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.
John Mattick is a Professor and research scientist at the Garvan Institute of Medical Research at the University of New South Wales (Australia).
John Mattick publishes lots of papers. Most of them are directed toward proving that almost all of the human genome is functional. I want to remind you of some of the things that John Mattick has said in the past so you'll be prepared to appreciate my next post [The Junk DNA Controversy: John Mattick Defends Design].
Mattick believes that the Central Dogma means DNA makes RNA makes protein. He believes that scientists in the past took this very literally and discounted the importance of RNA. According to Mattick, scientists in the past believed that genes were the only functional part of the genome and that all genes encoded proteins.
If that sounds familiar it's because there are many IDiots who make the same false claim. Like Mattick, they don't understand the Central Dogma of Molecular Biology and they don't understand the history that they are distorting.
Mattick believes that there is a correlation between the amount of noncoding DNA in a genome and the complexity of the organism. He thinks that the noncoding DNA is responsible for making tons of regulatory RNAs and for regulating expression of the genes. This belief led him to publish a famous figure (left) in Scientific American.
Mattick has many followers. So many, in fact, that the Human Genome Organization (HUGO) recently gave him an award for his contributions to the study of the human genome. Here's the citation. Theme Genomes
& Junk DNA
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.”
Let's see what this "true visionary" is saying this year. The first paper is "The dark matter rises: the expanding world of regulatory RNAs" (Clark et al., 2013). Here's the abstract ...
The ability to sequence genomes and characterize their products has begun to reveal the central role for regulatory RNAs in biology, especially in complex organisms. It is now evident that the human genome contains not only protein-coding genes, but also tens of thousands of non–protein coding genes that express small and long ncRNAs (non-coding RNAs). Rapid progress in characterizing these ncRNAs has identified a diverse range of subclasses, which vary widely in size, sequence and mechanism-of-action, but share a common functional theme of regulating gene expression. ncRNAs play a crucial role in many cellular pathways, including the differentiation and development of cells and organs and, when mis-regulated, in a number of diseases. Increasing evidence suggests that these RNAs are a major area of evolutionary innovation and play an important role in determining phenotypic diversity in animals.
This is his main theme. Mattick believes that a large percentage of the human genome is devoted to making regulatory RNAs that control development. He believes that the evolution of this complex regulatory network is responsible for the creation of complex organisms like humans, which, incidentally, are the pinnicle of evolution according to the figure shown above.
The second paper I want to highlight focuses on a slightly different theme. It's title is "Understanding the regulatory and transcriptional complexity of the genome through structure." (Mercer and Mattick, 2013). In this paper he emphasizes the role of noncoding DNA in creating a complicated three-dimensional chromatin structure within the nucleus. This structure is important in regulating gene expression in complex organisms. Here's the abstract ...
An expansive functionality and complexity has been ascribed to the majority of the human genome that was unanticipated at the outset of the draft sequence and assembly a decade ago. We are now faced with the challenge of integrating and interpreting this complexity in order to achieve a coherent view of genome biology. We argue that the linear representation of the genome exacerbates this complexity and an understanding of its three-dimensional structure is central to interpreting the regulatory and transcriptional architecture of the genome. Chromatin conformation capture techniques and high-resolution microscopy have afforded an emergent global view of genome structure within the nucleus. Chromosomes fold into complex, territorialized three-dimensional domains in concert with specialized subnuclear bodies that harbor concentrations of transcription and splicing machinery. The signature of these folds is retained within the layered regulatory landscapes annotated by chromatin immunoprecipitation, and we propose that genome contacts are reflected in the organization and expression of interweaved networks of overlapping coding and noncoding transcripts. This pervasive impact of genome structure favors a preeminent role for the nucleoskeleton and RNA in regulating gene expression by organizing these folds and contacts. Accordingly, we propose that the local and global three-dimensional structure of the genome provides a consistent, integrated, and intuitive framework for interpreting and understanding the regulatory and transcriptional complexity of the human genome.
Clark, M.B., Choudhary, A., Smith, M.A., Taft, R.J. and Mattick, J.S. (2013) The dark matter rises: the expanding world of regulatory RNAs. Essays in Biochemistry 54:1-16. [doi:10.1042/bse0540001]
Mercer, T.R. and Mattick, J.S. (2013) Understanding the regulatory and transcriptional complexity of the genome through structure. Genome research 23:1081-1088 [doi: 10.1101/gr.156612.113]
John Mattick and Jonathan Wells both believe that most of the DNA in our genome is functional. They do not believe that most of it is junk.
