BackgroundMicroRNAs (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.ResultsPhylogenetic 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.ConclusionCo-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.

Robertsonian rearrangements demonstrate one-break chromosome rearrangement and the reversible appearance and disappearance of telomeres and centromeres. Such events are quite discordant with classical cytogenetic theories, which assume all chromosome rearrangements to require at least two breaks and consider centromeres and telomeres as immutable structures rather than structures determined by mutable DNA sequences. Cytogenetic data from spontaneous and induced telomere-telomere fusions in mammals sup ort a molecular model of terminal DNA synthesis in which all ttelomeres are similar and recombine before replication and subsequent separation. This, along with evidence for a hypothetical DNA sequence, the kinetochore organizer, readily explains latent telomeres, latent centromeres, and re- Robertsonian rearrangements between rod chromosomes ( Fig. 1 upper) to produce metacentric biarmed chromosomes (Fig. 1 lower) are a common mechanism of karyotype evolution and occur spontaneously at an appreciable frequency in mammalian tissue culture (5) or even in the somatic tissue of certain fish (6). Reciprocal translocations (Fig. la) are consistent with Muller's rules. The reverse exchanges, Robertsonian fission of a metacentric into two rod chromosomes, have been observed, and some ( Fig. 1 b and c) appear as one-break rearrangements which do not require a centric fragment to supply a new centromere and telomeres to the new chromosomes (5,7,8). In addition, Robertsonian metacentrics generally possess twice the centric structure of rod chromosomes (7-10). In the grasshopper Neopodismopsis, Moens' (11) electron micrographs showed this doubled "knob"-like structure to be penetrated by twice as many microtubules as the single centric knob of rod chromosomes. Thus, a metacentric's centric region often appears doubled and capable of splitting by fission, each half becoming a functional centromere (8, 10).Robertsonian rearrangements, especially the fissions, reveal the inadequacy of Muller's rules, especially his concept of centromeres and telomeres as immutable structures (1), and imply some or all of the following: (i) dicentrics can be stable; (ii) fissions can result from one-break rearrangements; (iii) centromeres and telomeres can reversibly appear and disappear; and (iv) centromeres and telomeres can be terminal coincident structures.Dicentrics can be stable, showing parallel chromatid separation when the two centromeres are close together. Hair (12) observed an isodicentric through many vegetative generations in the plant Agropyron. The original dicentric was unstable at mitosis; criss-cross and interlocking separation produced a breakage-fusion cycle that resulted in shorter intercentric distances. Dicentrics with short intercentric regions, however, were mitotically stable, both centromeres on one chromatid separating to the same pole. Dicentrics can also be stable when one centromere is latent (see review, ref. 13). In humans, most Robertsonian metacentrics are dicentric (14) in that they show pericentric h...

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