The new world of RNA biology

John Mattick
Green Templeton College, Oxford

The genomic programming of complex organisms appears to have been misunderstood. The human genome contains just ~20,000 protein-coding genes, similar in number and with largely orthologous functions as those in other animals, including simple nematodes. By contrast, the extent of non-protein-coding DNA increases with increasing developmental complexity, reaching 98.5% in humans, presumably due to an expanded regulatory architecture. Moreover, it is now clear that the majority of the genome is differentially and dynamically transcribed to produce not only mRNAs but also tens if not hundreds of thousands of short and long non-protein-coding RNAs that show highly specific expression patterns and subcellular locations, with many shown to play important aetiological roles in development, brain function, cancer and other diseases.

These ‘noncoding’ RNAs function at many different levels of gene expression and cell biology, including translational control, subcellular domain formation, and guidance of the epigenetic processes that underpin development, brain function and physiological adaptation, augmented by the superimposition of plasticity by RNA editing, RNA modification and retrotransposon mobilization. The evidence is now overwhelming that there is a massive hidden layer of RNA-mediated regulatory and architectural functions in humans and other complex organisms and that the current model of gene regulation is incomplete. The challenge now is to determine the structure-function relationships of these RNAs and their mechanisms of action, as well as their place in the decisional hierarchy that controls human development, physiology, cognitive function and susceptibility to disorders.