title: The evolution of core proteins involved in microRNA biogenesis.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  Phylogenetic analyses show that all four miRNA pathway proteins were derived from large multiple protein families. As an example, vertebrate and invertebrate Argonaute (Ago) proteins diverged from a larger family of PIWI/Argonaute proteins found throughout eukaryotes. Further gene duplications among vertebrates after the evolution of chordates from urochordates but prior to the emergence of fishes lead to the evolution of four Ago paralogues. Invertebrate RISC RNA-binding proteins R2D2 and Loquacious are related to other RNA-binding protein families such as Staufens as well as vertebrate-specific TAR (HIV trans-activator RNA) RNA-binding protein (TRBP) and protein kinase R-activating protein (PACT). Export of small RNAs from the nucleus, including miRNA, is facilitated by three closely related karyopherin-related nuclear transporters, Exportin-5, Exportin-1 and Exportin-T. While all three exportins have direct orthologues in deutrostomes, missing exportins in arthropods (Exportin-T) and nematodes (Exportin-5) are likely compensated by dual specificities of one of the other exportin paralogues.
  
  
  CONCLUSIONS
  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.
authors: Bioinformatics, Molecular Discovery Research, GlaxoSmithKline, 1250 South Collegeville Road, UP1345, Collegeville, Pennsylvania 19426, USA. Dennis.6.Murphy@gsk.com
authors: Dennis
authors: D
authors: Murphy
authors: Barry
authors: B
authors: Dancis
authors: James R
authors: JR
authors: Brown
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001499:Bayes Theorem; D039642:Eukaryotic Initiation Factors / Q000235:genetics; D019143:Evolution, Molecular; D006801:Humans; D028884:Karyopherins / Q000235:genetics; D016013:Likelihood Functions; D035683:MicroRNAs / Q000235:genetics*; D010802:Phylogeny; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics; D043244:Ribonuclease III / Q000235:genetics
chemical_list: D039642:Eukaryotic Initiation Factors; D028884:Karyopherins; D035683:MicroRNAs; D016601:RNA-Binding Proteins; D043244:Ribonuclease III