John Mattick Wins Chen Award for Distinguished Academic Achievement in Human Genetic and Genomic Research

Shame on the Human Genome Organization (HUGO). It has awarded a prestigious prize (US $10,000) to John Mattick, director of the Centre for Molecular Biology and Biotechnology at the University of Queensland in Brisbane, Australia. Here's the report from the Sydney Morning Herald.

Making something of junk earns geneticist top award

WHEN Sydney geneticist John Mattick suggested junk DNA was anything but rubbish he was challenging an assumption that had underpinned genetics for 50 years.

''The ideas I put forward 10 years ago were quite radical but I thought I was right,'' Professor Mattick said.

He was. And tomorrow he will become the first Australian honoured with the Chen Award for distinguished academic achievement in human genetic and genomic research, awarded by the Human Genome Organisation.

For decades after James Watson and Francis Crick discovered DNA was a double helix, scientists believed most genes were the written instructions for proteins, the building blocks of all body processes. The assumption was true for bacteria but not complex organisms like humans, said Professor Mattick, the new executive director of the Garvan Institute.

In humans, more than 95 per cent of the genome contains billions of letters that do not make proteins, called non-coding DNA. ''When people bumped into all this DNA that didn't make proteins they thought it must be junk,'' he said. But Professor Mattick felt it was unlikely that useless material would survive hundreds of millions of years of evolution.

He found that the non-protein-coding sections of DNA had a function, to produce RNA.

"The obvious and very exciting possibility was that there is another layer of information being expressed by the genome - that the non-coding RNAs form a massive and previously unrecognised regulatory network that controls human development.''

Many scientists now believe this RNA is the basis of the brain's plasticity and learning, and may hold the secret to understanding many complex diseases.

Mattick is one of the most prominent, non-creationist, opponents of junk DNA. He has published numerous papers and articles promoting the idea that most of our genome contains genes for regulatory RNA molecules. Here's a summary of his view as posted on his lab website [Mattick Lab].

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.

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)¹ 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 proteins², 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.

It's certainly true that this is a radical idea. Is he right? The Sydney Morning Herald seems to think that Mattick's views have won the day and I assume the Human Genome Organization believes this as well. Here's an excerpt from the press release issued by Mattick's employer [Professor John Mattick wins prestigious HUGO Chen Award].

The Award Reviewing Committee commented that Professor Mattick’s “work on long non-coding RNA has dramatically changed our concept of 95% of our genome”, and that he has been a “true visionary in his field; he has demonstrated an extraordinary degree of perseverance and ingenuity in gradually proving his hypothesis over the course of 18 years.”

I'm pretty sure that there's no more than a handful of biochemists/molecular biologists who believe Mattick. They know that lots of noncoding DNA has a function—a fact that's been in the textbooks for almost fifty years—but they do not believe that most of our genome encodes functional regulatory RNAs. It's simply untrue that Mattick has proved his hypothesis over the past 18 years. Just the opposite has happened.

Theme

Genomes
& Junk DNAMost knowledgeable, intelligent, biochemists know that at least half of our genome is littered with pseudogenes and defective transposons and viruses. That's junk by any reasonable definition. They know that functional noncoding DNA makes up about 8% of the genome and when you add in the exons the total comes to no more than 10% [What's in Your Genome?].

Much of the remaining 40% is probably junk but that's still a debatable point. (Half of it is introns.) What's not debatable is whether all of this DNA contains genes for regulatory RNAs. Nobody (to a first approximation) believes that except for a few people who hand out prestigious awards. I don't recognize any of the people on the Chem Award Review Committee as experts in the study of genomes and genome evolution but maybe that's because I'm not an expert either.

I've written about Mattick several times over the past few years, usually to show why he is so wrong. For example, here's a post from July 2007: Junk DNA in New Scientist.

Most articles on junk DNA eventually get around to mentioning John Mattick who has been very vocal about his claim that the Central Dogma has been overturned and most of the genome consists of genes that encode regulatory RNAs (Mattick, 2004; Mattick, 2007). This article quotes a skeptic to provide some sense of balance and demonstrate that the scientific community is not overly supportive of Mattick.

Others are less convinced. Ewan Birney of the European Bioinformatics Institute in Cambridge, UK, has bet Mattick that of the processed RNAs yet to be assigned a function - representing 14 per cent of the entire genome - less than 20 per cent will turn out to be useful. "I'll get a case of vintage champagne if I win," Birney says.

