Trends in Genetics
Waste not, want not – transcript excess in multicellular eukaryotes
Introduction
Directed experimental and biocomputational efforts continue to expand the numbers of known small untranslated RNAs (utRNAs), such as small nucleolar RNAs (snoRNAs), micro RNAs (miRNAs), short interfering RNAs (siRNAs) or other tiny RNAs 1, 2. In addition, the cloning of full-length cDNAs has revealed several thousand large utRNAs 3, 4, 5 that resemble mRNAs in that they are polyadenylated, often spliced but lack substantial open reading frames (ORFs). Finally, various studies – most prominently microarray tiling 6, 7, 8, 9, 10, 11, 12, 13 – currently predict a plethora of additional transcripts. Hence, the complexity of utRNAs could easily exceed that of mRNAs.
Are all of these RNAs functional? My prediction is that thousands do indeed have cellular functions, including regulatory roles (e.g. as co-regulatory RNAs, including antisense transcripts 14, 15, 16, 17, 18), but by no means all of them. One way of distinguishing functional and non-functional utRNAs is to examine evolutionary conservation [19]. Recently, the targeted deletion of two large (1.5 and 0.8 million base pairs), non-genic loci was reported in mice that had apparently normal phenotypes [20]. Despite realizing our current limits of analysis, this came as a surprise, because the combined loci contain >1200 conserved sequences shared between mice and humans (>100 bp, >70% ungapped similarity). In addition, it is highly unlikely that neither locus is devoid of transcripts that densely map to other chromosomal regions 6, 7, 8, 10, 12, 13 and, thus, overlap at least some of the conserved regions. On the one hand, conservation, even of transcribed sequences, does not itself imply function. On the other hand, lack of conservation, or mosaic conservation, does not preclude function as we learned from untranslated H19 RNA, inactive X-specific transcripts (Xist), antisense X (inactive)-specific transcript (Tsix) or antisense Igf2r RNA (Air) [14]. This is merely an indication of the task lying ahead in our efforts to assign a function to thousands of utRNAs. However, without this knowledge, we cannot even hope to understand fully the workings of a cell or the molecular bases of many diseases.
Even if a large percentage of observed transcripts were to be explained by experimental shortcomings [13], the presence of thousands of non-functional RNAs (nfRNAs) seems hard to comprehend by Molecular and Cell Biologists. They tend to look at the cells and components of multicellular organisms much in the same way as those of unicellular organisms – as perfectly balanced entities wherein virtually every molecule has a ‘purpose’ or at least, if error-ridden, is neatly disposed of 21, 22. Therefore, it is not surprising that there are tendencies to try to assign a cellular function to all newly discovered RNA transcripts 15, 16, 18, 23. However, recent evidence points to RNAs that exist simply as cellular by-products. In yeast, conditional repression of the SER3 gene occurs by transcriptional interference initiated upstream. The resulting product of the SRG1 gene, the RNA itself, is non-functional [24].
Section snippets
Alternative splicing – a waste?
The excess of apparently useless DNA in the genomes of mammals (and many other multicellular organisms) should have taught us that its presence and even conservation does not necessarily imply function in biological systems. Another example of apparent waste is alternative splicing. Based on expressed sequence tags (ESTs), a sizeable percentage of human mRNA alternative splice forms contain premature stop codons and most likely do not yield functional proteins [25].
Darwin already recognized
Exaptation generates diversity
In the past few years it has become clear that non-functional genomic DNA is a vast reservoir for co-option (exaptation) of novel genes, or parts of genes [28], generating significant diversity over evolutionary time. At various stages of ‘decay’, segments of this superfluous genomic mass have the potential to be exapted. Even though the odds are against it, exaptation is a pervasive evolutionary force that is at least as important for evolution as the adaptive changes of existing genes or
Concluding remarks
Once more, economy recapitulates organismic evolution [40]. Like the music industry, which releases thousands of singles onto the market each year only a small percentage of which receive significant air play, the cell continuously churns out thousands of transcripts assembled from (parts of) retroposons, existing genes and/or the ever-changing, randomized genomic mass. Only a minority ever ‘hit the charts’ of purifying selection.
References (40)
The microRNA world: small is mighty
Trends Biochem. Sci.
(2003)Dark matter in the genome: evidence of widespread transcription detected by microarray tiling experiments
Trends Genet.
(2005)- et al.
A perfect message: RNA surveillance and nonsense-mediated decay
Cell
(1999) A bacterial RNA that functions as both a tRNA and an mRNA
Trends Biochem. Sci.
(1998)- et al.
Evidence that functional transcription units cover at least half of the human genome
Trends Genet.
(2004) How prevalent is functional alternative splicing in the human genome?
Trends Genet.
(2004)- et al.
Transposable elements are found in a large number of human protein-coding genes
Trends Genet.
(2001) Introns and exons: playgrounds of evolution
Origin of a substantial fraction of human regulatory sequences from transposable elements
Trends Genet.
(2003)Transposable elements in mammals promote regulatory variation and diversification of genes with specialized functions
Trends Genet.
(2003)
Imprinted expression of small nucleolar RNAs in brain: time for RNomics
Proc. Natl. Acad. Sci. U. S. A.
Identification of putative noncoding RNAs among the RIKEN mouse full-length cDNA collection
Genome Res.
Complete sequencing and characterization of 21,243 full-length human cDNAs
Nat. Genet.
RNomenclature
RNA Biol
Large-scale transcriptional activity in chromosomes 21 and 22
Science
The transcriptional activity of human Chromosome 22
Genes Dev.
Novel RNAs identified from an in-depth analysis of the transcriptome of human chromosomes 21 and 22
Genome Res.
Reconciling the numbers: ESTs versus protein-coding genes
Mol. Biol. Evol.
A comprehensive transcript index of the human genome generated using microarrays and computational approaches
Genome Biol.
A gene expression map for the euchromatic genome of Drosophila melanogaster
Science
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