Research
From GroupWiki
The central hypothesis/heuristic of the Mattick Lab is that the majority of the genomes of complex organisms is devoted to an RNA regulatory system, and that this was the enabling platform for the evolution and development of complex multicellular organisms.
[edit] The Genomic Programming of Complex Organisms: RNA Regulatory Networks in Mammalian Differentiation and Development
The central challenge in biology is to understand how our genome (which consists of two copies inherited from our parents, each containing 2.9 billion base pairs) encodes the information that directs our development from a single fertilized cell to a precisely sculptured organism of around 100 trillion differentiated cells, and how that information underpins the differences between individuals and species, including their cognitive capacity.
The human genome contains around 25,000 genes encoding proteins, less than rice and only 20% more than a simple worm comprised of just 1,000 cells. Most of the proteins encoded in the human genome have recognizable equivalents in other mammals and other animals, indicating that these organisms share a relatively common set of functional components. These protein-coding sequences account for less than 1.5% of the human genome, leading to the questions - what, if anything, is the function of the remainder of the sequences in the genomes of higher organisms and are they somehow related to our complexity?
These non-protein-coding sequences occur within genes (intervening sequences or “introns”) and between genes (“intergenic sequences”) a significant proportion of which (around 45%) are the descendents of past molecular invasions (transposons). These sequences are often lumped together and referred to as "junk DNA", because they do not code for protein, despite the fact that many if not most of these sequences are in fact expressed as non-protein-coding RNAs, which account for around 98% of all genomic output in humans. Indeed the prevailing assumption, based on bacterial molecular genetics and genomics, is that genes are generally synonymous with proteins, and genetic information is transduced by proteins, which comprise the structural and functional (analog) components of cells, and are also the primary agents by which the system is regulated.
We are working on the alternative hypothesis that the majority of the genomes of complex organisms is devoted to the regulation of development and that most of this information is transacted by noncoding RNAs. Both logic and the available evidence suggest that these RNAs form a highly parallel digital network that integrates complex suites of gene expression and controls the programmed responses required for the autopoeitic development of multicellular organisms. If this is correct, our current conceptions of the genomic information content and programming of complex organisms will have to be radically reassessed, with implications well beyond biology.
We are using bioinformatic and molecular genetic approaches to identify noncoding regions of the human genome that are under evolutionary and functional selection, and to map RNA regulatory networks in a variety of organisms, including yeast, worms, insects and mammals. We use mathematical and computational approaches to modeling and understanding complex regulatory networks, as well as a variety of molecular biological approaches to identify higher order nucleic acid structures and the proteins that recognize these complexes to convert digital RNA signals to analogue actions. We are also developing new databases and microarray chips to examine the expression of noncoding RNAs in humans and mice during development and in different disease states.
