Evolution and Junk DNA in Chicago

I just signed up for the SMBE Conference in Chicago in July. There's lots of cool talks about evolution but, in the end, I decided I just couldn't miss the session on "Where did 'junk' go?" with Wojciech Makalowski as organizer. Here's the blurb ...

Late Susumu Ohno once said "So much junk DNA in our genome" and the phrase junk DNA was born. For a long time mainstream scientists avoided these parts of the genome. However, over the years the picture slowly started to appear suggesting that the junk DNA hides a genomic treasure. With the completion of the current ENCODE project, junk DNA effectively disappeared because there's no longer useless DNA in the genome. This symposium will discuss the current understanding of these not-so-long-ago obscure areas of the genome, with special attention to transposable elements' activities and their evolutionary consequences. The integral part of the symposium will be general discussion of Ohno’s idea and its place in today's biology.

I'm familiar with Makalowski's way of thinking—it resembles the opinions of many Intelligent Design Creationists even though Makalowski is not a creationist [see Junk DNA: Scientific American Gets It Wrong (again)]. Back in 2007 he said,

Although very catchy, the term "junk DNA" repelled mainstream researchers from studying noncoding genetic material for many years. After all, who would like to dig through genomic garbage?

We know who's been invited to talk.

1. Josefa Gonzalez (Institut de Biologia Evolutiva, Barcelona, Spain)
   "Adaptation is the key concept in Evolutionary Biology. Understanding adaptation has important scientific and social implications since adaptation underlies processes such as the ability of species to survive in changing environments, resistance to antibiotics and cancer chemotherapies and host-pathogen interactions, among others.
   However, adaptation is to date a very poorly understood process largely because the current approaches to the study of adaptation are often exclusively based on a priori candidate genes or on searching for signals of selection at the DNA level giving us an incomplete and biased picture of the adaptive process.
   
   In our lab we aimed at understanding the molecular process of adaptation and its functional consequences. Towards this end, we study recent transposable element (TE)-induced adaptations in Drosophila melanogaster."
2. Valer Gotea (National Human Genome Institute, Bethesda, USA)
   "... it is not surprising that TEs [transposable elements] have a significant influence on the genome organization and evolution. What once was called junk now is considered a treasure. Although much progress has been achieved in understanding of a role that TEs play in a host genome, we are still far from a full understanding of the delicate evolutionary interplay between a host genome and the invaders"
3. Dan Graur (University of Houston, Houston, USA)
   "This absurd conclusion was reached through various means, chiefly (1) by employing the seldom used “causal role” definition of biological function and then applying it inconsistently to different biochemical properties, (2) by committing a logical fallacy known as “affirming the consequent,” (3) by failing to appreciate the crucial difference between “junk DNA” and “garbage DNA,” (4) by using analytical methods that yield biased errors and inflate estimates of functionality, (5) by favoring statistical sensitivity over specificity, and (6) by emphasizing statistical significance rather than the magnitude of the effect."
4. Dixie Mager (University of British Columbia, Canada)
   "The fact that transposable elements (TEs) can influence host gene expression was first recognized more than 50 years ago. However, since that time, TEs have been widely regarded as harmful genetic parasites-selfish elements that are rarely co-opted by the genome to serve a beneficial role. Here, we survey recent findings that relate to TE impact on host genes and remind the reader that TEs, in contrast to other noncoding parts of the genome, are uniquely suited to gene regulatory functions. We review recent studies that demonstrate the role of TEs in establishing and rewiring gene regulatory networks and discuss the overall ubiquity of exaptation. We suggest that although individuals within a population can be harmed by the deleterious effects of new TE insertions, the presence of TE sequences in a genome is of overall benefit to the population."
5. Masumi Nozawa (National Genetic Institute, Mishima, Japan)
   (I don't know anything about his work. Can anybody help?

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University press releases are a major source of science misinformation

Here's an example of a press release that distorts science by promoting incorrect information that is not found in the actual publication.

The problems with press releases are well-known but nobody is doing anything about it. I really like the discussion in Stuart Ritchie's recent (2020) book where he begins with the famous "arsenic affair" in 2010. Sandwalk readers will recall that this started with a press conference by NASA announcing that arsenic replaces phosphorus in the DNA of some bacteria. The announcement was treated with contempt by the blogosphere and eventually the claim was discproved by Rosie Redfield who showed that the experiment was flawed [The Arsenic Affair: No Arsenic in DNA!].

This was a case where the science was wrong and NASA should have known before it called a press conference. Ritchie goes on to document many cases where press releases have distorted the science in the actual publication. He doesn't mention the most egregious example, the ENCODE publicity campaign that successfully convinced most scientists that junk DNA was dead [The 10th anniversary of the ENCODE publicity campaign fiasco].

I like what he says about "churnalism" ...

In an age of 'churnalism', where time-pressed journalists often simply repeat the content of press releases in their articles (science news reports are often worded vitrually identically to a press release), scientists have a great deal of power—and a great deal of responsibility. The constraints of peer review, lax as they might be, aren't present at all when engaging with the media, and scientists' biases about the importance of their results can emerge unchecked. Frustratingly, once the hype bubble has been inflated by a press release, it's difficult to burst.

