Alternative splicing
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] 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.[9] Non-working splicing products are usually dealt with by post-transcriptional quality control.[10] 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.[11]
Alternative Splicing Media
Alternative splicing produces three protein isoforms. Protein A includes all of the exons, whereas Proteins B and C result from exon skipping.
Traditional classification of basic types of alternative RNA splicing events. Exons are represented as blue and yellow blocks, introns as lines in between.
Relative frequencies of types of alternative splicing events differ between humans and fruit flies.
Schematic cutoff from 3 splicing structures in the murine hyaluronidase gene. Directionality of transcription from 5' to 3' is shown from left to right. Exons and introns are not drawn to scale.
Spliceosome A complex defines the 5' and 3' ends of the intron before removal
Alternative splicing of dsx pre-mRNA
Alternative splicing of the Drosophila Transformer gene product.
Alternative splicing of the Fas receptor pre-mRNA
Related pages
References
- ↑ 1.0 1.1 1.2 Black, Douglas L.. Mechanisms of alternative pre-messenger RNA splicing. Annual Reviews of Biochemistry 72 (1) (2003). p. 291–336. doi:10.1146/annurev.biochem.72.121801.161720.
- ↑ multiexonic: those genes where the coding sections (exons) are separated by non-coding sections (introns)
- ↑ Pan, Q. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nature Genetics 40 (12) (2008). p. 1413–1415. doi:10.1038/ng.259.
- ↑ 4.0 4.1 4.2 Matlin, Arianne J.. Understanding alternative splicing: towards a cellular code. Nature Reviews 6 (5) (2005). p. 386–398. doi:10.1038/nrm1645.
- ↑ David, C.J.. The search for alternative splicing regulators: new approaches offer a path to a splicing code. Genes & Development 22 (3) (2008). p. 279–285. doi:10.1101/gad.1643108.
- ↑ Skotheim R.I. and Nees M. Alternative splicing in cancer: noise, functional, or systematic?. The International Journal of Biochemistry & Cell Biology 39 (7–8) (2007). p. 1432–49. doi:10.1016/j.biocel.2007.02.016.
- ↑ Bauer, Joseph Alan. A global view of cancer-specific transcript variants by subtractive transcriptome-wide analysis. PLOS ONE 4 (3) (2009). p. e4732. doi:10.1371/journal.pone.0004732.
- ↑ Fackenthal J; Godley L. Aberrant RNA splicing and its functional consequences in cancer cells. Disease Models & Mechanisms 1 (1) (2008). p. 37–42. doi:10.1242/dmm.000331.
- ↑ Deviating alternative splicing as a molecular subtype of microsatellite stable colorectal cancer. JCO Clinical Cancer Informatics 7 (7) (2023). p. e2200159. doi:10.1200/CCI.22.00159.
- ↑ Danckwardt S. Abnormally spliced beta-globin mRNAs: a single point mutation generates transcripts sensitive and insensitive to nonsense-mediated mRNA decay. Blood 99 (5) (2002). p. 1811–6. doi:10.1182/blood.V99.5.1811.
- ↑ Schmucker D.. Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity. Cell 101 (6) (2000). p. 671–684. doi:10.1016/S0092-8674(00)80878-8.