splicing was 90% of 190,000, that is, 171,000. Sternberg concluded that even if his estimate were off by a factor of two, the number of functional introns would still be far greater than Matheson's estimate. At the end of the blog war Moran admitted that at least 22,500 were introns involved in alternative splicing. This number is well above the alleged 1,000 introns. However this figure is still well below the evidence shown by Sternberg and based on peer-reviewed papers as in Wells, Jonathan (June 8, 2010). "The Fact-Free "Science" of Matheson, Hunt and Moran: Ridicule Instead of Reason, Authority Instead of Evidence". Evolution News and Views. http://www.evolutionnews.org/2010/06/the_factfree_science_of_mathes035521.html. Retrieved February 24, 2013.
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- Alternative splicing at wikipedia