John Mattick and Jonathan Wells use the same arguments in defense of their position and they quote one another. Both of them misrepresent the history of the junk DNA debate and both of them use an incorrect version of the Central Dogma of Molecular Biology to make a case for the stupidity of scientists. Neither of them understand the basic biochemistry of DNA binding proteins leading them to misinterpret low level transcription as functional. Jonathan Wells and John Mattick ignore much of the scientific evidence in favor of junk DNA. They don't understand the significance of the so-called "C-Value Paradox" and they don't understand genetic load. Both of them claim that junk DNA is based on ignorance.
The failure to recognize the implications of the non-coding DNA will go down I think as the biggest mistakes in the history of molecular biology.
John Mattick abc AustraliaJohn Mattick has just published a paper dealing with the controversy over the ENCODE results and junk DNA. As you might imagine, Mattick defends the idea that most of our genome is functional. He attempts to explain why most of the critics are wrong.
The title of the paper is "The extent of functionality in the human genome" (Mattick and Dinger, 2013). It's published in the HUGO Journal. Recall that HUGO (Human Genome Organization) gave Mattick a prestigious award for his contributions to genome research. (See The Dark Matter Rises for a discussion of these contributions.)
Mattick's paper begins by mentioning three of the papers that were critical of ENCODE results: Dan Graur's paper (Graur et al. 2013), Ford Doolittle's paper (Doolittle, 2013), and the paper by Niu and Jiang (2013).
He begins by addressing one of Dan Graur's points about conservation.
John Mattick and Paulo Amaral have written a book that promotes their views on the content of the human genome. It will be available next August. Their main thesis is that the human genome is full of genes for regulatory RNAs and there's very little junk. A secondary theme is that some very smart scientists have been totally wrong about molecular biology and molecular evolution for the past fifty years.
I pretty much know what's going to be in the book [see John Mattick presents his view of genomes]. I also know that most of his claims don't stand up to close scrutiny but that's not going to prevent it from being touted as a true paradigm shift. (It's actually a paradigm shaft.) I suspect it's going to get favorable reviews in Science and Nature.
The creationists are committed to proving that most of our genome is functional because otherwise the idea of an intelligent designer doesn't make a lot of sense. They reject all of the evidence that supports junk DNA and they vehemently reject the notion that 90% of our genome is junk.
I was recently alerted to a video on junk DNA produced by Creation Ministries International in which they quote John Mattick.
A leading figure in genetics, Prof. John Mattick said ...'the failure to recognize the implications of the non-coding DNA will go down as the biggest mistake in the history of molecular biology'.
The creationists are making the common mistake of equating noncoding DNA and junk DNA but the quotation sounded accurate to me since John Mattick makes similar mistakes in his publications. I decided to try and find the exact quotation and reference and the closest I could come to a direct quote was in a paper by Mattick from 2007 (Mattick, 2007). He's referring to introns—here's the exact quotation.
It should be noted that the power and precision of digital communication and control systems has only been broadly established in the human intellectual and technological experience during the past 20–30 years, well after the central tenets of molecular biology were developed and after introns had been discovered. The latter was undoubtedly the biggest surprise (Williamson, 1977), and its misinterpretation possibly the biggest mistake, in the history of molecular biology. Although introns are transcribed, since they did not encode proteins and it was inconceivable that so much non-coding RNA could be functional, especially in an unexpected way, it was immediately and almost universally assumed that introns are non-functional and that the intronic RNA is degraded (rather than further processed) after splicing. The presence of introns in eukaryotic genomes was then rationalized as the residue of the early assembly of genes that had not yet been removed and that had utility in the evolution of proteins by facilitating domain shuffling and alternative splicing (Crick, 1979; Gilbert, 1978; Padgett et al., 1986). Interestingly, while it has been widely appreciated for many years that DNA itself is a digital storage medium, it was not generally considered that some of its outputs may themselves be digital signals, communicated viaRNA.
However, the idea of the biggest mistake in molecular biology predates that reference. Mattick is quoted in a Scientific American article by W. Wayt Gibbs where Gibbs is discssing the "suprising" fact that regulatory sequences are conserved and that some genes are noncoding genes (Gibbs, 2003).
