The significance of RNA for cellular function and genome evolution by Jürgen Brosius
One surprising discovery that has arisen from the human genome project is that humans do not have considerably more protein-genes than other mammals. For example, 99% of mouse genes have human homologues. Consequently, at most 1 200 (4%), but possibly as few as 300 (1%), of human genes have arisen since the rodent and primate lineages diverged about 65-110 million years ago. Moreover, based solely on the ‘gene count’, our 30 000 genes render us barely more complex than fish or other vertebrates, only seven to ten times more complex than E. coli and three times more than a the ‘lowly’ bread mould!
Another surprising fact is that actual protein-coding regions of genes comprise a mere 1.5% of our 3 billion base pairs. The remaining 98.5% represent non-protein-coding RNA such as introns, intergenic sequences, control elements, 5’ and 3’ untranslated sequences of mature mRNAs, and non-messenger RNAs. Introns usually interrupt protein-coding regions of genes and range in size from several hundreds or thousands of base pairs to longer than 100-kilo bases! These numerical considerations alone mandate that the ‘silent’ majority of genomes can no longer be ignored, and call into question the very definition of what a ‘gene’ really is. If species differences do not lie in the numbers or varieties of ‘protein-coding’ genes, perhaps the remainder of our genome can help to explain them.
Back to the future
To help understand what were, until recently, virtually disregarded regions of our molecular inheritance, we look back many millions of years to the ‘RNA world’ when RNA in primitive cells harboured both genetic information and carried out enzymatic reactions. In two major evolutionary transitions, proteins gradually replaced most of the catalytic functions of RNA, then later RNA was converted to DNA as genetic material. However, even today, RNA continues to shape genomes via retroposition, the virtually unabated conversion of RNA to DNA and random integration in genomes. Furthermore, phylogenetic comparisons of genomes and the RNAs they encode document that extant cellular RNAs are not merely remnants of the bygone RNA world, but they also function as RNA molecules, without being translated into proteins, in a broad spectrum of cellular activities.
Proposed 2-D step-loop structure of BC1, a functional, non-protein-coding RNA in rodents. BC1 RNA (b, hippocampus) and its human analog BC200 RNA(c, cerebral cortex) are found only in the brain of rodents and humans, respectively where they are particularly localized in the dendritic processes of neurons.
Courtesy: M. Bundman & J. Brosius, Institute for Experimental Pathology, University of Muenster
A dazzling array of previously unknown, functional RNAs has recently been discovered, including the H19 RNA which probably plays a role in human cancer, the Xist RNA implicated in the developmental inactivation of sex chromosomes, and the MRP RNA associated with cartilage-hair hypoplasia. Many small RNAs exist in unforeseen compartments of the cell, from the nucleus to the synapses of nerve cells. Among these are the small nucleolar RNAs (snoRNAs) associated with the neuro-developmental Prader-Willi Syndrome. The exciting class of micro and short interfering RNAs (miRNAs, siRNAs) regulates the levels of expressed proteins by influencing their mRNAs. Many of these RNAs are not ubiquitously expressed but are found only in certain tissues or cell types at certain stages in development. Hence, they play important roles in organismal development beginning at the stem cell stage. Disturbances of these molecular RNA switches are thus likely to underlie a number of human diseases. Conversely, the use of miRNAs and siRNAs as therapeutic tools holds much promise in counteracting disturbances of gene expression in a wide spectrum of diseases (including infectious diseases), thus highlighting our need to know more about the properties and pathways of functional RNAs.
RNA was responsible for the evolution of today’s DNA genes but new RNA molecules continue to evolve and, via the process of retroposition, are rapidly changing chromosomal landscapes. Perhaps it is such retropositional events that, as the engines of species evolution, constitute the important differences in closely related species, such as human and chimpanzee. Therefore, by examining the roles of RNAs in the process of evolution, their numerous roles in modern cellular function become more evident.
Institute of Experimental Pathology, ZMBE,
University of Münster, Germany
Professor Jürgen Brosius is a partner in the FP6 STREP project 'RIBOREG –Novel roles of non-coding RNAs in differentiation and disease'.