Press releases of all sorts are failing us but university press releases are the most disappointing because we expect universities to be credible sources of information. It's obvious that scientists have to accept the blame for deliberately distorting their findings but surely the information offices at universities are also at fault? I once suggested that every press release has to include a statement, signed by the scientists, saying that the press release accurately reports the results and conclusions that are in the published article and does not contain any additional information or speculation that has not passed peer review.

Let's look at a recent example where the scientists would not have been able to truthfully sign such a statement.

A group of scientists based largely at The University of Sheffield in Sheffield (UK) recently published a paper in Nature on DNA damage in the human genome. They noted that such damage occurs preferentially at promoters and enhancers and is associated with demethylation and transcription activation. They presented evidence that the genome can be partially protected by a protein called "NuMA." I'll show you the abstract below but for now that's all you need to know.

The University of Sheffield decided to promote itself by issuing a press release: Breaks in ‘junk’ DNA give scientists new insight into neurological disorders. This title is a bit of a surprise since the paper only talks about breaks in enhancers and promoters and the word "junk" doesn't appear anywhere in the published report in Nature.

The first paragraph of the press release isn' very helpful.

‘Junk’ DNA could unlock new treatments for neurological disorders as scientists discover how its breaks and repairs affect our protection against neurological disease.

What could this mean? Surely they don't mean to imply that enhancers and promoters are "junk DNA"? That would be really, really, stupid. The rest of the press release should explain what they mean.

The groundbreaking research from the University of Sheffield’s Neuroscience Institute and Healthy Lifespan Institute gives important new insights into so-called junk DNA—or DNA previously thought to be non-essential to the coding of our genome—and how it impacts on neurological disorders such as Motor Neurone Disease (MND) and Alzheimer’s.

Until now, the body’s repair of junk DNA, which can make up 98 per cent of DNA, has been largely overlooked by scientists, but the new study published in Nature found it is much more vulnerable to breaks from oxidative genomic damage than previously thought. This has vital implications on the development of neurological disorders.

Oops! Apparently, they really are that stupid. The scientists who did this work seem to think that 98% of our genome is junk and that includes all the regulatory sequences. It seems like they are completely unaware of decades of work on discovering the function of these regulatory sequences. According The University of Sheffield, these regulatory sequences have been "largely overlooked by scientists." That will come as a big surprise to many of my colleagues who worked on gene regulation in the 1980s and in all the decades since then. It will probably also be a surprise to biochemistry and molecular biology undergraduates at Sheffield—at least I hope it will be a surprise.

Professor Sherif El-Khamisy, Chair in Molecular Medicine at the University of Sheffield, Co-founder and Deputy Director of the Healthy Lifespan Institute, said: “Until now the repair of what people thought is junk DNA has been mostly overlooked, but our study has shown it may have vital implications on the onset and progression of neurological disease."

I wonder if Professor Sherif El-Khamisy can name a single credible scientist who thinks that regulatory sequences are junk DNA?

There's no excuse for propagating this kind of misinformation about junk DNA. It's completely unnecessary and serves only to discredit the university and its scientists.

Ray, S., Abugable, A.A., Parker, J., Liversidge, K., Palminha, N.M., Liao, C., Acosta-Martin, A.E., Souza, C.D.S., Jurga, M., Sudbery, I. and El-Khamisy, S.F. (2022) A mechanism for oxidative damage repair at gene regulatory elements. Nature, 609:1038-1047. doi:[doi: 10.1038/s41586-022-05217-8]

Oxidative genome damage is an unavoidable consequence of cellular metabolism. It arises at gene regulatory elements by epigenetic demethylation during transcriptional activation1,2. Here we show that promoters are protected from oxidative damage via a process mediated by the nuclear mitotic apparatus protein NuMA (also known as NUMA1). NuMA exhibits genomic occupancy approximately 100 bp around transcription start sites. It binds the initiating form of RNA polymerase II, pause-release factors and single-strand break repair (SSBR) components such as TDP1. The binding is increased on chromatin following oxidative damage, and TDP1 enrichment at damaged chromatin is facilitated by NuMA. Depletion of NuMA increases oxidative damage at promoters. NuMA promotes transcription by limiting the polyADP-ribosylation of RNA polymerase II, increasing its availability and release from pausing at promoters. Metabolic labelling of nascent RNA identifies genes that depend on NuMA for transcription including immediate–early response genes. Complementation of NuMA-deficient cells with a mutant that mediates binding to SSBR, or a mitotic separation-of-function mutant, restores SSBR defects. These findings underscore the importance of oxidative DNA damage repair at gene regulatory elements and describe a process that fulfils this function.

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ENCODE and their current definition of "function"

ENCODE has mostly abandoned it's definition of function based on biochemical activity and replaced it with "candidate" function or "likely" function, but the message isn't getting out.

Back in 2012, the ENCODE Consortium announced that 80% of the human genome was functional and junk DNA was dead [What did the ENCODE Consortium say in 2012?]. This claim was widely disputed, causing the ENCODE Consortium leaders to back down in 2014 and restate their goal (Kellis et al. 2014). The new goal is merely to map all the potential functional elements.

