A junk-filled genome
Review of: What’s In Your Genome? 90% of Your Genome Is Junk, by Laurence A. Moran, 2023. University of Toronto Press. 392 pp. ISBN: 9781487508593
Norman A Johnson
Evolution, qpad176, [10.1093/evolut/qpad176]
"The subject matter in this book is not easy. Molecular biologists might well be challenged by the population genetics theory, while the biochemistry details may vex evolutionary biologists. Moran does an excellent job at presenting both of these aspects. I am also glad that he provided a historical perspective, showing that many of the current debates have a long history.
In the Preface, Moran states that he was motivated to write this book in part due to what he views as failures in science communication regarding the nature of the genome. He reminds us about the importance of accuracy in science communication: “No matter how good your style, if the substance of what you are communicating is flawed, then you are not a good science communicator” (xiii). Narratives are useful in communicating science, but when they (or the hype) get in the way of telling the truth, the science, and the science communication suffer."
I know Stephen Meyer and I have discussed his views on creationism many times. Some of the issues he raises are quite interesting and they aren't easy to refute. In this video from 2020, he presents two standard creationist objections to evolution: the Cambrian explosion, and the probability of evolving a gene.1
The Zoonomia project aligned the genome sequences of 240 mammalian species and determined that only 10.7% of the human genome is conserved. This is consistent with the idea that about 90% of our genome is junk.
The April 28, 2023 issue of science contains eleven papers reporting the results of a massive study comparing the genomes of 240 mammalian species. The issue also contains a couple of "Perspectives" that comment on the work.
There are a million potential transcription regulatory sites in the human genome. How many of these function as true regulatory sites?
One of the important questions about the human genome concerns how gene expression is regulated. The main controversy is over the number of functional regulatory sites and how that relates to abundant junk DNA. Here's how one group addresses the problem by looking at the conservation of regulatory sites in mammals. Sequence conservation is best genomics proxy for identifying functional sites.
Andrews, G., Fan, K., Pratt, H.E., Phalke, N., Zoonomia Consortium, Karlsson, E.K., Lindblad-Toh, K., Gazal, S., Moore, J.E. and Weng, Z. (2023) Mammalian evolution of human cis-regulatory elements and transcription factor binding sites. Science 380:eabn7930. [doi: 10.1126/science.abn7930]
Understanding the regulatory landscape of the human genome is a long-standing objective of modern biology. Using the reference-free alignment across 241 mammalian genomes produced by the Zoonomia Consortium, we charted evolutionary trajectories for 0.92 million human candidate cis-regulatory elements (cCREs) and 15.6 million human transcription factor binding sites (TFBSs). We identified 439,461 cCREs and 2,024,062 TFBSs under evolutionary constraint. Genes near constrained elements perform fundamental cellular processes, whereas genes near primate-specific elements are involved in environmental interaction, including odor perception and immune response. About 20% of TFBSs are transposable element–derived and exhibit intricate patterns of gains and losses during primate evolution whereas sequence variants associated with complex traits are enriched in constrained TFBSs. Our annotations illuminate the regulatory functions of the human genome.
The authors introduce the issue by pointing out two different views of functional regulatory sites. First, there's the ENCODE view, which maps the binding sites of 1600 transcription factors and the associated methylation and histone modification patterns. This analysis creates a database of almost one million candidate cis-regulatory elements (cCREs). Second, there's the evolutionary perspective, which looks at conservation of regulatory sites as the prime indicator of function. Only a fraction of candidate sites are conserved. Does this mean that most of the cCREs are not functional?
Andrews et al. set out to identify all of the cCRE's and transcription factor binding sites (TFBSs) that show evidence of conservation using an alignment of 241 mammalian genomes from the Zoonomia database and a program called phyloP.
They began with more than 920,000 human cCREs from the ENCODE Consortium results. Their results indicate that 47.5% of all CREs are highly conserved because they align to almost all of the 240 non-human mammalian genomes. (I have no idea how the phyloP program calculates "conservation.") That means approximately 439,000 sites that are likely to be genuine regulatory sequences covering 4% of the human genome. If there are 25,000 genes then this means that each gene requires about 17 regulatory sequences.
