Professor John Mattick, Executive Director, Garvan Institute, Sydney, NSW
It appears that human genetic programming has been misunderstood for the past 50 years because of the assumption that most genetic information is transacted by proteins. Surprisingly, however, the number and functional repertoire of protein-coding genes is similar between humans and simple animals such as nematodes. On the other hand, the extent of non-protein-coding DNA, much of which is retrotransposon-derived, increases with increasing developmental complexity, reaching 98.8% in humans. The majority of these sequences are dynamically transcribed, producing enormous numbers of long and short non-protein-coding RNAs with precise expression patterns and subcellular locations. The emerging evidence indicates that these RNAs form a massive network of regulatory information that orchestrates gene expression during development, including the organization of chromatin structure and the site-specificity of the chromatin-modifying complexes that control epigenetic memory, and that alterations in the structure or expression of these networks play a role in cancer and neurological diseases. Moreover, the transcriptome is far from fully characterised, with targeted array capture analyses revealing thousands of new exons and isoforms in cancer gene loci, and at least 1,500 new lncRNA genes in ‘intergenic’ regions associated with complex diseases. It is also evident that cognitive evolution has been accompanied by the superimposition of epigenetic plasticity by RNA editing, reaching its zenith in primates, and that this is the basis of the environment-epigenome interactions that underpin physiological adaptation and brain function. Retrotransposons also appear to contribute to genomic plasticity and somatic mosaicism, especially in the brain. Thus, what was dismissed as ‘junk’ because it was not understood holds the key to understanding human evolution, development, diversity and intelligence.