Under the subtitle "Mostly Useless," Pearson correctly summarizes the scientific consensus. (I wish she had used this as the title of the article. The actual title is somewhat misleading. Editors?)

Whatever the answer turns out to be, no one is saying that most of our genome is vital after all. "You could chuck three-quarters of it," Birney speculates. "If you put a gun to my head, I'd say 10 per cent has a function, maybe," says Lunter. "It's very unlikely to be higher than 50 per cent."

Most researchers agree that 50 per cent is the top limit because half of our genome consists of endless copies of parasitic DNA or "transposons", which do nothing except copy and paste themselves all over the genome until they are inactivated by random mutations. A handful are still active in our genome and can cause diseases such as breast cancer if they land in or near vital genes.

One of the most annoying things about Mattick is the way he distorts the meaning of the Central Dogma of Molecular Biology and the history of genome studies. It's simply not true that the Central Dogma means what he thinks it means in his 2003 paper. And it's simply not true that biochemists thought that all genes encoded proteins—at least not in the past 50 years [Basic Concepts: The Central Dogma of Molecular Biology].

The central dogma of biology holds that genetic information normally flows from DNA to RNA to protein. As a consequence it has been generally assumed that genes generally code for proteins, and that proteins fulfil not only most structural and catalytic but also most regulatory functions, in all cells, from microbes to mammals. However, the latter may not be the case in complex organisms. A number of startling observations about the extent of non-protein coding RNA (ncRNA) transcription in the higher eukaryotes and the range of genetic and epigenetic phenomena that are RNA-directed suggests that the traditional view of genetic regulatory systems in animals and plants may be incorrect. (Mattick 2003)

It's also annoying that Mattick equates "noncoding DNA" with "junk DNA." It seems like he never heard of functional noncoding sequences like centromeres, telomeres, regulatory sequences, origins of replication, etc and he assumes that most biochemists were just as ignorant back in the 1970s. Of course they weren't ... and they also knew about genes for ribosomal RNA and transfer RNA so the idea that all noncoding DNA was considered junk is, how shall it put it?, ... stupid.

This lack of rigor in his arguments does not inspire confidence.

One of the issues in the debate concerns the fraction of our genome that is transcribed to produce functional RNA molecules. My colleagues at the University of Toronto claim that much of the observed transcription is junk RNA that's due to aberrant (error-prone) transcription. Mattick has challenged their results in the scientific literature and that debate is one of the reasons why there's still a scientific controversy over the exact amount of functional RNAs [Pervasive Transcription]. If most of those scattered little bits of very low abundance RNAs are junk RNAs then Mattick is wrong and HUGO has made a huge mistake. As I said above, I think the majority of biochemists now think that only a fraction (less that 20%) of our genome is devoted to making functional regulatory RNAs.

Returning to rigor, Mattick is famous for the silly figure (right) in his 2004 Scientific American article. I first wrote about it in 2007 [Genome Size, Complexity, and the C-Value Paradox], pointing out the obvious flaws. Ryan Gregory liked it so much he coined a new term for such figures: Dog Ass Plots! Ryan was the one who alerted me to the award from HUGO to John Mattick and all he does on his blog is post the press release and the famous Dog Ass Plot as though nothing more need be said [Making something of junk earns geneticist top award.]!

Ryan is probably right but I couldn't resist saying a few more things. :-)

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[Hat Tip: Ryan Gregory: Making something of junk earns geneticist top award.]

1. It's actually 3.2 billion base pairs [How Much of Our Genome Is Sequenced?] but why should anyone working on genomes cares about such quibbles?

2. It's actually closer to 20,500 [How Much of Our Genome Is Sequenced?] but we all know how hard it is to update a lab website. The number he gives was true five years ago and that's probably close enough for an expert in the human genome.

Mattick, J.S. (2003) Challenging the dogma: the hidden layer of non-protein-coding RNAs in complex organisms. BioEssays 25:930-939.

Mattick, J.S. (2004) The hidden genetic program of complex organisms. Sci. Am. 291:60-7.

Mattick, J.S. (2007) A new paradigm for developmental biology. J. Exp. Biol. 210:1526-47. [PubMed Abstract]