“I think this will come to be a classic story of orthodoxy derailing objective analysis of the facts, in this case for a quarter of a century,” Mattick says. “The failure to recognize the full implications of this—particularly the possibility that the intervening noncoding sequences may be transmitting parallel information in the form of RNA molecules—may well go down as one of the biggest mistakes in the history of molecular biology.”
The discovery of introns in the mid-1970s was definitely a surprise but it's not true, as Mattick implies, that they were immediately assumed to be junk. In fact, as he points out, there was a lot of debate over the possible role of introns in the evolution of protein-coding genes where they could stimulate exon shuffling. Later on, the presence of introns was recognized to be an essential component of alternative splicing.
Once more and more sequences were published it became apparent that neither their size nor their sequences were conserved except for the spliceosome recognition sequences. It soon became obvious that their sequences were evolving at the neutral rate demonstrating that they were mostly junk. Mattick assumes that this conclusion—that introns are mostly junk—is one of the biggest mistakes in molecular biology. I think the opposite is true. I think that the failure of most molecular biologists to understand junk DNA is a huge mistake.
The creationists are misquoting Mattick when they say that the classification of all noncoding as junk is the biggest mistake in molecular biology. In the quotations above, Mattick is specifically referrring to introns but I'm sure he won't be upset to be misquoted in that manner since he firmly believes that most noncoding DNA is functional.
There's a bit of an ironic twist here. If it were true that knowledgeable scientists in the 1970s actually believed that all noncoding DNA was junk then I'd have to agree that this would have been a big (biggest?) mistake. But they didn't and it wasn't a big mistake. As I've said many times, no knowledgeable scientist ever said that all noncoding DNA was junk since they (we) all knew about noncoding genes, regulatory sequences, centromeres, and origins of replication, all of which are functional noncoding DNA. We now know that about 1% of our genome is coding sequences and about 9% is functional noncoding DNA. The other 90% is junk.
John Mattick is a Professor and research scientist at the Garvan Institute of Medical Research at the University of New South Wales (Australia). He received an award from the Human Genome Organization for ....
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.”
John Mattick is the most prominent defender of the idea that the human genome is full of functional sequences. In fact, he is just about the only scientist of any prominence who's on that side of the debate. His main "evidence" is the fact that genomes are pervasively transcribed and that most of the transcripts are functional. Let's look at his latest review paper to see how well this argument stands up to close scrutiny (Mattick, 2018).1
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.”
Mattick follows his usual format by giving us his version of history. He has argued for the past 15 years that the scientific community has been reluctant to accept the evidence of massive amounts of regulatory RNA genes because it conflicts with the standard paradigm of the supremacy of proteins. In the past he has claimed that this paradigm is based on the Central Dogma which states, according to him, that the only real function of DNA is to make proteins [How Much Junk in the Human Genome?]. As we shall see, he hasn't abandoned that argument but at least he no longer refers to the Central Dogma for support
Paradigm shifts are rare but paradigm shafts are common. A paradigm shaft is when a scientist describes a false paradigm that supposedly ruled in the past then shows how their own work overthrows that old (false) paradigm.1 In many cases, the data that presumably revolutionizes the field is somewhat exaggerated.
John Mattick's view of eukaryotic RNAs is a classic example of a paradigm shaft. At various times in the past he has declared that molecular biology used to be dominated by the Central Dogma, which, according to him, supported the concept that the only function of DNA was to produce proteins (Mattick, 2003; Morris and Mattick, 2014). More recently, he has backed off this claim a little bit by conceding that Crick allowed for functional RNAs but that proteins were the only molecules that could be involved in regulation. The essence of Mattick's argument is that past researchers were constrained by adherance to the paradigm that the only important functional molecules were proteins and RNA served only an intermediate role in protein synsthesis.
Stop the presses! Revise the textbooks! John Mattick and his collaborators have discovered how genes are controlled in mammals.
Anyone who knows Mattick's past history will know what's coming—Mattick overthrew the Central Dogma of Molecular Biology over six years ago (Mattick, 2003; Mattick, 2004).1,2
An international consortium of scientists, including researchers from The University of Queensland (UQ), have probed further into the human genome than ever before.
They have discovered how genes are controlled in mammals, as well as the tiniest genetic element ever found.
