Editing MicroRNA (section)

==Evolution==
miRNAs are well [[conserved sequence|conserved]] in both plants and animals, and are thought to be a vital and evolutionarily ancient component of gene regulation.<ref>{{cite journal | vauthors = Axtell MJ, Bartel DP | title = Antiquity of microRNAs and their targets in land plants | journal = The Plant Cell | volume = 17 | issue = 6 | pages = 1658–73 | date = June 2005 | pmid = 15849273 | pmc = 1143068 | doi = 10.1105/tpc.105.032185 }}</ref><ref name="pmid15136036">{{cite journal | vauthors = Tanzer A, Stadler PF | title = Molecular evolution of a microRNA cluster | journal = Journal of Molecular Biology | volume = 339 | issue = 2 | pages = 327–35 | date = May 2004 | pmid = 15136036 | doi = 10.1016/j.jmb.2004.03.065 | citeseerx = 10.1.1.194.1598 }}</ref><ref>{{cite journal | vauthors = Chen K, Rajewsky N | title = The evolution of gene regulation by transcription factors and microRNAs | journal = Nature Reviews Genetics | volume = 8 | issue = 2 | pages = 93–103 | date = February 2007 | pmid = 17230196 | doi = 10.1038/nrg1990 | s2cid = 174231 }}</ref><ref name="pmid17465887">{{cite journal | vauthors = Lee CT, Risom T, Strauss WM | title = Evolutionary conservation of microRNA regulatory circuits: an examination of microRNA gene complexity and conserved microRNA-target interactions through metazoan phylogeny | journal = DNA and Cell Biology | volume = 26 | issue = 4 | pages = 209–18 | date = April 2007 | pmid = 17465887 | doi = 10.1089/dna.2006.0545 }}</ref><ref name="Peterson2010"/> While core components of the microRNA pathway are conserved between [[plant]]s and [[animal]]s, miRNA repertoires in the two kingdoms appear to have emerged independently with different primary modes of action.<ref name="pmid18715673">{{cite journal | vauthors = Shabalina SA, Koonin EV | title = Origins and evolution of eukaryotic RNA interference | journal = Trends in Ecology & Evolution | volume = 23 | issue = 10 | pages = 578–87 | date = October 2008 | pmid = 18715673 | pmc = 2695246 | doi = 10.1016/j.tree.2008.06.005 | bibcode = 2008TEcoE..23..578S }}</ref><ref>{{cite journal | vauthors = Axtell MJ, Westholm JO, Lai EC | title = Vive la différence: biogenesis and evolution of microRNAs in plants and animals | journal = Genome Biology | volume = 12 | issue = 4 | pages = 221 | date = 2011 | pmid = 21554756 | pmc = 3218855 | doi = 10.1186/gb-2011-12-4-221 | doi-access = free }}</ref>

microRNAs are useful [[Phylogenetics|phylogenetic]] markers because of their apparently low rate of evolution.<ref name=Wheeler2009/> microRNAs' origin as a regulatory mechanism developed from previous RNAi machinery that was initially used as a defense against exogenous genetic material such as viruses.<ref>{{cite journal | vauthors = Pashkovskiy PP, Ryazansky SS | title = Biogenesis, evolution, and functions of plant microRNAs | journal = Biochemistry. Biokhimiia | volume = 78 | issue = 6 | pages = 627–37 | date = June 2013 | pmid = 23980889 | doi = 10.1134/S0006297913060084 | s2cid = 12025420 }}</ref> Their origin may have permitted the development of morphological innovation, and by making gene expression more specific and 'fine-tunable', permitted the genesis of complex organs<ref name="Heimberg2008"/> and perhaps, ultimately, complex life.<ref name=Peterson2010>{{cite journal | vauthors = Peterson KJ, Dietrich MR, McPeek MA | title = MicroRNAs and metazoan macroevolution: insights into canalization, complexity, and the Cambrian explosion | journal = BioEssays | volume = 31 | issue = 7 | pages = 736–47 | date = July 2009 | pmid = 19472371 | doi = 10.1002/bies.200900033 | s2cid = 15364875 | doi-access = free }}</ref> Rapid bursts of morphological innovation are generally associated with a high rate of microRNA accumulation.<ref name=Wheeler2009>{{cite journal | vauthors = Wheeler BM, Heimberg AM, Moy VN, Sperling EA, Holstein TW, Heber S, Peterson KJ | title = The deep evolution of metazoan microRNAs | journal = Evolution & Development | volume = 11 | issue = 1 | pages = 50–68 | year = 2009 | pmid = 19196333 | doi = 10.1111/j.1525-142X.2008.00302.x | s2cid = 14924603 }}</ref><ref name=Heimberg2008>{{cite journal | vauthors = Heimberg AM, Sempere LF, Moy VN, Donoghue PC, Peterson KJ | title = MicroRNAs and the advent of vertebrate morphological complexity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 8 | pages = 2946–50 | date = February 2008 | pmid = 18287013 | pmc = 2268565 | doi = 10.1073/pnas.0712259105 | bibcode = 2008PNAS..105.2946H | doi-access = free }}</ref>