... the Encyclopedia of DNA Elements Project [ENCODE] was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types.

The new goal was repeated when the ENCODE III results were published in 2020, although you had to read carefully to recognize that they were no longer claiming to identify functional elements in the genome and they were raising no objections to junk DNA [ENCODE 3: A lesson in obfuscation and opaqueness].

Non-Darwinian Evolution in 1969: The Case for Junk DNA

I've been having a discussion with Elizabeth Liddle in the comments to: Barry Arrington, Junk DNA, and Why We Call Them Idiots . I think it's important to understand why scientists first started thinking that most of our genome is junk. It's important to understand that these scientists were not Darwinists and their predictions were not based on an understanding of natural selection.

Let's look at a famous paper by Jack Lester King and Thomas Hughes Jukes.¹ The title of the paper is "Non-Darwinian Evolution" and it was published 44 years ago in the May 16, 1969 issue of Science [read it at: Science 164:788-798].

The subtitle of the paper is "Most evolutionary change in proteins may be due to neutral mutations and genetic drift" but that's not what I want to talk about. This paper is among the first to predict the presence of large amounts of junk DNA in our genome. King and Jukes didn't call it "junk"—that term was introduced by Susumu Ohno in 1972—but that doesn't matter. When King and Jukes talk about "superfluous DNA" they mean "junk."

Here's the relevant part of the paper ...

The 10th anniversary of the ENCODE publicity campaign fiasco

On Sept. 5, 2012 ENCODE researchers, in collaboration with the science journal Nature, launched a massive publicity campaign to convince the world that junk DNA was dead. We are still dealing with the fallout from that disaster.

The Encyclopedia of DNA Elements (ENCODE) was originally set up to discover all of the functional elements in the human genome. They carried out a massive number of experiments involving a huge group of researchers from many different countries. The results of this work were published in a series of papers in the September 6th, 2012 issue of Nature. (The papers appeared on Sept. 5th.)

How to Make a Scientific Argument

The debate over the amount of junk in our genome is a genuine scientific debate. There are legitimate scientific points of view on both sides although the weight of evidence and logic is tilting heavily in favor of junk DNA. It looks more and more like most (~90%) of our genome is junk.

The problem with the debate is that the scientific literature is full of papers attacking junk DNA while there are very few papers promoting it. This is partly because there haven't been any new discoveries in favor of junk DNA. On the other hand, there have been quite a few discoveries showing that some small part of the genome that was thought to be junk might have a function. Even though these discoveries make an insignificant contribution to the big picture, they are often blown up out of all proportion and promoted as an end to junk DNA.

A recent paper in PLoS Genetics illustrates the problem.

The ENCODE Data Dump and the Responsibility of Science Journalists

ENCODE (ENcyclopedia Of DNA Elements) is a massive consortium of scientists dedicated to finding out what's in the human genome.

They published the results of a pilot study back in July 2007 (ENCODE, 2007) in which they analyzed a specific 1% of the human genome. That result suggested that much of our genome is transcribed at some time or another or in some cell type (pervasive transcription). The consortium also showed that the genome was littered with DNA binding sites that were frequently occupied by DNA binding proteins.

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Genomes & Junk DNAAll of this suggested strongly that most of our genome has a function. However, in the actual paper the group was careful not to draw any firm conclusions.

... we also uncovered some surprises that challenge the current dogma on biological mechanisms. The generation of numerous intercalated transcripts spanning the majority of the genome has been repeatedly suggested, but this phenomenon has been met with mixed opinions about the biological importance of these transcripts. Our analyses of numerous orthogonal data sets firmly establish the presence of these transcripts, and thus the simple view of the genome as having a defined set of isolated loci transcribed independently does not seem to be accurate. Perhaps the genome encodes a network of transcripts, many of which are linked to protein-coding transcripts and to the majority of which we cannot (yet) assign a biological role. Our perspective of transcription and genes may have to evolve and also poses some interesting mechanistic questions. For example, how are splicing signals coordinated and used when there are so many overlapping primary transcripts? Similarly, to what extent does this reflect neutral turnover of reproducible transcripts with no biological role?

This didn't stop the hype. The results were widely interpreted as proof that most of our genome has a function and the result featured prominently in the creationist literature.

Junk DNA and the Scientific Literature

 
A discussion about junk DNA has broken out in the comments to Monday's Molecule #128: Winners.

Charlie Wagner, an old talk.origins fan, wonders why junk DNA advocates are still around given that there have been several recent papers questioning the idea that most of our genome is junk.

Charlie asks ...

So why are Larry and many others still clinging to the myth of "junk DNA"? Do they not read the literature?

Of course we read the literature, Charlie, but unlike you we read all of the literature. You can't just pick out the papers that support your position and assume that the question has been settled.

The skill in reading the scientific literature is to put things into perspective and maintain a certain degree of skepticism. It's just not true that everything published in scientific journals is correct. An important part of science is challenging the consensus and many scientists try to make their reputation by coming up with interpretations that break new ground. The success of science depends on the few that are correct but let's not forget that most of them turn out to be wrong.

