Feature: Epigenetics key to human evolution

Professor John Mattick suggests that RNA and epigenetics are a major driving force behind evolution.

Humans possess the most complex Rnome – the RNA equivalent of a genome – of any animal, allowing us to at least lay technical claim to being the most highly evolved species on Earth. Prune down the enormous assemblage of non-coding RNAs (ncRNAs) that are thought to coordinate the activity of our 20,000-odd protein-coding genes, and you might end up with something like a nematode worm, one of the simplest multicellular animals.

“The basic toolkit for multicellular development, such as the Hox body-patterning genes and the Wnt cell-polarity genesare all there in worms,” says Professor John Mattick, of the Institute for Molecular Bioscience at the University of Queensland, and a pioneer in the still-new frontier of Rnomics.

Mattick says the genetic programming of complex organisms has been largely misunderstood for the past 50 years because of the assumption that proteins transact most genetic information. He says that even after more than half a billion years of evolutionary divergence, most genes are still recognisably common to all animal species. All animals share a basic complement of about 20,000 protein-coding genes. In humans, protein-coding genes account for only 1.2 per cent of genomic DNA.

“It is now clear that the majority of the mammalian genome is transcribed into non-protein coding RNA, and that there are tens, if not hundreds of thousands, of long and short RNAs in mammals that show specific expression patterns and sub-cellular locations,” says Mattick. “Our studies indicate that these RNAs form a massive, hidden network of regulation that regulates epigenetic processes, and directs the precise patterns of gene expression during growth and development.”

Thus, the differences between species and individuals emerge from the relative complexity of their RNA-encoded regulatory architectures. Human tissues teem with non-protein-coding RNAs.

“It is now obvious that the differences between us and other animals are not just embedded in the combinatorics of a similar complement of transcription factors,” says Mattick. “They stem from a massive expansion in humans of the genome’s RNA regulatory architecture.”

Digging through the Rnome

The field grows apace: a trickle of research papers in the mid-1990s has become a flood, with around 270 papers on non-coding RNAs published in 2008. Mattick says his IMB team and others around the world are finding more and more tangible evidence for the functionality of tens of thousands of non-coding RNA molecules in the human genome.

He thinks their most important function is to regulate epigenetic processes such as DNA methylation and histone modifications, which are involved in gene silencing and activation at thousands of positions around the genome during differentiation and development.

“Another surprising thing to emerge is that some ncRNAs are involved in formation and function of subcellular organelles, like paraspeckles.” Discovered in 2002 by Dr Archa Fox of the WA Institute for Medical Research, paraspeckles are tiny (0.2-1μm) complexes of RNA and protein found in the interstices in chromatin in the nucleus. They appear when mammalian cells differentiate, and they vary in size, shape and number in different cell types. Recent research indicates they serve as a localised reserve of long non-coding RNAs within the nucleus. These non-coding RNAs can be released quickly to activate transcription of stress-response genes, allowing the cell to respond rapidly to stress signals.

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