New microRNAs are created in multiple ways. Novel microRNAs can originate from the random formation of hairpins in "non-coding" sections of DNA (i.e. [[Intron|introns or intergene]] regions), but also by the duplication and modification of existing microRNAs.<ref name=Nozawa2010/> microRNAs can also form from inverted duplications of protein-coding sequences, which allows for the creation of a foldback hairpin structure.<ref>{{cite journal | vauthors = Allen E, Xie Z, Gustafson AM, Sung GH, Spatafora JW, Carrington JC | title = Evolution of microRNA genes by inverted duplication of target gene sequences in Arabidopsis thaliana | journal = Nature Genetics | volume = 36 | issue = 12 | pages = 1282–90 | date = December 2004 | pmid = 15565108 | doi = 10.1038/ng1478 | s2cid = 11997028 }}</ref> The rate of evolution (i.e. nucleotide substitution) in recently originated microRNAs is comparable to that elsewhere in the non-coding DNA, implying evolution by neutral drift; however, older microRNAs have a much lower rate of change (often less than one substitution per hundred million years),<ref name=Peterson2010/> suggesting that once a microRNA gains a function, it undergoes purifying selection.<ref name=Nozawa2010/> Individual regions within an miRNA gene face different evolutionary pressures, where regions that are vital for processing and function have higher levels of conservation.<ref>{{cite journal | vauthors = Warthmann N, Das S, Lanz C, Weigel D | title = Comparative analysis of the MIR319a microRNA locus in Arabidopsis and related Brassicaceae | journal = Molecular Biology and Evolution | volume = 25 | issue = 5 | pages = 892–902 | date = May 2008 | pmid = 18296705 | doi = 10.1093/molbev/msn029 | doi-access = free }}</ref> At this point, a microRNA is rarely lost from an animal's genome,<ref name=Peterson2010/> although newer microRNAs (thus presumably non-functional) are frequently lost.<ref name=Nozawa2010>{{cite journal | vauthors = Nozawa M, Miura S, Nei M | title = Origins and evolution of microRNA genes in Drosophila species | journal = Genome Biology and Evolution | volume = 2 | pages = 180–89 | date = July 2010 | pmid = 20624724 | pmc = 2942034 | doi = 10.1093/gbe/evq009 }}</ref> In ''[[Arabidopsis thaliana]]'', the net flux of miRNA genes has been predicted to be between 1.2 and 3.3 genes per million years.<ref>{{cite journal | vauthors = Fahlgren N, Jogdeo S, Kasschau KD, Sullivan CM, Chapman EJ, Laubinger S, Smith LM, Dasenko M, Givan SA, Weigel D, Carrington JC | title = MicroRNA gene evolution in Arabidopsis lyrata and Arabidopsis thaliana | journal = The Plant Cell | volume = 22 | issue = 4 | pages = 1074–89 | date = April 2010 | pmid = 20407027 | pmc = 2879733 | doi = 10.1105/tpc.110.073999 }}</ref> This makes them a valuable phylogenetic marker, and they are being looked upon as a possible solution to outstanding phylogenetic problems such as the relationships of [[arthropod]]s.<ref name="pmid20486135">{{cite journal | vauthors = Caravas J, Friedrich M | title = Of mites and millipedes: recent progress in resolving the base of the arthropod tree | journal = BioEssays | volume = 32 | issue = 6 | pages = 488–95 | date = June 2010 | pmid = 20486135 | doi = 10.1002/bies.201000005 | s2cid = 20548122 }}</ref> On the other hand, in multiple cases microRNAs correlate poorly with phylogeny, and it is possible that their phylogenetic concordance largely reflects a limited sampling of microRNAs.<ref>{{cite journal | vauthors = Kenny NJ, Namigai EK, Marlétaz F, Hui JH, Shimeld SM | title = Draft genome assemblies and predicted microRNA complements of the intertidal lophotrochozoans Patella vulgata (Mollusca, Patellogastropoda) and Spirobranchus (Pomatoceros) lamarcki (Annelida, Serpulida) | journal = Marine Genomics | volume = 24 | pages = 139–46 | date = December 2015 | pmid = 26319627 | doi = 10.1016/j.margen.2015.07.004 | number = 2 | bibcode = 2015MarGn..24..139K | url = https://ora.ox.ac.uk/objects/uuid:ace9e039-b307-47f1-839c-3a28e189af64 }}</ref>