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Genomes & Junk DNA
The trick is to recognize the new ideas that may be on to something and ignore those that aren't. This isn't easy but experienced scientists have a pretty good track record. Inexperienced scientists may not be able to distinguish between legitimate challenges to dogma and ones that are frivolous. The problem is even more severe for non-scientists and journalists. They are much more likely to be sucked in by the claims in the latest paper—especially if it's published in a high profile journal.

Lots of scientists don't like the idea of junk DNA because it doesn't fit into their view of how evolution works. They gleefully announce the demise of junk DNA whenever another little bit of noncoding DNA is discovered to have a function. They also attach undue significance to recent studies showing that a large part of mammalian genomes are transcribed at one time or another in spite of the fact that this phenomenon has been known for decades and is perfectly consistent with what we know about spurious transcription.

I've addressed many of the specific papers in previous postings. You can review my previous postings by clicking on the Theme Box URL. The bottom line is "don't trust everything you read in the recent scientific literature."

Another good rule of thumb is never trust any paper that doesn't give you a fair and accurate summary of the "dogma" they are opposing. When you challenge the concept of junk DNA, for example, it's not good enough to just present a piece of new evidence that may not fit the current "dogma." You also have to deal with all the evidence that was used to create the consensus view in the first place and show how it can be better explained by your new model. A good place to start is The Onion Test.

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The figure is from Mattick (2007), an excellent example of what I'm talking about. This is a paper attacking the current consensus on junk DNA but in doing so it uses a figure that reveals an astonishing lack of understanding of genomes. This makes everything else in paper suspect. The figure was chosen by Ryan Gregory to be the classic example of a Dog's Ass Plot.

Mattick, J.S. (2004) The hidden genetic program of complex organisms. Sci Am. 291:60-67.

Revisiting the genetic load argument with Dan Graur

The genetic load argument is one of the oldest arguments for junk DNA and it's one of the most powerful arguments that most of our genome must be junk. The concept dates back to J.B.S. Haldane in the late 1930s but the modern argument traditionally begins with Hermann Muller's classic paper from 1950. It has been extended and refined by him and many others since then (Muller, 1950; Muller, 1966).

Does Excess Genomic DNA Protect Against Mutation?

Many eukaryotic genomes have a large amount of "excess" DNA that doesn't have any of the functions we normally assign to DNA (protein-coding, regulatory, origins of replication, centromeres, RNA genes etc.). Many of us think this is junk DNA. It has no function and could easily be dispensed with.

One of the adaptive explanations for this excess DNA is that it protects the functional DNA from mutations. Ryan Gregory thinks this is a serious scientific hypothesis even though he's skeptical. He has a wonderful post that reviews the history of the idea and how the hypothesis should be tested [Does junk DNA protect against mutation?].

The bottom line is that this hypothesis is not taken very seriously by the scientific community for some very good reasons.

First, most spontaneous mutations in the germ line seem to be due to errors in DNA replication. The overall rate of evolutionary change is consistent with the mutation rate of DNA replication + repair, suggesting that it is the dominant form of mutation. This mutation rate is based on the number of nucleotides replicated. What this means is that the rate of mutation in functional DNA is independent of how much other DNA is being replicated. Excess DNA offers no protection from the spontaneous error rate of DNA replication.

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However, the protection hypothesis may be applicable to other kinds of mutation such as those caused by chemicals or ionizing radiation. In multicellular organisms such as animals, fungi, and plants, this possible protection may prolong the lifetime of somatic cells or prevent them from becoming deregulated (e.g., cancer).

The idea is that excess DNA may shield the functional DNA from the effects of these mutagens but this would only work if the excess DNA was specifically organized so that it surrounded the functional DNA and provided physical shielding. There's no evidence that this is the case and, furthermore, it doesn't make much sense. The functional DNA in a nucleus is already shielded by lots of proteins, lipids and membranes so it's unlikely that a bit more DNA is going to make a difference.

Not only that, but some kinds of DNA damage caused by these mutagens will cause strand breakage. What does that mean? It means that the larger the genome the greater the chance that damage will occur. In other words, excess DNA leads to greater rates of mutation, not lower rates of mutation, for those types of mutagens. Ryan Gregory shows results from several studies during the 1970s that establish that fact.

I sympathize with Ryan's call for experimental support of the hypothesis but I'd also like to point out that not only does it not have direct evidence to back it up but it's not even theoretically feasible. It's just a bad hypothesis based largely on a misunderstanding of mutations and how they arise.

Also, the protection hypothesis doesn't pass The Onion Test which is one of the first requirements for an adaptive explanation of junk DNA.

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Stephen Jay Gould and Sydney Brenner Agree on Junk DNA

It's no secret that I'm a big fan of Stephen Jay Gould. I'm also a big fan of Sydney Brenner. Here's Gould writing in The Structure of Evolutionary Theory (pages 1269-1270). This is long and complicated but if you want to understand junk DNA and why it conflicts with Darwinism, then you've got to make the effort. I especially like the idea that Gould understands the difference between junk DNA, which can't be explained by any adaptive mechanism, and "selfish DNA," which isn't junk and has a Darwinian explanation. Many people don't get this.

Gould and Brenner are talking about repetitive DNA. This includes highly repetitive sequences of simple repeats and moderately repetitive sequences that include the transposons.

