Editing Alternative splicing (section)

==Discovery==
Alternative splicing was first observed in 1977.<ref>{{cite journal | vauthors = Chow LT, Gelinas RE, Broker TR, Roberts RJ | title = An amazing sequence arrangement at the 5' ends of adenovirus 2 messenger RNA | journal = Cell | volume = 12 | issue = 1 | pages = 1–8 | date = September 1977 | pmid = 902310 | doi = 10.1016/0092-8674(77)90180-5 | s2cid = 2099968 | author-link4 = Richard J. Roberts }}</ref><ref>{{cite journal | vauthors = Berget SM, Moore C, Sharp PA | title = Spliced segments at the 5' terminus of adenovirus 2 late mRNA | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 74 | issue = 8 | pages = 3171–5 | date = August 1977 | pmid = 269380 | pmc = 431482 | doi = 10.1073/pnas.74.8.3171 | bibcode = 1977PNAS...74.3171B | doi-access = free }}</ref> The [[adenovirus]] produces five primary transcripts early in its infectious cycle, prior to viral DNA replication, and an additional one later, after DNA replication begins. The early primary transcripts continue to be produced after DNA replication begins. The additional primary transcript produced late in infection is large and comes from 5/6 of the 32kb adenovirus genome. This is much larger than any of the individual adenovirus mRNAs present in infected cells. Researchers found that the primary RNA transcript produced by adenovirus type 2 in the late phase was spliced in many different ways, resulting in mRNAs encoding different viral proteins. In addition, the primary transcript contained multiple [[polyadenylation]] sites, giving different 3' ends for the processed mRNAs.<ref name=Leff86>{{cite journal | vauthors = Leff SE, Rosenfeld MG, Evans RM | title = Complex transcriptional units: diversity in gene expression by alternative RNA processing | journal = Annual Review of Biochemistry | volume = 55 | issue = 1 | pages = 1091–117 | year = 1986 | pmid = 3017190 | doi = 10.1146/annurev.bi.55.070186.005303 }}</ref><ref name="pmid719751">{{cite journal | vauthors = Chow LT, Broker TR | title = The spliced structures of adenovirus 2 fiber message and the other late mRNAs | journal = Cell | volume = 15 | issue = 2 | pages = 497–510 | date = October 1978 | pmid = 719751 | doi = 10.1016/0092-8674(78)90019-3 | s2cid = 44642349 }}</ref><ref name="pmid729004">{{cite journal | vauthors = Nevins JR, Darnell JE | title = Steps in the processing of Ad2 mRNA: poly(A)+ nuclear sequences are conserved and poly(A) addition precedes splicing | journal = Cell | volume = 15 | issue = 4 | pages = 1477–93 | date = December 1978 | pmid = 729004 | doi = 10.1016/0092-8674(78)90071-5 | s2cid = 39704416 }}</ref>

In 1981, the first example of alternative splicing in a [[Transcription (genetics)|transcript]] from a normal, [[endogenous]] gene was characterized.<ref name=Leff86/> The gene encoding the [[thyroid]] hormone [[calcitonin]] was found to be alternatively spliced in mammalian cells. The primary transcript from this gene contains 6 exons; the [[calcitonin]] mRNA contains exons 1–4, and terminates after a polyadenylation site in exon 4. Another mRNA is produced from this pre-mRNA by skipping exon 4, and includes exons 1–3, 5, and 6. It encodes a protein known as CGRP ([[calcitonin gene related peptide]]).<ref name="pmid7207587">{{cite journal | vauthors = Rosenfeld MG, Amara SG, Roos BA, Ong ES, Evans RM | title = Altered expression of the calcitonin gene associated with RNA polymorphism | journal = Nature | volume = 290 | issue = 5801 | pages = 63–5 | date = March 1981 | pmid = 7207587 | doi = 10.1038/290063a0 | s2cid = 4318349 | bibcode = 1981Natur.290...63R }}</ref><ref name="pmid6952224">{{cite journal | vauthors = Rosenfeld MG, Lin CR, Amara SG, Stolarsky L, Roos BA, Ong ES, Evans RM | title = Calcitonin mRNA polymorphism: peptide switching associated with alternative RNA splicing events | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 79 | issue = 6 | pages = 1717–21 | date = March 1982 | pmid = 6952224 | pmc = 346051 | doi = 10.1073/pnas.79.6.1717 | bibcode = 1982PNAS...79.1717R | doi-access = free }}</ref> Examples of alternative splicing in immunoglobin gene transcripts in mammals were also observed in the early 1980s.<ref name=Leff86/><ref name="pmid6786756">{{cite journal | vauthors = Maki R, Roeder W, Traunecker A, Sidman C, Wabl M, Raschke W, Tonegawa S | title = The role of DNA rearrangement and alternative RNA processing in the expression of immunoglobulin delta genes | journal = Cell | volume = 24 | issue = 2 | pages = 353–65 | date = May 1981 | pmid = 6786756 | doi = 10.1016/0092-8674(81)90325-1 | s2cid = 13208589 }}</ref>

Since then, many other examples of biologically relevant alternative splicing have been found in eukaryotes.<ref name=Black/> The "record-holder" for alternative splicing is a ''D. melanogaster'' gene called [[Dscam]], which could potentially have 38,016 splice variants.<ref name=Schmucker>{{cite journal | vauthors = Schmucker D, Clemens JC, Shu H, Worby CA, Xiao J, Muda M, Dixon JE, Zipursky SL | display-authors = 6 | title = Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity | journal = Cell | volume = 101 | issue = 6 | pages = 671–84 | date = June 2000 | pmid = 10892653 | doi = 10.1016/S0092-8674(00)80878-8 | s2cid = 13829976 | doi-access = free }}</ref>

In 2021, it was discovered that the genome of adenovirus type 2, the adenovirus in which alternative splicing was first identified, was able to produce a much greater variety of splice variants than previously thought.<ref name = Westergren>{{cite journal | vauthors = Westergren Jakobsson A, Segerman B, Wallerman O, Lind SB, Zhao H, Rubin CJ, Pettersson U, Akusjärvi G | display-authors = 6 | title = The Human Adenovirus Type 2 Transcriptome: An Amazing Complexity of Alternatively Spliced mRNAs | journal = Journal of Virology | volume = 95 | issue = 4 | date = November 2020 | pmid = 33239457 | pmc = 7851563 | doi = 10.1128/JVI.01869-20 | url = }}</ref> By using next generation sequencing technology, researchers were able to update the human adenovirus type 2 transcriptome and document the presence of 904 splice variants produced by the virus through a complex pattern of alternative splicing. Very few of these splice variants have been shown to be functional, a point that the authors raise in their paper.
::"An outstanding question is what roles the menagerie of novel RNAs play or whether they are spurious molecules generated by an overloaded splicing machinery."<ref name = Westergren />