Editing Alternative splicing (section)

==Adaptive significance==

Genuine alternative splicing occurs in both protein-coding genes and non-coding genes to produce multiple products (proteins or non-coding RNAs). External information is needed in order to decide which product is made, given a DNA sequence and the initial transcript. Since the methods of regulation are inherited, this provides novel ways for mutations to affect gene expression.<ref name=Fackenthal/>

Alternative splicing may provide evolutionary flexibility. A single point mutation may cause a given exon to be occasionally excluded or included from a transcript during splicing, allowing production of a new [[protein isoform]] without loss of the original protein.<ref name=Black/> Studies have identified intrinsically disordered regions (see [[Intrinsically unstructured proteins]]) as enriched in the non-constitutive exons<ref name=Romero>{{cite journal | vauthors = Romero PR, Zaidi S, Fang YY, Uversky VN, Radivojac P, Oldfield CJ, Cortese MS, Sickmeier M, LeGall T, Obradovic Z, Dunker AK | display-authors = 6 | title = Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 22 | pages = 8390–5 | date = May 2006 | pmid = 16717195 | pmc = 1482503 | doi = 10.1073/pnas.0507916103 | bibcode = 2006PNAS..103.8390R | doi-access = free }}</ref> suggesting that protein isoforms may display functional diversity due to the alteration of functional modules within these regions. Such functional diversity achieved by isoforms is reflected by their expression patterns and can be predicted by machine learning approaches.<ref>{{cite journal | vauthors = Li HD, Menon R, Omenn GS, Guan Y | title = The emerging era of genomic data integration for analyzing splice isoform function | journal = Trends in Genetics | volume = 30 | issue = 8 | pages = 340–7 | date = August 2014 | pmid = 24951248 | pmc = 4112133 | doi = 10.1016/j.tig.2014.05.005 }}</ref><ref name=Eksi>{{cite journal | vauthors = Eksi R, Li HD, Menon R, Wen Y, Omenn GS, Kretzler M, Guan Y | title = Systematically differentiating functions for alternatively spliced isoforms through integrating RNA-seq data | journal = PLOS Computational Biology | volume = 9 | issue = 11 | pages = e1003314 | date = Nov 2013 | pmid = 24244129 | pmc = 3820534 | doi = 10.1371/journal.pcbi.1003314 | bibcode = 2013PLSCB...9E3314E | doi-access = free }}</ref> Comparative studies indicate that alternative splicing preceded multicellularity in evolution, and suggest that this mechanism might have been co-opted to assist in the development of multicellular organisms.<ref name=Irimia>{{cite journal | vauthors = Irimia M, Rukov JL, Penny D, Roy SW | title = Functional and evolutionary analysis of alternatively spliced genes is consistent with an early eukaryotic origin of alternative splicing | journal = BMC Evolutionary Biology | volume = 7 | pages = 188 | date = October 2007 | issue = 1 | pmid = 17916237 | pmc = 2082043 | doi = 10.1186/1471-2148-7-188 | bibcode = 2007BMCEE...7..188I | doi-access = free }}</ref>

Research based on the [[Human Genome Project]] and other genome sequencing has shown that humans have only about 30% more genes than the roundworm ''[[Caenorhabditis elegans]]'', and only about twice as many as the fly ''[[Drosophila melanogaster]]''. This finding led to speculation that the perceived greater complexity of humans, or vertebrates generally, might be due to higher rates of alternative splicing in humans than are found in invertebrates.<ref name=ewing>{{cite journal | vauthors = Ewing B, Green P | title = Analysis of expressed sequence tags indicates 35,000 human genes | journal = Nature Genetics | volume = 25 | issue = 2 | pages = 232–4 | date = June 2000 | pmid = 10835644 | doi = 10.1038/76115 | s2cid = 19165121 }}</ref><ref name=Crollius>
{{cite journal | vauthors = Roest Crollius H, Jaillon O, Bernot A, Dasilva C, Bouneau L, Fischer C, Fizames C, Wincker P, Brottier P, Quétier F, Saurin W, Weissenbach J | display-authors = 6 | title = Estimate of human gene number provided by genome-wide analysis using Tetraodon nigroviridis DNA sequence | journal = Nature Genetics | volume = 25 | issue = 2 | pages = 235–8 | date = June 2000 | pmid = 10835645 | doi = 10.1038/76118 | s2cid = 44052050 }}</ref> However, a study on samples of 100,000 [[expressed sequence tag]]s (EST) each from human, mouse, rat, cow, fly (''D. melanogaster''), worm (''C. elegans''), and the plant ''[[Arabidopsis thaliana]]'' found no large differences in frequency of alternatively spliced genes among humans and any of the other animals tested.<ref>
{{cite journal | vauthors = Brett D, Pospisil H, Valcárcel J, Reich J, Bork P | title = Alternative splicing and genome complexity | journal = Nature Genetics | volume = 30 | issue = 1 | pages = 29–30 | date = January 2002 | pmid = 11743582 | doi = 10.1038/ng803 | s2cid = 2724843 }}</ref> Another study, however, proposed that these results were an artifact of the different numbers of ESTs available for the various organisms. When they compared alternative splicing frequencies in random subsets of genes from each organism, the authors concluded that vertebrates do have higher rates of alternative splicing than invertebrates.<ref name=Kim>{{cite journal | vauthors = Kim E, Magen A, Ast G | title = Different levels of alternative splicing among eukaryotes | journal = Nucleic Acids Research | volume = 35 | issue = 1 | pages = 125–31 | year = 2006 | pmid = 17158149 | pmc = 1802581 | doi = 10.1093/nar/gkl924 }}</ref>