Alternative splicing

File:Pre-mRNA to mRNA.svg
Exons and introns in pre-mRNA: forming mature mRNA by splicing. The UTRs are non-coding parts of exons at the ends of the mRNA.
File:Splicing overview.jpg
Alternative splicing produces two protein isoforms.

Alternative splicing allows DNA to code for more than one protein. It varies the exon make-up of the messenger RNA.

In alternative splicing the exons of the pre-messenger RNA produced by transcription are reconnected in different ways during RNA splicing.

This produces different mature messenger RNAs from the same gene. They get translated into different proteins. Thus, a single gene may code for multiple proteins.[1]

Alternative splicing is normal in eukaryotes. It greatly increases the diversity of proteins that can be encoded by the genome.[1] In humans, ~95% of multiexonic genes are alternatively spliced.[2][3][4]

There are various kinds of alternative splicing: the most common is exon skipping. An exon may be included in mRNAs under some conditions or in particular tissues, and omitted from the mRNA in others.[1] There are splicing activators that promote the use of a particular splice site, and splicing repressors that reduce the use of a particular site. New types of alternative splicing are being found.[4][5]

Abnormal variations in splicing occur in disease. Many human genetic disorders come from splicing variants.[4] Abnormal splicing variants may also contribute to the development of cancer.[6][7][8] Non-working splicing products are usually dealt with by post-transcriptional quality control.[9] That is, they are chopped up by enzymes.

Source of diversity

Alternative splicing (the re-combination of different exons) is a major source of genetic diversity in eukaryotes. One particular Drosophila gene (DSCAM) can be alternatively spliced into 38,000 different mRNA.[10]

References

  1. 1.0 1.1 1.2 Black, Douglas L. (2003). "Mechanisms of alternative pre-messenger RNA splicing". Annual Reviews of Biochemistry 72 (1): 291–336. doi:10.1146/annurev.biochem.72.121801.161720. PMID 12626338. 
  2. multiexonic: those genes where the coding sections (exons) are separated by non-coding sections (introns)
  3. Pan, Q et al. (2008). "Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing". Nature Genetics 40 (12): 1413–1415. doi:10.1038/ng.259. PMID 18978789. 
  4. 4.0 4.1 4.2 Matlin, AJ; Clark F, Smith CWJ (2005). "Understanding alternative splicing: towards a cellular code". Nature Reviews 6 (5): 386–398. doi:10.1038/nrm1645. PMID 15956978. 
  5. David, C.J.; Manley, J.L. (2008). "The search for alternative splicing regulators: new approaches offer a path to a splicing code". Genes & Development 22 (3): 279. doi:10.1101/gad.1643108. PMID 18245441. 
  6. Skotheim R.I. and Nees M (2007). "Alternative splicing in cancer: noise, functional, or systematic?". The international journal of biochemistry & cell biology 39 (7-8): 1432–49. doi:10.1016/j.biocel.2007.02.016. PMID 17416541. 
  7. Bauer, Joseph Alan et al. (2009). "A global view of cancer-specific transcript variants by subtractive transcriptome-wide analysis". PLoS ONE 4 (3): e4732. doi:10.1371/journal.pone.0004732. PMC 2648985. PMID 19266097. 
  8. Fackenthal J; Godley L (2008). "Aberrant RNA splicing and its functional consequences in cancer cells" (Free full text). Disease models & mechanisms 1 (1): 37–42. doi:10.1242/dmm.000331. PMC 2561970. PMID 19048051. 
  9. Danckwardt S et al. (2002). "Abnormally spliced beta-globin mRNAs: a single point mutation generates transcripts sensitive and insensitive to nonsense-mediated mRNA decay". Blood 99 (5): 1811–6. doi:10.1182/blood.V99.5.1811. PMID 11861299. http://bloodjournal.hematologylibrary.org/cgi/content/full/99/5/1811. 
  10. Schmucker D. et al. (2000). "Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity". Cell 101 (6): 671–684. doi:10.1016/S0092-8674(00)80878-8. PMID 10892653.