Abstract

Bioinformatic, genomic and experimental evidence all suggest that the genetic programming of complex organisms has been misunderstood for the past 50 years, because of the assumption – largely true for the unicellular prokaryotes, but not for multicellular eukaryotes – that most genetic information is transacted by proteins. The human genome comprises 3 billion base pairs of DNA sequence information. It programs the development of a precisely sculptured individual of about 100 trillion cells with hundreds of different muscles, bones and organs, as well as the brain. It contains about 20,000 protein-coding genes, surprisingly about the same number and in large part with similar functions as those in tiny worms that have only 1,000 cells. On the other hand, the extent of non-protein-coding DNA increases with increasing complexity, reaching 98.8% in humans, suggesting that much of the information required to program development may reside in these sequences. Moreover it is now evident the majority of the mammalian genome is transcribed, mainly into non-protein-coding RNAs (ncRNAs), and that there are tens if not hundreds of thousands of long and short RNAs in mammals that show specific expression patterns and subcellular locations. Our studies indicate that these RNAs form a massive hidden network of regulatory information that regulates epigenetic processes and directs the precise patterns of gene expression during growth and development. It also appears that RNA is central to brain development, learning and memory, and that animals, especially primates, have developed sophisticated RNA editing systems to modify hardwired genetic information in response to experience, that in turn can modulate epigenetic memory, some of which may be inherited. Thus RNA may represent the computational engine of the cell and the major substrate for gene-environment interactions. Moreover, what was dismissed as junk because it was not understood may hold the key to understanding human evolution, development and cognition, as well as our idiosyncrasies and susceptibilities to complex diseases.