Challenging the dogma: the hidden layer of non‐protein‐coding RNAs in complex organisms

Abstract

The central dogma of biology holds that genetic information normally flows from DNA to RNA to protein. As a consequence it has been generally assumed that genes generally code for proteins, and that proteins fulfil not only most structural and catalytic but also most regulatory functions, in all cells, from microbes to mammals. However, the latter may not be the case in complex organisms. A number of startling observations about the extent of non-protein-coding RNA (ncRNA) transcription in the higher eukaryotes and the range of genetic and epigenetic phenomena that are RNA-directed suggests that the traditional view of the structure of genetic regulatory systems in animals and plants may be incorrect. ncRNA dominates the genomic output of the higher organisms and has been shown to control chromosome architecture, mRNA turnover and the developmental timing of protein expression, and may also regulate transcription and alternative splicing. This paper re-examines the available evidence and suggests a new framework for considering and understanding the genomic programming of biological complexity, autopoietic development and phenotypic variation.

Identification and characterization of a novel transcript down‐regulated in Dlx1/Dlx2 and up‐regulated in Pax6 mutant telencephalon

“…These genes have been shown to control chromosome architecture, mRNA turnover, the developmental timing of protein expression and alternative splicing (Mattick, 2001(Mattick, , 2003. Noncoding RNAs are now also regarded as important regulators of transcription, particularly in intergenic regions.…”

Expanding the ‘central dogma’: the regulatory role of nonprotein coding genes and implications for the genetic liability to schizophrenia

“…The understanding of the importance of ncRNA regulation of gene expression is an emerging area of active research with many methodological challenges. 5 The results of animal and plant research to date suggest that ncRNAs are likely to be a major regulatory mechanism of gene expression regulation in humans. Pertinent examples are discussed above, although numerous other ncRNA regulatory mechanisms exist.…”

“…4 For example, ncRNA may regulate protein synthesis by decelerating or accelerating mRNA degradation. [5][6][7][8] Control mechanisms may target the mRNA degradation enzymes or some other aspect of the propensity of the mRNA to be degraded, thus impacting the steady concentration (ie 'half-life') of the mRNA. 9 These newly discovered control mechan-isms for protein expression are often referred to as the 'tip of the iceberg', anticipating that yet undiscovered regulatory functions of ncRNAs are likely to be critical to the development and function of complex organisms.…”

“…RISC ncRNA complex may then interact with the transcribed mRNA (4). Perfectly complementary ncRNA and mRNA binding will then subject the mRNA to cleavage and degradation (5). Imperfectly complementary ncRNA:mRNA may allow the mRNA to bind with ribosomes, but interferes with translation (6).…”

Evolutionary patterns of non-coding RNAs

“…Since the discovery of microRNAs [219,228,237] and the development of RNAi as a general technique for manipulating translation [93], there is mounting evidence that ncRNAs in fact dominate the regulatory networks of the cell [21,157,273,274,391]: The E. coli genome encodes more than 50 small RNA genes at least some of which (e.g. MicF, OxyS, DsrA, Spot42, RhyB) act by base-pairing to activate or repress translation [127,383].…”