R-nomics and the central dogma of biology

Mighty oaks from little acorns grow. And if Professor John Mattick's latest findings in mammalian embryos hold true for plants, plant molecular geneticists are likely to find that the entire developmental process coordinated by non-coding RNAs.

The Brisbane molecular geneticist has engineered his own equivalent of the acorn-to-oak miracle by growing a small group of molecular geneticists, transplanted to the campus of the University of Queensland 18 years ago, into one of Australia's most dynamic and internationally respected new bioscience research centres: the Institute for Molecular Bioscience.

Over that period, the founding director of the IMB also found time to establish himself as a pioneer and leading player in the hot new field of RNA-omics - more simply, R-nomics. R-nomics is now shining incandescent new light on almost all that science thought it knew about genes, gene regulation and development.

Richard Dawkins shocked 20th century sensibilities by suggesting that humans, birds, bees and bacteria can be considered intricate machines built by alliances of genes for the selfish purpose of self-replication.

Mattick and his collaborators in the international R-nomics research community are now challenging even Dawkins' iconoclastic take on deus ex machina, with a model that places regulatory RNA - not selfish DNA - at the centre of genomic activity. The RNA regulatory system is the reason why our genomes are so large.

Given the excitement surrounding the RNA revolution, Mattick is likely to draw a large audience when he describes his most recent research to the ComBio conference in Brisbane this month.

RNA transactions

In 2004, Mattick told the Horizons in Livestock Science annual conference on the Gold Coast it was clear that biology's central dogma was incomplete.

"My general thesis is that we have misunderstood human genetic programming for 50 years," he told ALS, "because of the presumption, largely true for microorganisms but not for complex organisms, that most genes encode proteins.

"Most genetic information in mammals and other complex organisms is transacted by RNA."

At Horizons, Mattick said it is also emerging that non-coding RNAs, and not the protein-coding genes themselves, are the main source of variation between individuals, and species.

Only 10,000 of the three million polymorphisms that collectively determine human individuality lie within the protein-coding exons of genes: the remainder - 99.7 per cent - lie in non-protein coding sequences that specify non-coding RNAs.

Mattick and his collaborators recently conducted a comprehensive analysis of several thousand non-coding RNAs that were found to be dynamically regulated during differentiation in a number of key systems including embryonic stem cells, muscle cells and early gonadal cells. They found that hundreds, and in some cases, thousands, of RNA transcripts are dynamically regulated, and the patterns of non-coding RNA expression mirrors the expression protein-coding messenger RNAs. Their coincident expression patterns hints that that non-coding RNAs are intimately involved in regulating and coordinating gene expression, as he and his colleagues predicted.

"This is the first stage in our efforts to demonstrate that these RNA transcripts are not some sort of non-specific noise, but are functional," Mattick says.

"What we're really doing is opening the window on this hidden world of RNA expression.

"RNA appears to be setting the parameters to control growth processes."

Digital and analog

Mattick has described the activity of RNAs as essentially digital in nature, with proteins forming the functional, analog components of the system. "RNA forms the control system, the regulatory architecture that controls the deployment of the analog working parts. It turns out that these control systems constitute the majority of our genome, which was totally unexpected," he says.

Three things conspired to keep this reality hidden from our view for half a century.

"First, we were intellectually unprepared for the possibility that genetic information might be transmitted in this way.

"Second, the system has very subtle genetic signatures. Mutations in noncoding RNAs will largely result in design variation, rather than the usually catastrophic component damage that results from mutations in protein-coding sequences, implying that the majority of variation that determines our individuality lies in RNA-coding regions of the genome."

The proteome - the formal term for the analog components - is largely similar between humans and other mammals. Mattick likens the various orthologs of proteins found in different species to steering wheels in modern cars.

"They have a slightly different design different, but they serve the same basic functions.

"The third reason is that these noncoding RNAs were biochemically invisible. Many are expressed in relatively low amount, and nobody seriously would have thought that small, 22-nucleotide RNA molecules at the bottom of a gel would prove to be significant.

"The latest information suggests that at least 70 per cent and possibly 90 per cent of the human genome is actually transcribed - the genome is almost completely full of genes coding for functional RNAs.

"They also occur on both DNA strands. At least 70 per cent of genes have anti-sense transcripts.

"The evidence is increasing that these transcripts are meaningful. If we're right about this, it means they're fundamentally about programming. "The theory that most of the genome is evolving neutrally is wrong. Most of these noncoding RNAs are quite evolutionarily plastic, and are evolving at different rates, in most cases more rapidly than sequences coding for multi-tasking proteins, which are subject to strict structure-function constraints."

Mattick says the new picture is one of dynamic evolution, occurring mainly within genes coding for RNAs that regulate gene activity, and often with profound consequences for patterns of gene expression in the organism.

"I've maintained for many years that the majority of evolution is occurring at the level of the regulatory architecture of the genome, because changing the design of the analog components without compromising their function is very difficult, because most of them are multi-tasked. "Indeed, it appears that the majority of human genomic programming is devoted to RNA-based regulatory circuitry."

According to Mattick, the presumption that most genetic information is transacted by proteins has led to a fundamental misunderstanding of the genetic programming of human differentiation and development - particularly in relation to the brain, where RNA transactions appear to be at their most complex.

Research and relatives win out

Mattick, named winner of the $10,000 CSIRO Eureka Prize for Leadership in Science in August, has stepped down as founding director of IMB to return to research.

The citation for the award credited him with helping engineer Queensland's Smart State campaign, and said he had been instrumental in creating a series of research institutes; the Centre for Molecular Biology and Cellular Biology (CMCB), and the Australian Genome Research Facility.

He had recently brought the CMCB and other research centres at the University of Queensland together with CSIRO to form the Queensland Bioscience Precinct, now home to more than 700 scientists.

The University of Queensland recruited Mattick in 1988 to build up the university's capacity in molecular biology and biotechnology. He was already one of CSIRO's outstanding young molecular geneticists.

Although UQ was ranked as one of Australia's leading universities, Queensland in 1988 was an unpromising future hub for advanced molecular biology and Australia's infant biotechnology industry.

Queensland had just elected a new Labor Government after 20 years of rule by arch-conservative Premier Joh Bjelke-Petersen, whose enthusiasm for developing the Sunshine State did not extend to its intellectual resources.

Today, Queensland is challenging Victoria's historic pre-eminence in bioscience and biomedical research. The state's biotechnology industry is flourishing under the patronage of the Beattie administration - Queensland was the lone dissenter when all other Australian states and territories imposed moratoria on genetically modified crops in 2004.

Mattick is "delighted" with his Eureka Prize. "It has been an amazing journey - we started as a small molecular biology research centre in 1988, but the university funded us in relatively generous terms and gave us the resources we needed.

"We've built up the centre by recruiting exceptionally good people.

"Eighteen years later, with a lot of hard work, and a lot of support from the state and federal governments, we've ended up with a research institute that employs more than 400 scientists.

"A review of our first five years of operation last year showed that, in terms of quantity of research papers produced, and our impact factor, estimated by citation frequency, we are performing on a par with the very best institutes in Australia.

"We're delighted by that - we're a relatively young institute, but we have some fabulous people.

"It has been wonderful, and in the end, extremely satisfying to lead the IMB to where it is today, but it has now grown very big. "I found I had three important jobs - to run an elite institute, to prosecute my research, which has enormous potential, and to look after my family. "I think I can do any two of those jobs well, but to try to do all three, especially given the size to which the institute had grown and the potential importance of my research, was to compromise all three.

"I decided that I needed to give more attention to my family and to my research, so I had to relinquish the directorship."