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Evolutionary Genomics of MicroRNAs and Their Relatives

Profile image of Ivo L HofackerIvo L Hofacker

2010, Evolutionary …

Abstract
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MicroRNAs (miRNAs) are small noncoding RNAs that play critical roles in gene regulation across various species, with significant evolutionary implications. This paper discusses the evolutionary genomics of miRNAs, highlighting their biogenesis, functional properties, and evolutionary dynamics within different taxa, including vertebrates and plants. The study reveals the complex history of miRNA clusters, involving duplications and losses while emphasizing the diverse origins and roles of miRNAs derived from transposable elements.

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at large? Two remarkable discoveries helped to dispel Hanover, New Hampshire 03755 these doubts. The first of these was that let-7 RNA is phylogenetically conserved-in size and nucleotide sequence-in essentially all the bilaterally symmetric ani-Animal genomes contain an abundance of small genes mals (Pasquinelli et al., 2000). Moreover, let-7 has a that produce regulatory RNAs of about 22 nucleotides similar developmental profile in diverse taxa, suggesting in length. These microRNAs are diverse in sequence the conservation of an ancient developmental timing and expression patterns, and are evolutionarily widepathway. Indeed, homologs of the worm let-7 target, spread, suggesting that they may participate in a wide lin-41, can be found in insects and vertebrates with their range of genetic regulatory pathways. let-7 complementary sites intact. These findings indicated that the lin-4 and let-7 class of regulatory genes Cells contain a variety of noncoding RNAs, including was not just a worm oddity, and likely represents a gene components of the machinery of gene expression, such family that has evolved from an ancient ancestral small as tRNAs and rRNAs, and regulatory RNAs that influence RNA gene. the expression of other genes (see Eddy, 2001 for a A second discovery that supported the relative ubiqrecent review, as well as references therein). Lately, it uity of tiny RNAs like lin-4 and let-7 was the finding that has become increasingly apparent that noncoding RNAs small antisense RNAs of about 22 nt in length (called are impressively diverse, and that a significant fraction siRNAs) are central to RNA interference (RNAi) (see of the genes of all organisms do not encode proteins. Sharp, 2001 and references therein). RNAi is an evolu-One class of small noncoding RNAs-the microRNAs tionarily conserved genetic surveillance mechanism that (or miRNAs)-has recently been recognized to be quite can degrade an mRNA in response to the presence numerous and phylogenetically extensive (Lee and of double-stranded RNA corresponding to the targeted Ambros, 2001; Lau et al., 2001; Lagos-Quintana et al., mRNA. lin-4 and let-7 are not siRNAs (they do not trigger 2001). microRNA genes produce tiny transcripts of degradation of their targets), but the ubiquity of siRNAs about 22 nucleotides ‫22ف(‬ nt) in length that probably suggested that small RNAs of the size of lin-4 and let-7 function as antisense regulators of other RNAs. As exhave been part of the eukaryotic milieu for a very long pected for a newly described large gene family, there time. Indeed, the lin-4 and let-7 ‫22ف‬ nt RNAs are proare at the moment far more hypotheses and unanswered cessed from their stem-loop precursor transcripts by questions than there are concrete facts. the same enzyme, Dicer, that generates the ‫22ف‬ nt Genetic Identification of microRNAs in Caenorhabditis siRNAs from a dsRNA trigger (Grishok et al., 2001; Hutelegans: The lin-4 and let-7 Gene Products vagner et al., 2001; Bernstein et al., 2001; Ketting et The best-studied miRNA genes are C. elegans lin-4 and al., 2001). Since Dicer is phylogenetically widespread, let-7, which were identified from the genetic analysis of genes like lin-4 and let-7 could also be commonplace. developmental timing in the nematode (see Rougvie, Stealth Genes No Longer 2001 for a review, and references therein). let-7 or lin-4 If other tiny RNA genes like lin-4 and let-7 lurk undiscovmutant worms fail to execute certain developmental ered in animal genomes, how would they be unmasked? switches, resulting in the abnormal repetition of certain Because these genes would be noncoding, traditional larval stages. The cloning of first lin-4 (Lee et al., 1993) computational gene finding methods tuned to protein and later let-7 (Reinhart et al., 2000) revealed these two coding potential would miss them, and they would not genes to be particularly deviant-unusually small, enbe represented in conventional cDNA libraries prepared coding no protein products, and producing exceedingly from polyadenylated mRNA. However, they would be short ‫22ف(‬ nt) transcripts from characteristic hairpin expected to produce hairpin precursor transcripts of RNA precursors (Figure 1). The 22 nt lin-4 and 21 nt let-7 about 70 nt, and mature RNAs of about 22 nt. Therefore, RNAs are antisense translational repressors of mRNAs genes like lin-4 and let-7 should emerge from structurethat encode proteins of the heterochronic developmental based informatics searches of noncoding genomic setiming pathway of the worm (Lee et al. 1993; Wightman quences, and from cDNA cloning efforts tailored to very et al., 1993; Moss et al., 1997; Slack et al., 2000). For small transcripts. example, lin-4 RNA is complementary to sequences in Recently, methods were developed to clone cDNAs corthe 3Ј untranslated region (UTR) of lin-14 and lin-28 responding to the ‫22ف‬ nt siRNAs produced during RNAi mRNAs. The synthesis of LIN-14 and LIN-28 proteins is (Elbashir et al. 2001a). These methods were adapted to repressed by lin-4 during the early larval stages of C. the preparation of cDNAs corresponding to size-selected elegans development to cause the proper sequence of ‫22ف(‬ nt) RNAs expressed in worms, flies, and human stage-specific developmental events. cells (Lee and Ambros, 2001; Lau et al., 2001; Lagos-When first described, lin-4 and let-7 seemed to be Quintana et al., 2001). From these cDNA libraries, dozens unique, since no similar tiny regulatory RNA had been of sequences corresponding to novel transcripts of about 22 nt were identified, and dubbed "microRNAs." The genes that produce these transcripts are located

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Non-coding RNAs such as microRNAs (miRNAs) are very tiny ribonucleotides having an essential role in gene regulation at both post-transcriptional and translational levels. They are very conserved and expressed in worms, flies, plants, and mammals in a sequence-specific manner. Furthermore, it is now possible to clone miRNAs using the new genome editing tool CRISPR/cas9, which shows benefit in control of untargeted effect. In this special issue, we tried to cover researches associated with functional roles of miRNAs accross model and complex organisms.

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