Their discoveries will be published in three milestone papers in leading journal Nature Genetics.
John Mattick is famous for arguing that there's a correlation between genome size and complexity; notably in a 2004 Scientific American article (Mattick, 2004) [Genome Size, Complexity, and the C-Value Paradox ]. That's the article that has the famous Dog-Ass Plot (left) with humans representing the epitome of complexity and genome size. He claims that this correlation is evidence that most of the genomes of complex animals must have a function. He repeats this claim in a recent paper (see below).
RNA has long been regarded primarily as the intermediate between genes and proteins. It was a surprise then to discover that eukaryotic genes are mosaics of mRNA sequences interrupted by large tracts of transcribed but untranslated sequences, and that multicellular organisms also express many long ‘intergenic’ and antisense noncoding RNAs (lncRNAs). The identification of small RNAs that regulate mRNA translation and half-life did not disturb the prevailing view that animals and plant genomes are full of evolutionary debris and that their development is mainly supervised by transcription factors. Gathering evidence to the contrary involved addressing the low conservation, expression, and genetic visibility of lncRNAs, demonstrating their cell-specific roles in cell and developmental biology, and their association with chromatin-modifying complexes and phase-separated domains. The emerging picture is that most lncRNAs are the products of genetic loci termed ‘enhancers’, which marshal generic effector proteins to their sites of action to control cell fate decisions during development.
Parrington addresses this issue on page 63 by describing experiments from the late 1960s showing that there was a great deal of noncoding DNA in our genome and that only a few percent of the genome was devoted to encoding proteins. He also notes that the differences in genome sizes of similar species gave rise to the possibility that most of our genome was junk. Five pages later (page 69) he reports that scientists were surprised to find only 30,000 protein-coding genes when the sequence of the human genome was published—"... the other big surprise was how little of our genomes are devoted to protein-coding sequence."
Contradictory stuff like that makes it every hard to follow his argument. On the one hand, he recognizes that scientists have known for 50 years that only 2% of our genome encodes proteins but, on the other hand, they were "surprised" to find this confirmed when the human genome sequence was published.
He spends a great deal of Chapter 4 explaining the existence of introns and claims that "over 90 per cent of our genes are alternatively spliced" (page 66). This seems to be offered as an explanation for all the excess noncoding DNA but he isn't explicit.
In spite of the fact that genome comparisons are a very important part of this debate, Parrington doesn't return to this point until Chapter 10 ("Code, Non-code, Garbage, and Junk").
We know that the C-Value Paradox isn't really a paradox because most of the excess DNA in various genomes is junk. There isn't any other explanation that makes sense of the data. I don't think Parrington appreciates the significance of this explanation.
The examples quoted in Chapter 10 are the lungfish, with a huge genome, and the pufferfish (Fugu), with a genome much smaller than ours. This requires an explanation if you are going to argue that most of the human genome is functional. Here's Parrington's explanation ...
Yet, despite having a genome only one eighth the size of ours, Fugu possesses a similar number of genes. This disparity raises questions about the wisdom of assigning functionality to the vast majority of the human genome, since, by the same token, this could imply that lungfish are far more complex than us from a genomic perspective, while the smaller amount of non-protein-coding DNA in the Fugu genome suggests the loss of such DNA is perfectly compatible with life in a multicellular organism.
Not everyone is convinced about the value of these examples though, John Mattick, for instance, believes that organisms with a much greater amount of DNA than humans can be dismissed as exceptions because they are 'polyploid', that is, their cells have far more than the normal two copies of each gene, or their genomes contain an unusually high proportion of inactive transposons.
In other words, organisms with larger genomes seem to be perfectly happy carrying around a lot of junk DNA! What kind of an argument is that?
Mattick is also not convinced that Fugu provides a good example of a complex organism with no non-coding DNA. Instead, he points out that 89% of this pufferfish's DNA is still non-protein-coding, so the often-made claim that this is an example of a multicellular organism without such DNA is misleading.
[Mattick 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.
Hugo Award Committee Seriously? That's the best argument he has? He and Mattick misrepresent what scientists say about the pufferfish genome—nobody claims that the entire genome encodes proteins—then they ignore the main point; namely, why do humans need so much more DNA? Is it because we are polyploid?