Junk & Jonathan: Part 7—Chapter 4

This is part 7 of my review of The Myth of Junk DNA. For a list of other postings on this topic see the link to Genomes & Junk DNA in the "theme box" below or in the sidebar under "Themes."

The title of Chapter 4 is Introns and the Splicing Code. It opens with a brief description of eukaryotic genes and alternative splicing. Here's a better description of splicing for those who want a quick refresher: RNA Splicing: Introns and Exons. Alternative splicing is when a transcript can be spliced in at least two different ways to produce 2 distinct mRNAs. Each of them will make a different, but related, protein. The process has been known for thirty years and the mechanism is well-understood. It's described very well in a Wikipedia article: Alternative Splicing.

Here's some important background information from Junk in Your Genome: Protein-Encoding Genes.

The minimum size of a eukaryotic intron is less than 50 bp. For a typical mammalian intron, the essential sequences in the introns are: the 5′ splice site (~10 bp); the 3′ splice site (~30 bp): the branch site (~10 bp); and enough additional RNA to form a loop (~30 bp). This gives a total of 80 bp of essential sequence per intron or 20,500 × 7.2 × 80 = 11.8 Mb. Thus, 0.37% of the genome is essential because it contains sequences for processing RNA.

In other words, assuming that introns aren't all junk we can estimate how much of the intron sequence is essential for it's function by taking into account the known regulatory sequences and the amount needed to form a loop.

The rest of an intron sequence may be junk. If it is, then we would expect to see two things.

• Considerable variation is intron size from species to species.
• Frequent examples of transposons, endogenous retroviruses, and even other genes inserting into introns.

This is exactly what we see [Junk in Your Genome: Intron Size and Distribution]. There's no indication that intron sequences are conserved or essential.

Jonathan Wells explains that alternative splicing is important in some genes. He is correct. He then explains that there are sequences in introns that regulate alternative splicing. He's correct about that as well. We've been writing this up in the textbooks and teaching it in introductory biochemistry courses since early in the 1980s. The classic example is the determination of sex in Drosophila—it's largely controlled by alternative splicing and we know a great deal about which proteins bind to which sequences in the introns to promote or repress a given splice site [Sex in the fruit fly Drosophila melanogaster].

Nothing new here. We know about binding sites and we know that most of them are 10 bp or less. Their presence makes no significant difference in our calculations of junk DNA. I get the distinct impression that Wells and the other IDiots don't really understand splicing and alternative splicing.

Here's a series of blog posts I did last year when Richard Sternberg tried to pretend that he knew something about molecular biology and alternative splicing. Later on, Jonathan Wells weighs in to try and help his friend but ends up showing that he too, is in way over his head.

Creationists, Introns, and Fairly Tales

IDiots Do Arithmetic a Second Time - Same Result

Jonathan Wells Weighs in on Alternative Splicing

Having "proven" that something like 0.03% of our genome may not be junk, Wells then goes on to describe other sequences that are found in introns. Some of these are regulatory sequences or enhancers. These aren't common, but they do exist. They're usually located in the 5′ intron and they are often associated with alternative transcription start sites. The total amount of non-junk DNA due to regulatory sequences has already been taken into account in my calculations (Junk in Your Genome: Protein-Encoding Genes) and it doesn't matter whether these regulatory sequences are intergenic or included within an intron.

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Genomes
& Junk DNAWells also notes that many genes for small RNAs are located within introns. These include some of the genes for the splicing machinery, tRNA genes, snoRNA genes etc. He doesn't mention that introns are also loaded with Alu sequences and other transposable elements (mostly defective). The presence of the these insertions show us that cells don't discriminate between intron sequences that make up 25% of the genome and the remaining 65% that's mostly junk. They are all targets for inserting small genes and transposons. No surprises here.

Finally, on the last page of Chapter 4, Wells devotes two paragraphs to a genuine scientific argument. The idea is that long introns might be necessary to delay transcription. This idea has been around for a long time. It was originally proposed over 25 years ago as an explanation for the long introns found in Drosophila HOX genes, especially Ubx.

If a gene has several long introns it can stretch out over 100 kb (100,000 bp). The typical RNA polymerase II elongation complex transcribes at a rate of 50 bp per second so it will take more than 30 minutes to transcribe these long genes. The idea is that the presence of long introns delays appearance of the regulatory proteins during development. This seems unlikely because there are many other, more efficient, ways of regulating gene expression. As a matter of fact, the argument can be easily turned upside down.

Genes that need to be transcribed quickly have very short introns or none at all. The heat shock inducible genes, for example, don't even have introns. These genes need to be expressed rapidly when a cell encounters stressful conditions. Their non-inducible homologues all have respectable introns so it looks like there has been selection for losing introns in these genes.

Similarly, there are often testes specific genes than lack introns. The supposition is that these variant family members have lost introns so they can be quickly transcribed during spermatogenesis. The globin genes have relatively small introns and they are also expressed at a high rate in erythroblasts.

Genes that are infrequently transcribed tend to accumulate large introns. This includes most developmentally regulated transcription factors that only need to produce a small number of proteins at a specific time in the life of the organism. These observations are consistent with the idea that excess junk in intron sequences is removed when necessary. It's actually evidence that those sequences are junk.