The next step was to examine 15.6 million TFBSs with a median length of 10 bp covering 5.7% of the human genome. They classified 32.5% of these sequences as highly conserved using the mysterious phyloP program. That means about 5.1 million functional transcription factor binding sites, but later on they reduce this to 2 million covering 0.8% of the genome. This is equivalent to an average of 80 per gene.
I don't believe that the authors have identified functional sites. There is no critical analysis of the results or the methodology and no attempt to rationalize the extraordinary claim that every gene requires so many regulatory sites. About 10,000 genes are regular housekeeping genes, such as those encoding the standard metabolic enzymes, and it's difficult to imagine that those genes require such complex regulation.
Most of the genes in eukaryotes contain introns that are removed by splicing during processing of the primary transcript. In some cases the gene produces two different functional RNAs due to differential splicing of the introns. If the product is mRNA then two different versions of the protein can be made as shown in the figure from my book What's in Your Genome? This mechanism is known as alternative splicing.
True alternative splicing is rare—less than 5% of all genes are alternatively spliced.1 However, when you analyze all of the transcripts in a tissue you will invariably detect many transcripts from junk DNA and many low abundance splice variants. Those transcripts and splice variants are due to transcription errors and splicing errors. Splicing errors arise from the presence of weak splice sites that are occasionally recognized by the normal spliceosome or by the splice factors responsible for true alternative splicing.
The latest summary of the number of genes in the human genome gets the number of protein-coding genes correct but their estimate of the number of known non-coding genes is far too high.
In order to have a meaningful discussion about molecular genes, we have to agree on the definition of a molecular gene. I support the following definition (see What Is a Gene?).
Jonathan McLatchie is an Intelligent Design Creationist who now blogs frequently on the Discovery website Evolution News [sic]. His latest post is How NOT to Argue Against Irreducible Complexity where he defends the claim that the human male reproductive apparatus is irreducibly complex and therefore must be a product of intelligent design.
You can read the post yourself to see how ID proponents argue. I want to make another point.
McLatchie thinks that the irreducible complexity argument is very powerful evidence for intelligent design. He writes,
The argument from irreducible complexity against evolution and for design has always held strong intuitive appeal for me, and it has hence become my argument of choice in discussions about the scientific merits of evolution versus design.
Let's look at the logic of the argument from irreducible complexity. Assume that we have identified a structure that's irreducibly complex. There are three possible ways to deal with its origin.
There is a plausible naturalistic explanation for the evolution of the irreducibly complex structure.
There is currently no detailed naturalistic explanation that accounts for the evolution of the irreducibly complex structure.
It is impossible for there to ever be a naturalistic explanation; therefore, god did it.
We know that there are good naturalistic explanations for the evolution of irreducibly complex structures. In fact, McLatchie mentions some of them that refuted his earlier claims. Behe has also backed off some of his claims in light of evidence that irreducibly complex structures can evolve without the help of god(s). This establishes that the mere existence of an irreducibly complex structure is not evidence for intelligent design.
Here's how Behe explains it on page 40 of Darwin's Black Box.
Even if a system is irreducibly complex (and thus cannot have been produced directly), however, one cannot definitively rule out the possibility of an indirect, circuitous route.
In some cases there is currently no good naturalistic explanation for the evolution of an irreducibly complex structure. This could be due to a real difficulty in coming up with a plausible scenario or it could be due to the fact that no scientist has bothered to do the investigation required because they don't care. In either case, the current lack of an explanation is not, in itself, evidence for an intelligent designer.
The third possibility is the one that counts. If you can prove that a naturalistic explanation is impossible then there must be a non-naturalistic explanation such as aliens, or god(s). McLatchie says the the sperm flagellum is irreducibly complex and that he cannot imagine how it could have evolved naturally. According to creationist logic, it follows that some alien, or some god, must have designed the original sperm flagellum.
McLatchie won't tell us when this happened or why the intelligent designer was so interested in sperm, but that's typical of Intelligent Design Creationsts—they require detailed explanations from scientists but not from their fellow creationists.
Evelyn Fox Keller died a few days ago (Sept. 22, 2023). She was a professor of History and Philosopher of Science at the Massachusetts Institute of Technology (Boston, MA, USA). Most of the obituaries praise her for her promotion of women scientists and her critiques of science as a male-dominated discipline. More recently, she turned her attention to molecular biology and genomics and many philosophers (and others) seem to think that she made notable contributions in that area as well.
