Alternative splicing

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.
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.
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.

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

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. 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.

Abnormal variations in splicing occur in disease. Many human genetic disorders come from splicing variants. Abnormal splicing variants may also contribute to the development of cancer. High-throughput sequencing of RNA can for example be used to measure the genome-scale amount of deviating alternative splicing, such as in a cohort of colorectal cancers, where high amount of aberrant splicing was associated to poor patient survival. Non-working splicing products are usually dealt with by post-transcriptional quality control. 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.

References

  1. 1 2 3 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. S2CID 23576288.
  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. S2CID 9228930.
  4. 1 2 3 Matlin, Arianne J.; Clark, Francis; Smith, Christopher W. J. (2005). "Understanding alternative splicing: towards a cellular code". Nature Reviews. 6 (5): 386–398. Bibcode:2005NRMCB...6..386M. doi:10.1038/nrm1645. PMID 15956978. S2CID 14883495.
  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): 279–285. doi:10.1101/gad.1643108. PMC 2731647. 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. Bibcode:2009PLoSO...4.4732H. 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ↑ Strømme JM, Johannessen B, Skotheim RI (2023). "Deviating alternative splicing as a molecular subtype of microsatellite stable colorectal cancer". JCO Clinical Cancer Informatics. 7 (7) e2200159. doi:10.1200/CCI.22.00159. PMID 36821799.
  10. ↑ 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.
  11. ↑ Schmucker D.; et al. (2000). "Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity". Cell. 101 (6): 671–684. Bibcode:2000Cell..101..671S. doi:10.1016/S0092-8674(00)80878-8. PMID 10892653. S2CID 13829976.