Trends in Genetics
Non-coding RNAs: hope or hype?
Introduction
RNAs are split into two distinct classes: messenger RNAs (mRNAs), which are translated into proteins, and the non-protein-coding RNAs (ncRNAs), which function at the RNA level. For many years it was believed that there were only a few ncRNAs, and they (e.g. tRNAs, rRNAs and spliceosomal RNAs) were considered accessory components to aid protein functioning. To some degree, these beliefs were fostered by the time-consuming and laborious techniques required to identify these RNAs experimentally, and by the lack of sequenced genomes and appropriate bioinformatics approaches needed to detect them computationally. Thus, identification of novel ncRNA species and elucidation of their function occurred rather by chance than by systematic screens. Hence, even large RNA classes, such as snoRNAs and microRNAs, remained undetected for many years.
Nevertheless, over time it became apparent that there are numerous ncRNAs, and that their cellular functions – on their own or in protein complexes – are varied and important (for reviews, see Refs 1, 2, 3, 4, 5). In the past few years, new experimental strategies, termed ‘experimental RNomics’, were developed that demonstrated that the number of ncRNAs in genomes of model organisms is much greater than was previously anticipated (Box 1). The application of experimental RNomics from Escherichia coli to Homo sapiens resulted in the identification of numerous novel ncRNA candidates. However, the function of approximately half of these ncRNA candidates could not be deduced because they lacked the sequence or structural motifs that would have enabled their assignment to an existing ncRNA class 6, 7, 8, 9, 10, 11, 12, 13. Meanwhile, new computational approaches (Box 2) have also detected experimentally verified ncRNAs, particularly in the compact genomes of species of Bacteria 14, 15, 16 and Archaea [17].
These results have fuelled speculation that ncRNAs might be important to understanding the increased complexity observed in mammals, because mammalian genomes have only slightly more protein-coding genes than ‘lower organisms’ such as flies or worms [4]. It remains to be seen whether the current hope and excitement surrounding the discovery of novel ncRNAs is well deserved or whether all of the hype will soon vanish.
Section snippets
ncRNAs: the present
Much of the recent research on ncRNAs has focused on improving our understanding of the functions of two large classes of ncRNAs: (i) small nucleolar RNAs (snoRNAs); and (ii) the microRNA (miRNA) and small interfering RNA (siRNA) family, in addition to the identification of new ncRNA candidates that apparently do not belong to any known ncRNA family.
ncRNAs: the future
The number of known ncRNAs and putative ncRNAs of unknown function has increased dramatically in the past few years (Figure 1). Moreover, particularly in higher eukaryotes, there is still room in the genome for the discovery of novel ncRNA genes. Only a fraction of the genome (i.e. ∼1.4% in humans) is translated into proteins, whereas ∼27% is transcribed as introns and UTRs but not translated 48, 59, 62, 67, 68, 69. In addition, ∼25% of mammalian genomes are predicted to be transcribed but not
Concluding remarks
What can we conclude from all of the hype on the new ncRNA transcriptional data? Do these results demonstrate – as has been recently proposed – that the ‘main output of the genomes of complex organisms is genetically active but non-coding RNA [4]’? Or are these transcripts primarily ‘junk’ RNA? The honest answer at this point is we still do not know. However, emerging computational and experimental approaches are beginning to lead not only to the identification of all ncRNAs in different model
Acknowledgements
We apologize to all colleagues whose work could not be cited owing to space limitations. We thank Jörg Vogel, John Mattick and Michael Pheasant for providing unpublished data and Todd Lowe for helpful suggestions and for critical reading of the article. We also thank one of the referees for extensive valuable comments and suggestions. This work was supported by a grant from the Austrian Science Foundation, FWF (ZFP 171370), to A.H. and a FWF grant (P16932) to N.P.
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