It's safe to say that John Parrington doesn't understand the C-value argument. We already know that Mattick doesn't understand it and neither does Jonathan Wells, who also wrote a book on junk DNA [John Mattick vs. Jonathan Wells]. I suppose John Parrington prefers to quote Mattick instead of Jonathan Wells—even though they use the same arguments—because Mattick has received an award from the Human Genome Organization (HUGO) for his ideas and Wells hasn't [John Mattick Wins Chen Award for Distinguished Academic Achievement in Human Genetic and Genomic Research].
Most of the human genome is transcribed at some time or another in some tissue or another. The phenomenon is now known as pervasive transcription. Scientists have known about it for almost half a century.
At first the phenomenon seemed really puzzling since it was known that coding regions accounted for less than 1% of the genome and genetic load arguments suggested that only a small percentage of the genome could be functional. It was also known that more than half the genome consists of repetitive sequences that we now know are bits and pieces of defective transposons. It seemed unlikely back then that transcripts of defective transposons could be functional.
Part of the problem was solved with the discovery of RNA processing, especially splicing. It soon became apparent (by the early 1980s) that a typical protein coding gene was stretched out over 37,000 bp of which only 1300 bp were coding region. The rest was introns and intron sequences appeared to be mostly junk.
A few weeks ago I criticized Philip Ball for an article he published in Nature: DNA: Nature Celebrates Ignorance. Phil has responded to my comments and he has given me permission to quote from his response. I think this is going to stimulate discussion on some very interesting topics.
The role of small RNAs is one of those topics. There are four types of RNA inside cells: tRNA, ribosomal RNA (rRNA), messenger RNA (mRNA), and a broad category that I call “small RNAs.”
The small RNAs include those required for splicing and those involved in catalyzing specific reactions. Many of them play a role in regulating genes expression. These roles have been known for at least three decades so there haven’t been any conceptual advances in the big picture for at least that long.
What’s new is an emphasis on the abundance and importance of small regulatory RNAs. Some workers believe that the human genomes contains thousands of genes for small RNAs that play an important role in regulating gene expression. That’s a main theme for those interpreting the ENCODE results. Several prominent scientists have written extensively about the importance of this “new information” on the abundance of small RNAs and how it assigns function to most of our genome.
I'm discussing a recent paper published by Nils Walter (Walter, 2024). He is arguing against junk DNA by claiming that the human genome contains large numbers of non-coding genes.
This is the fifth post in the series. The first one outlines the issues that led to the current paper and the second one describes Walter's view of a paradigm shift/shaft. The third post describes the differing views on how to define key terms such as 'gene' and 'function.' In the fourth post I discuss his claim that differing opinions on junk DNA are mainly due to philosophical disagreements.
This is a post about alternative splicing. I've avoided using that term in the title because it's very misleading. Alternative splicing produces a number of different products (RNA or protein) from a single intron-containing gene. The phenomenon has been known for 35 years and there are quite a few very well-studied examples, including several where all of the splice regulatory factors have been characterized.
There's plenty of evidence that most of the DNA in mammalian genomes is junk [Five Things You Should Know if You Want to Participate in the Junk DNA Debate]. There's also plenty of evidence that as much as 10% of these genomes are functional in some way or another. This is a lot more DNA than the amount in coding regions but that shouldn't surprise anyone since we've known about functional noncoding DNA for half a century.
Lot's of genes specify functional RNA molecules. The best known ones are the genes for ribosomal RNAs, tRNAs, the spliceosomal RNAs, and a variety of other catalytic RNAs. A host of small regulatory RNAs have been characterized in bacteria over the past five decades (Waters and Storz, 2009) and in the past few decades a variety of different types of small RNAs have been identified in eukaryotes (see Sharp, 2009). These include miRNAs, siRNAs, piRNAs, and others (Malone and Hannon, 2009; Carthew and Sontheimer, 2009).
I just got my copy of the July 14th issue of New Scientist so I can comment on the article Why 'junk DNA' may be useful after all by Aria Pearson. RPM at evolvgen thinks it's pretty good [Junk on Junk] and so does Ryan Gregory at Genomicron [New Scientist gets it right]. I agree. It's one of the best articles on the subject that I've seen in a long time.
First off, Aria Pearson does not make the common mistake of assuming that junk DNA is equivalent to non-coding DNA. The article makes this very clear by pointing out that we've known about regulatory sequences since the 1970's. The main point of the article is to discuss recent results that reveal new functions for some of the previously unidentified non-coding DNA that was classified as junk.