So far we covered the evidence of probable function in Chapter 3 and seen that Wells does not critically examine the data on pervasive transcription but simply assumes it is correct. He then makes the unsubstantiated claim that evidence of transcription is evidence of function. He's wrong about the claim that most of our genome is transcirbed and he's wrong to assume that all transcripts are functional. Nothing in that chapter supported his claim that junk DNA is a myth.

In this chapter we see the first evidence for specific functions of noncoding DNA. The presence of regulatory sequences in introns has been well known for decades and it has no impact on the estimates of junk DNA. The idea that big introns might be adaptive regardless of sequence is possible but not reasonable. In fact, the evidence suggests strongly that big introns full of junk DNA can be detrimental in some cases. Nothing in Chapter 4 provides convincing evidence that junk DNA is a myth.

What about pseudogenes? Are they a myth? That's covered in Chapter 5.

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A note about references
The IDiots are promoting this book by bragging about multiple references that challenge the concept of junk DNA [Jonathan Wells offers over 600 references to recent peer-reviewed literature]. Chapters 1 and 2 were introductions to the problem. They had a total of 51 references. Chapter 3 had 62 references but, as we have seen, they don't add up to a convincing case. There were plenty of references that should have been included if a scientific case was going to be made. Chapter 4 has 63 references but only three of them address a substantive argument against junk DNA in introns. All three make the same point; namely that long introns delay transcription.

That's a total of 176 references so far with nothing much to show for them. There are 432 references in the rest of the book. There are 26 references to known IDiots including 8 references to the work of Jonathan Wells.

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Birds of a feather: epigenetics and opposition to junk DNA

There's an old saying that birds of a feather flock together. It means that people with the same interests tend to associate with each other. It's extended meaning refers to the fact that people who believe in one thing (X) tend to also believe in another (Y). It usually means that X and Y are both questionable beliefs and it's not clear why they should be associated.

I've noticed an association between those who promote epigenetics far beyond it's reasonable limits and those who reject junk DNA in favor of a genome that's mostly functional. There's no obvious reason why these two beliefs should be associated with each other but they are. I assume it's related to the idea that both beliefs are presumed to be radical departures from the standard dogma so they reinforce the idea that the author is a revolutionary.

Or maybe it's just that sloppy thinking in one field means that sloppy thinking is the common thread.

Here's an example from Chapter 4 of a 2023 edition of the Handbook of Epigenetics (Third Edition).

The central dogma of life had clearly established the importance of the RNA molecule in the flow of genetic information. The understanding of transcription and translation processes further elucidated three distinct classes of RNA: mRNA, tRNA and rRNA. mRNA carries the information from DNA and gets translated to structural or functional proteins; hence, they are referred to as the coding RNA (RNA which codes for proteins). tRNA and rRNA help in the process of translation among other functions. A major part of the DNA, however, does not code for proteins and was previously referred to as junk DNA. The scientists started realizing the role of the junk DNA in the late 1990s and the ENCODE project, initiated in 2003, proved the significance of junk DNA beyond any doubt. Many RNA types are now known to be transcribed from DNA in the same way as mRNA, but unlike mRNA they do not get translated into any protein; hence, they are collectively referred to as noncoding RNA (ncRNA). The studies have revealed that up to 90% of the eukaryotic genome is transcribed but only 1%–2% of these transcripts code for proteins, the rest all are ncRNAs. The ncRNAs less than 200 nucleotides are called small noncoding RNAs and greater than 200 nucleotides are called long noncoding RNAs (lncRNAs).

In case you haven't been following my blog posts for the past 17 years, allow me to briefly summarize the flaws in that paragraph.

• The central dogma has nothing to do with whether most of our genome is junk
• There was never, ever, a time when knowledgeable scientists defended the idea that all noncoding DNA is junk
• ENCODE did not "prove the significance of junk DNA beyond any doubt"
• Not all transcripts are functional; most of them are junk RNA transcribed from junk DNA

So, I ask the same question that I've been asking for decades. How does this stuff get published?

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Junk DNA is gradually making its way into mainstream textbooks

The idea that most of the human genome is junk originated more that 50 years ago. Since then, evidence in support of this concept has steadily accumulated but it has been stongly resisted by most biochemists and molecular biologists. Opposition is even stronger among scientists in other fields and in the general public thanks to a steady stream of anti-junk articles in the popular press.

Much of this opposition to junk DNA stems from a massive publiciy campaign launched by ENCODE researchers and the leading science journals back in 2012.

It's likely that most of the controversy over junk DNA is related to differing views on evolution and the power of natural selection. Most people think that natural selection is very powerful so that modern species must be extremely well-adapted to their present environment. They tend to believe that complexity is simply a reflection of sophisticated fine-tuning and this must apply to the human genome. According to this view, the presence of huge amounts of DNA with an unknown function is just a temporary situation and in the next few years most of this 'dark matter' will turn out to have a function. It has to have a function otherwise natural selection would have eliminated it.