In his new book "What’s in Your Genome?", Laurence A. Moran shows that all the research done in the decades since that letter was written has confirmed what Crick, Jukes, and other specialists believed all along: much of our DNA is indeed a kind of “junk.”
This is a video of a debate that took place in Kraków, Poland on June 2, 2023. The topic was "Intelligent design in nature—illusion or reality?" (Spoiler alert! - the answer is "illusion.") The participants were Michael Behe and Richard v. Sternberg for the creationists and Michael Ruse and Malgorzata Moczydlowska-Vidal for the science/philosophy side. The video is almost three hours long and I don't recommend watching the whole thing.
Ruse, as usual, is incoherant and more focused on religion and telling Christians how they should behave. The Polish paleontologist didn't do a very good job of addressing the claims of the creationists.1 Michael Behe gave his standard pitch about irreducible complexity and the bacterial flagellum.
The interesting part was Sternberg's defense of intelligent design. I hadn't seen him before although I've been familiar with his writings over the past twenty years. His opening presentation begins at 17:50 and it's worth watching to see how important the junk DNA debate is to the ID crowd.
Sternberg begins by noting that he was skeptical of the arguments put forward by Richard Dawkins in "The Selfish Gene" where Dawkins says that 98% of our DNA is noncoding junk. (Dawkins never said any such thing!) Sternberg says that when he started looking for function in this part of the genome he found that it was replete with function. Then he brings up the ENCODE results and claims that they challenged the concept of a gene (not true). Sternberg says that the new definition of a gene is that it is polyfunctional and "constantly changing in real time." He says,
... how can you have a theory based on an entity that you cannot define and how can you discuss the evolution of something that is kind of this amorphous notion ...
Sternberg seems to think that redefining the gene shows that evolutionary biology is out of touch with reality. He claims that the discovery of the epigenome is futher evidence that there are multiple layers of information that take us far beyond the theory of neo-Darwinism that was crafted in the nineteen teens and the 1920s.
Sternberg reflects the views of many Intelligent Design Creationists who tout the "debunking" of junk DNA as one of their greatest intellectual achievements because they predicted all along that there couldn't be large amounts of junk DNA in our genome because that's incompatible with intelligent design. What's different in the case of Richard Sternberg is that the discovery of function in most of our genome is what led him to the position that design is the best explanation.
I find it strange that Intelligent Design Creationists are relying so heavily on the so-called debunking of junk DNA, especially since in Sternberg's case he is well aware of the fact that some prominent scientists have criticized ENCODE. It's a risky strategy to put so much emphasis on a result that may turn out to be wrong. If our genome is mostly junk DNA (it is!) then the major part of their argument for design falls apart.
From reading the ID literature, it seems that they are supremely confident that most of our genome will turn out to be full of function. It will be interesting to see how they respond when the scientific community concludes that 90% of our genome is junk. From my perspective, they are digging themselves into a deep hole that will be very difficult to climb out of. Maybe it's time to stop digging?
Sternberg made one quip that's worth highlighting. At about 1:46:20 he talks about a saying that he learned in the air force; you don't receive flak unless you're over a significant target. That's cute. He uses it to explain why intelligent design is coming under such heavy attack. He is, of course, correct. When you drop bombs on people you can expect them to get upset. When you attack some of the most important concepts in science you can expect some pushback. That doesn't mean your bombing is justified. If it were justified then scientists would embrace your criticisms instead of shooting them down.
Sternberg scores big at 2:51:11 when he asks, "Can there be Darwinian evolution ... or any evolution in general, without natural selection?" The correct answer is yes. Malgorzata Moczydlowska-Vidal says no and so does Michael Ruse. Ruse then goes on to explain why he dismisses random genetic drift. Sternberg then explains neutral evolution and Michael Lynch's drift-barrier hypothesis and why some biologists use them to explain some of the ID challenges. Sternberg (and Behe) appear to know more about evolution than their opponents.
1. She concentrated on presenting evidence for the history of life but both Behe and Sternberg accept common descent and the correct age of the Earth.
This is a very slick video from the Discovery Institute. It shows you what we are up against. Anyone who thinks they can easily refute the claims in this video hasn't tried.