One such result is that reported Pennacchio et al. (2006) in Nature last year. They analyzed sequences in the human genome that showed a high degree of identity to sequences in the pufferfish genome. The idea is that these presumably conserved sequences must have a function. Pennacchio et al. (2006) tested them to see it they would help regulate gene expression and they found that 45% of the ones they tested functioned as enhancers. In other words, they stimulated the expression of adjacent genes in a tissue specific manner. The authors estimate that about half of the "conserved" elements play a role in regulating gene expression.
There are a total of 3,124 conserved elements and their average length is 1,270 bp. This accounts for 3.9 × 106 bp out of a total genome size of 3.2 × 109 bp or about 0.1% of the genome. The New Scientist article acknowledges, correctly, that more than 95% of the genome could still be junk.
Is this all junk DNA? Unlike most other science journalists, Pearson addresses this question with a certain amount of skepticism and she makes an effort to quote conflicting opinions. For example, Pearson mentions experiments claiming that ~90% of the genome is transcribed. Rather than just repeating the hype of the researchers making this claim, Pearson quotes skeptics who argue that this RNA might be just "noise."
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.
The ENCODE project made a big splash in the blogosphere last month (ENCODE Project Consortium, 2007). This study purported to show that much of the human genome was transcribed, leading to the suggestion that most of what we think is junk actually has some function. Aria Pearson interviewed Ewan Birney (see above) who is involved in the ENCODE project.
The real surprise is that ENCODE has identified many non-coding sequences in humans that seem to have a function, yet are not conserved in rats and mice. There seem to be just as many of these non-conserved functional sequences as there are conserved ones. One explanation is that these are the crucial sequences that make humans different from mice. However, Birney thinks this is likely to be true of only a tiny proportion of these non-conserved yet functional sequences. Instead, he thinks most are neutral. "They have appeared by chance and neither hinder nor help the organism."
Put another way, just because a certain piece of DNA can do something doesn't mean we really need it to do whatever it does. Such DNA may be very like computer bloatware: functional in one sense yet useless as far as users are concerned.
This is a perspective you don't often see in popular articles about junk DNA and Pearson is to be commended for taking the time and effort to find the right scientific perspective.
The article concludes by reporting the efforts to delete large amounts of mouse DNA in order to test whether they are junk or not. The results show that much of the conserved bits of DNA can be removed without any harmful effects. Some researchers urge caution by pointing out that very small effects may not be observed in laboratory mice but may be important for evolution in the long term.
ENCODE Project Consortium (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447:799-816. [PubMed Abstract]
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].
Pennacchio, L.A., Ahituv, N., Moses, A.M., Prabhakar, S., Nobrega, M.A., Shoukry, M., Minovitsky, S., Dubchak, I., Holt, A., Lewis, K.D., Plajzer-Frick, I., Akiyama, J., De Val, S., Afzal, V., Black, B.L., Couronne, O., Eisen, M.B., Visel, A., Rubin, E.M. (2006) In vivo enhancer analysis of human conserved non-coding sequences. Nature 444(7118):499-502.
Postgenomics is a compendium of twelve scholarly articles by philosophers and sociologists who write about the implication of the human genome sequence and subsequent work on interpreting the results. The volume is edited by Sarah Richardson, a professor in Social Sciences (History of Science) at Harvard University (Boston, Massachusetts, USA), and by Hallam Stevens, a professor of History at Nanyang Technology University in Singapore (Singapore).
The first essay is by Stevens and Richardson and it outlines the goal of the book.
A hard-hitting review will be published in Annual Review of Genomics and Human Genetics. It shows that the case for large numbers of functional lncRNAs is grossly exaggerated.
A long-time Sandwalk reader (Ole Kristian Tørresen) alerted me to a paper that's coming out next October in Annual Review of Genomics and Human Genetics. (Thank-you Ole.) The authors of the review are Chris Ponting from the University of Edinburgh (Edinburgh, Scotland, UK) and Wilfried Haerty at the Earlham Institute in Norwich, UK. They have been arguing the case for junk DNA for the past two decades but most of their arguments are ignored. This paper won't be so easy to ignore because it makes the case forcibly and critically reviews all the false claims for function. I'm going to quote a few juicy parts because I know that many of you will not be able to access the preprint.