The Function Wars Part VI: The problem with selected effect function

The term "Function Wars" refers to the debate over the meaning of 'function,' especially in the context of junk DNA.¹ That debate intensified in 2012 after the ENCODE publicity campaign that tried to redefine function to mean anything they want as long as it refutes junk DNA. This is the sixth in a series of posts exploring the debate and why it's important, or not. Links to the other five posts can be found at the bottom or this post.

The world is not inhabited exclusively by fools and when a subject arouses intense interest and debate, as this one has, something other than semantics is usually at stake.
Stephen Jay Gould (1982)Much of the discussion seems like quibbling over semantics but I'm reminded of a similar debate over the mode of evolution: is it gradual or punctuated? As Gould pointed out in 1982, there's a serious issue underlying the debate—an issue that shouldn't get lost in bickering over the meaning of 'gradualistic.' The same warning applies here. It's important to determine how much of the human genome is junk and that requires an understanding of what we mean by junk DNA. However, it's easy to get distracted by focusing on the exact meaning of the word 'function' instead of looking at the big picture.

Jonathan M Flunks the Onion Test, Again

 

A few weeks ago I explained why Jonathan M is an IDiot [A Twofer]. The topic was junk DNA. Jonathan M had posted an article on Uncommon Descent where he claimed that The Onion Test is an argument in favor of junk DNA [Thoughts on the “C-Value Enigma”, the “Onion Test” and “Junk DNA”].

I explained, as politely as I could (not), that the onion test was not an argument in support of junk DNA. It's a "test" for those who think they can explain the presence of large amounts of supposedly functional DNA that looks a lot like junk. The "test" is to apply your reasoning to the genomes of various onion species to see if it makes sense.

Do you think that the excess DNA protects against mutations? Then why do some onions need a lot more protection than humans?

Do you think that the extra DNA can be explained by alternative splicing? Why do some onion species need more alternative splicing than others?

Do you think that most of the extra DNA is required for regulating gene expression? Then why do onions need more sophisticated regulation than humans?

This ain't rocket science. The description of the Onion Test is pretty easy to understand—unless, of course, you are an IDiot.

Jonathan M has taken another shot at attacking the Onion Test. This time his article appears on the official blog of The Discovery Institure: Why the "Onion Test" Fails as an Argument for "Junk DNA". The title sort of gives it away, doesn't it? We're still dealing with an IDiot.

Briefly stated, the often cited "onion test" observes that onion cells have many times more DNA than human cells do. And since the onion is considered to be relatively simple as compared to us, this discrepancy -- it is argued -- can only be accounted for if the preponderance of its DNA is, in fact, junk or non-functional. Let's see whether the concept really holds any water.

Let's go over this one more time. The Onion Test is a "test." (Look up the word "test" in the dictionary.) It's designed as a thought experiment to test a hypothesis about the possible function of large amounts of noncoding DNA. If you think you have an explanation for why most of the human genome has a function then you should explain how that accounts for the genomes of onions. Ryan Gregory knew that most so-called explanations look very silly when you try using them to account for genome size in onion species.

The Onion Test is not an argument in favor of junk DNA. It's a reality check on speculations about function.

Jonathan M still doesn't get it.

Are we surprised?

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Jonathan Wells Talks About Sequence Conservation

Paul McBride (paulmc) tried to convince the readers on Uncommon Descent that there was evidence for junk DNA. One of the lines of evidence has to do with sequence conservation. If most of the genome sequences are not conserved between species this strongly suggests that they have no function, although it doesn't rule out a function that is independent of sequence.

Wells addresses this argument in: Jonathan Wells on Darwinism, Science, and Junk DNA. Before analyzing his response, it's worth reviewing what he wrote in The Myth of Junk DNA.

In chapter 5, Wells talks about sequence conservation as evidence of function—specifically the fact that the sequences of some potential pseudogenes are more conserved that would be expected if they were really pseudogenes [Junk & Jonathan: Part 8—Chapter 5]. That's an important argument and, if true, it would point to a function. The irony is that Wells doesn't believe in common descent so, from his perspective, these are not conserved sequences due to negative natural selection. Nevertheless, he is happy to use evolutionary arguments whenever it suits him.

Five questions for Intelligent Design Creationists

A few Intelligent Design Creationists are beginning to learn about evolution. A few days ago, I speculated about what would happen if they really did start to understand modern evolutionary theory and the massive amount of data that supports the basic facts of evolution [What would happen if Intelligent Design Creationists understood evolution?].

Vincent Torley has responded. He illustrates the problems they will face and reveals some of the rationalizations that they might use to avoid the most severe symptoms of cognitive dissonance [see Professor Larry Moran poses five questions for the ID movement].

Let's take a look at what has to say. Remember that Vincent Torley doesn't speak for all Intelligent Design Creationists but he does have posting privileges on Uncommon Descent and he is frequently praised by some of the ID leaders who post there. I think we can assume that his views are typical.

Here's his response to each of the five questions.

Advice from Jonathan Wells on Junk DNA

 

Copied from Uncommon Descent (Denyse O'Leary): What advice, on junk DNA, would Jonathan Wells give Francis Collins or Richard Dawkins?.

