It looks like you're using an Ad Blocker.
Please white-list or disable AboveTopSecret.com in your ad-blocking tool.
Some features of ATS will be disabled while you continue to use an ad-blocker.
Five different papers have recently appeared that used computational approaches to predict microRNA targets in Drosophila [5-7], and mammals [8,9]. These studies only considered hits occurring within 3'-UTR regions that were conserved across related species, and favored or required a short region of perfect complementarity towards the 5'-end of microRNAs. However, there is reason to suspect that the rules governing microRNA-target interactions may not be universal. For example, in plants, most of the known microRNAs bind in a perfect or near-perfect manner to mRNA targets located within the protein coding region (cds) [10,11]. In contrast, in C. elegans  and Drosophila , known microRNAs lack long stretches (>10) of complementarity with their targets and generally interact within the 3'-untranslated region (3'-UTR). Furthermore, whereas the 5'-ends of many Drosophila microRNAs recognize 5–6 nt. common motifs within the target, these motifs are not a general feature of mammalian microRNAs . Thus, it is conceivable that human microRNA targets do not follow the same constraints as observed in C. elegans and Drosophila.
In the present paper, we have performed an unbiased statistical analysis of the manner in which human microRNAs interact complementarily with human mRNAs present in the NCBI human RefSeq database, looking for characteristics that differ significantly as compared with scrambled versions of the same microRNA sequences. The results demonstrate several novel features of human microRNA-mRNA interactions that differ from C. elegans and Drosophila, and identify a short-list of promising candidate microRNA-mRNA target pairs that are unlikely to have arisen by chance.
In humans, protein expression largely depends on a “microRNA code” - a highly integrated functional network within which microRNA molecules work in a cooperative manner. MicroRNA show specific expression profiles in different normal / pathological cells and tissues, and are directly involved in numerous pathologies such as cancers, CNS diseases, metabolic diseases and certain viral infections. However, only a subset of these microRNA and their targets are known today. Actigenics has developed a powerful discovery platform that allows identification, validation and analysis of microRNA and their function in any cellular and tissue context. Well-designed algorithms allow identification of the set of functional targets for each microRNA and of the subset of microRNA acting in a coordinated fashion to regulate specific biological processes.
MBE Advance Access originally published online on February 22, 2008
Molecular Biology and Evolution 2008 25(5):929-938; doi:10.1093/molbev/msn040
Adaptive Evolution of Newly Emerged Micro-RNA Genes in Drosophila
Jian Lu*, Yonggui Fu, Supriya Kumar*, Yang Shen, Kai Zeng, Anlong Xu, Richard Carthew and Chung-I Wu*,
Accepted for publication February 4, 2008.
How often micro-RNA (miRNA) genes emerged and how fast they evolved soon after their emergence are some of the central questions in the evolution of miRNAs. Because most known miRNA genes are ancient and highly conserved, these questions can be best answered by identifying newly emerged miRNA genes. Among the 78 miRNA genes in Drosophila reported before 2007, only 5 are confirmed to be newly emerged in the genus (although many more can be found in the newly reported data set; e.g., Ruby et al. 2007; Stark et al. 2007; Lu et al. 2008). These new miRNA genes have undergone numerous changes, even in the normally invariant mature sequences. Four of them (the miR-310/311/312/313 cluster, denoted miR-310s) were duplicated from other conserved miRNA genes. The fifth one (miR-303) appears to be a very young gene, originating de novo from a non-miRNA sequence recently. We sequenced these 5 miRNA genes and their neighboring regions from a worldwide collection of Drosophila melanogaster lines. The levels of divergence and polymorphism in these miRNA genes, vis-à-vis those of the neighboring DNA sequences, suggest that these 5 genes are evolving adaptively. Furthermore, the polymorphism pattern of miR-310s in D. melanogaster is indicative of hitchhiking under positive selection. Thus, a large number of adaptive changes over a long period of time may be essential for the evolution of newly emerged miRNA genes.
BMC Evol Biol. 2008; 8: 92.
Published online 2008 March 25. doi: 10.1186/1471-2148-8-92. PMCID: PMC2287173
The evolution of core proteins involved in microRNA biogenesis
Dennis Murphy,1 Barry Dancis,1 and James R Brown1
MicroRNAs (miRNAs) are a recently discovered class of non-coding RNAs (ncRNAs) which play important roles in eukaryotic gene regulation. miRNA biogenesis and activation is a complex process involving multiple protein catalysts and involves the large macromolecular RNAi Silencing Complex or RISC. While phylogenetic analyses of miRNA genes have been previously published, the evolution of miRNA biogenesis itself has been little studied. In order to better understand the origin of miRNA processing in animals and plants, we determined the phyletic occurrences and evolutionary relationships of four major miRNA pathway protein components; Dicer, Argonaute, RISC RNA-binding proteins, and Exportin-5.
Co-opting particular isoforms from large, diverse protein families seems to be a common theme in the evolution of miRNA biogenesis. Human miRNA biogenesis proteins have direct, orthologues in cold-blooded fishes and, in some cases, urochordates and deutrostomes. However, lineage specific expansions of Dicer in plants and invertebrates as well as Argonaute and RNA-binding proteins in vertebrates suggests that novel ncRNA regulatory mechanisms can evolve in relatively short evolutionary timeframes. The occurrence of multiple homologues to RNA-binding and Argonaute/PIWI proteins also suggests the possible existence of further pathways for additional types of ncRNAs.
Evolutionary analyses of miRNA gene families have revealed a combination of older ancestral relationships and recent lineage-specific diversification. The human genome itself likely encodes for a few hundred miRNAs, many of which have recognizable homologues to miRNA genes in different species (orthology) as well as amongst themselves (paralogy) . Several families of miRNA genes, such as let-7, are highly conserved amongst different vertebrate and invertebrate species . In addition, genomic organization of miRNA genes is often recognizable across diverse species such as the mir-196 and mir-10 gene families that likely co-evolved with Hox proteins  and the mir-17 gene cluster which has apparently undergone a complex series of gene duplication and loss in vertebrates . However, miRNAs can also have restrictive taxonomic distribution such as the Early Embryonic microRNA Cluster (EEmiRC) locus of six pre-miRNA precursors restricted to placental (eutherian) mammals . Many miRNA genes found in primates, including humans, are absent in other mammals [21,26]. Similar patterns of conservation and diversification have been observed for miRNAs in across plant species .