microRNAs feature in the [[genome]]s of most eukaryotic organisms, from the [[brown algae]]<ref name="pmid20520714">{{cite journal | vauthors = Cock JM, Sterck L, Rouzé P, Scornet D, Allen AE, Amoutzias G, Anthouard V, Artiguenave F, Aury JM, Badger JH, Beszteri B, Billiau K, Bonnet E, Bothwell JH, Bowler C, Boyen C, Brownlee C, Carrano CJ, Charrier B, Cho GY, Coelho SM, Collén J, Corre E, Da Silva C, Delage L, Delaroque N, Dittami SM, Doulbeau S, Elias M, Farnham G, Gachon CM, Gschloessl B, Heesch S, Jabbari K, Jubin C, Kawai H, Kimura K, Kloareg B, Küpper FC, Lang D, Le Bail A, Leblanc C, Lerouge P, Lohr M, Lopez PJ, Martens C, Maumus F, Michel G, Miranda-Saavedra D, Morales J, Moreau H, Motomura T, Nagasato C, Napoli CA, Nelson DR, Nyvall-Collén P, Peters AF, Pommier C, Potin P, Poulain J, Quesneville H, Read B, Rensing SA, Ritter A, Rousvoal S, Samanta M, Samson G, Schroeder DC, Ségurens B, Strittmatter M, Tonon T, Tregear JW, Valentin K, von Dassow P, Yamagishi T, Van de Peer Y, Wincker P | title = The Ectocarpus genome and the independent evolution of multicellularity in brown algae | journal = Nature | volume = 465 | issue = 7298 | pages = 617–21 | date = June 2010 | pmid = 20520714 | doi = 10.1038/nature09016 | bibcode = 2010Natur.465..617C | doi-access = free }}</ref> to the animals. However, the difference in how these microRNAs function and the way they are processed suggests that microRNAs arose independently in plants and animals.<ref>{{cite journal | vauthors = Cuperus JT, Fahlgren N, Carrington JC | title = Evolution and functional diversification of MIRNA genes | journal = The Plant Cell | volume = 23 | issue = 2 | pages = 431–42 | date = February 2011 | pmid = 21317375 | pmc = 3077775 | doi = 10.1105/tpc.110.082784 }}</ref>

Focusing on the animals, the genome of ''[[Mnemiopsis leidyi]]''<ref name="RyanPang2013">{{cite journal | vauthors = Ryan JF, Pang K, Schnitzler CE, Nguyen AD, Moreland RT, Simmons DK, Koch BJ, Francis WR, Havlak P, Smith SA, Putnam NH, Haddock SH, Dunn CW, Wolfsberg TG, Mullikin JC, Martindale MQ, Baxevanis AD | title = The genome of the ctenophore Mnemiopsis leidyi and its implications for cell type evolution | journal = Science | volume = 342 | issue = 6164 | pages = 1242592 | date = December 2013 | pmid = 24337300 | pmc = 3920664 | doi = 10.1126/science.1242592 | author12-link = Steven Haddock }}</ref> appears to lack recognizable microRNAs, as well as the nuclear proteins [[Drosha]] and [[Pasha (protein)|Pasha]], which are critical to canonical microRNA biogenesis. It is the only animal thus far reported to be missing Drosha. MicroRNAs play a vital role in the regulation of gene expression in all non-ctenophore animals investigated thus far except for ''[[Trichoplax adhaerens]]'', the first known member of the phylum [[Placozoa]].<ref name="maxwell2012">{{cite journal | vauthors = Maxwell EK, Ryan JF, Schnitzler CE, Browne WE, Baxevanis AD | title = MicroRNAs and essential components of the microRNA processing machinery are not encoded in the genome of the ctenophore Mnemiopsis leidyi | journal = BMC Genomics | volume = 13 | issue = 1 | pages = 714 | date = December 2012 | pmid = 23256903 | pmc = 3563456 | doi = 10.1186/1471-2164-13-714 | doi-access = free }}</ref>

Across all species, in excess of 5000 different miRNAs had been identified by March 2010.<ref name=Dimond2010>{{cite journal | vauthors = Dimond PF |date=15 March 2010 |access-date=10 July 2010 |title=miRNAs' Therapeutic Potential | journal = Genetic Engineering & Biotechnology News |volume=30 |issue=6 |page=1 |url=http://www.genengnews.com/gen-articles/mirnas-therapeutic-potential/3216/ |archive-url=https://web.archive.org/web/20100719042114/http://www.genengnews.com/gen-articles/mirnas-therapeutic-potential/3216/ |archive-date=19 July 2010 |url-status=dead }}</ref> Whilst short RNA sequences (50&nbsp;– hundreds of base pairs) of a broadly comparable function occur in bacteria, bacteria lack true microRNAs.<ref name="pmid16717284">{{cite journal | vauthors = Tjaden B, Goodwin SS, Opdyke JA, Guillier M, Fu DX, Gottesman S, Storz G | title = Target prediction for small, noncoding RNAs in bacteria | journal = Nucleic Acids Research | volume = 34 | issue = 9 | pages = 2791–802 | year = 2006 | pmid = 16717284 | pmc = 1464411 | doi = 10.1093/nar/gkl356 }}</ref>