From the Salvo Magazine interview with Jonathan Wells, by Casey Luskin. Wells is the author of The Myth of Junk DNA:

If you could have lunch with Francis Collins and Richard Dawkins, what would you say to them about their use of the “junk DNA” argument? [that there is no design in life]

Actually, Collins no longer relies on “junk DNA.” In 2007 he announced in an interview for Wired magazine that he had “stopped using the term.” In 2010 he wrote that “discoveries of the past decade, little known to most of the public, have completely overturned much of what used to be taught in high school biology. If you thought the DNA molecule comprised thousands of genes but far more ‘junk DNA,’ think again” (The Language of Life, pp. 5–6). Unfortunately, his followers at the BioLogos Institute (which he founded) seem to be unaware of this, because they continue to promote the myth that most of our DNA is junk. I would encourage Collins to set them right.

UD News does not think Collins would succeed. They are not Collins’s followers, they are Darwin’s men. They do not seek more knowledge than Darwin had. They seek to make what he knew part of the bedrock of Christianity.

Unlike Collins, Dawkins seems utterly oblivious to recent developments in genomics. I would encourage him to read some of the scientific literature.

Why? Dawkins can command international attention for not keeping up to date – because millions of tax burdens feel he speaks for them – and they don’t need to keep up to date either. Their champions are fronts for the dead orthodoxies that keep them in place.

Dear Jonathan Wells and Denyse O'Leary,

I have read The Myth of Junk DNA and I have read the scientific literature. What advice would you give me?

Why don't you respond to my review of The Myth of Junk DNA? What are you afraid of?

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Kat Arney interviews me on her podcast

I had a long chat with Kat Arney a few weeks ago and she has now taken the best parts of that conversation and put them in her latest Genetics Society podcast: Genes, junk and the 'dark genome'. My comments are in the last twelve minutes. At the end, Kat asks me "Is there like one thing you would really want a student or researcher, working in genetics today to really understand about the human genome?"

Kat was kind enough to write a blurb for my book last year where she said,

What's in Your Genome? is a thought-provoking and pugnatious book that will make you wonder afresh at the molecular intracies of life. When it comes to our genomes, we humans are nothing special—Moran makes a convincing argument that the vast majority of our sloppy human genome is not mysterious genetic treasures but boring junk.

In this podscast, she combines my thoughts on the human genome with those of two people who don't agee with the idea that the human genome is full of junk. Here's a brief summary of their positions.

Naomi Allen is Chief Scientist at UK Biobank, a consortium that's sequencing the genomes of UK citizens. So far, they've published data on 500,000 genome sequences. I wrote about one of their more significant findings last year (August, 2022) where they reported on the fraction of the human genome that was under purifying selection. This is an excellent proxy for functional DNA and the results are in line with (my) expectations: less that 10% of the genome is conserved and most of it is in the non-coding fraction [Identifying functional DNA (and junk) by purifying selection.

It's too bad that Kat's interview with Naomi Allen doesn't mention that important result, especially since the podcast is about junk DNA. Here's how Naomi Allen begins her part of the interview.

Whole genome sequencing enables researchers to look at all of the genetic variation across the entire genome. So not just in the 2% of the genome that encodes for proteins, but all of the genetic variation, much of which was previously considered "junk DNA" precisely because we didn't know what it did.

This is disappointing for two important reasons. First, surely in 2023 we've gone beyond the tired myth that all of the information in the human genome was concentrated in coding DNA? Second, no knowledgeable scientist ever said that all non-coding DNA was junk DNA and the idea of junk DNA was not based on ignorance so surely it's time to stop repeating that myth as well.

The rest of that interview focuses on how mapping genetic variation could contribute to our understanding of health and disease. I would have loved to ask how Biobanks proposes to do this if most of the variation is in junk DNA and also ask whether mutations in junk DNA can contribute to genetic disease. (They can.)

Danuta Jeziorska is the CEO of Nucleome Therapeutics, a company that's described as "spun out of Oxford University with a new set of technologies for exploring the dark genome." Kat asks her about the dark genome and here's her response.

So if you think about it, we have 22,000 genes in our genome, and we can compare that to having 22,000 ingredients in the fridge. We use the same set of ingredients to create different meals, just like how we have the same DNA within each cell, but then we have hundreds of different cell types. So this dark genome determines the combination of ingredients of the genes that you take and at which level you use them, to produce the different cell types that build our body. And you can just imagine that if you make a mistake in that - so let's say that you add the wrong ingredients in the wrong meal, you can mess up the meal. And in this same way you can mess up the cell type. So if you, for example, if you don't produce enough of haemoglobin to transport oxygen around the body, you will end up with a genetic form of anaemia or if you turn on a gene that's not supposed to be turned on, like an oncogene, you may end up having cancer.

So the dark genome is now very well understood as the mechanism that is causing diseases.

This is a slightly different definition of the dark genome than those I discussed in a recent post [What is the "dark matter of the genome"?]. In that post I suggested that most scientists were referring to all of the functions in non-coding DNA but Danuta Jeziorska seems to be restricting her use of "dark genome" to just regulatory sequences. In the rest of the interview she goes on to describe various types of regulatory sequences, with an emphasis on 3D structure, and to explain that many common genetic diseases are caused by mutations in regulatory sequences. Her company is using machine learning to find the functional elements in the dark genome and which variants are associated with disease. They are also investing in drug discovery.

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