Intelligent Design Creationists know exactly what they are doing and they are very good at it. There are so many thing wrong with this video that it would take a book to correct them all and, furthermore, you would have to convince people that their entire worldview has to change in order to really understand biology. I bet there are many scientists who couldn't deal with a video like this and that's a problem.
Real biology is messy and sloppy. Things do not look as neatly designed as Richard Dawkins and the creationists would have you believe. I've tried to present the case for a sloppy worldview in my latest book.
You know you're in for a treat when papers published in a (previously) reputable journal make frequent references to Dennis Noble and James Shapiro.
The purpose of this post is to demonstrate that you shouldn't let creationist amateurs publish anti-evolution rants in scientific journals.
I want to discuss two papers that were recently published in the journal Progress in Biophysics and Molecular Biology. This used to be a very reputable journal but its reputation suffered a big blow in 2018 when it published a paper on panspermia. The current editor-in-chief at the time, Denis Noble, defended that article on the grounds that the origin of life is an unsolved problem and all points of view deserve to be covered in a scientific journal. Denis Noble is still on the editorial board along with Tom L. Blundell and Delphine Dean (see editorial board) and they now have to answer for publishing two creationist papers by Olen R. Brown and David A. Hullender.
John Mattick continues to promote the idea that he is leading a paradigm shift in molecular biology. He believes that he and his colleagues have discovered a vast world of noncoding genes responsible for intricate gene regulation in complex eukaryotes. The latest salvo was fired a few months ago in June 2023.
Mattick, J.S. (2023) A Kuhnian revolution in molecular biology: Most genes in complex organisms express regulatory RNAs. BioEssays:2300080. [doi: 10.1002/bies.202300080]
Thomas Kuhn described the progress of science as comprising occasional paradigm shifts separated by interludes of ‘normal science’. The paradigm that has held sway since the inception of molecular biology is that genes (mainly) encode proteins. In parallel, theoreticians posited that mutation is random, inferred that most of the genome in complex organisms is non-functional, and asserted that somatic information is not communicated to the germline. However, many anomalies appeared, particularly in plants and animals: the strange genetic phenomena of paramutation and transvection; introns; repetitive sequences; a complex epigenome; lack of scaling of (protein-coding) genes and increase in ‘noncoding’ sequences with developmental complexity; genetic loci termed ‘enhancers’ that control spatiotemporal gene expression patterns during development; and a plethora of ‘intergenic’, overlapping, antisense and intronic transcripts. These observations suggest that the original conception of genetic information was deficient and that most genes in complex organisms specify regulatory RNAs, some of which convey intergenerational information.
This paper is promoted by a video in which he explains why there's a Kuhnian revolution under way. This paper differs from most of his others on the same topic because Mattick now seems to have acquired some more knowledge of the mutation load argument and the neutral theory of evolution. Now he's not only attacking the so-called "protein centric" paradigm but also the Modern Synthesis. Apparently, a slew of "anomalies" are casting doubt on several old paradigms.
This is still a paradigm shaft but it's a bit more complicated than his previous versions (see: John Mattick's paradigm shaft). Now his "anomalies" include not only large numbers of noncoding genes but also the C-value paradox, repetitive DNA, introns, enhancers, gene silencing, the g-value enigma, pervasive transcription, transvection, and epigenetics. Also, he now seems to be aware of many of the arguments for junk DNA but not so aware that he can reference any of his critics.1 His challenges to the Modern Synthesis include paramutation which, along with epigenetics, violate the paradigm of the Moden Synthesis because of non-genetic inheritance.
But the heart of his revolution is still the discovery of massive numbers of noncoding genes that only he and a few of his diehard colleague can see.
The genomic programming of developmentally complex organisms was misunderstood for much of the last century. The mammalian genome harbors only ∼20 000 protein-coding genes, similar in number and with largely orthologous functions as those in other animals, including simple nematodes. On the other hand, the extent of non-protein-coding DNA increases with increasing developmental and cognitive complexity, reaching 98.5% in humans. Moreover, high throughput analyses have shown that the majority of the mammalian genome is differentially and dynamically transcribed during development to produce tens if not hundreds of thousands of short and long non-protein-coding RNAs that show highly specific expression patterns and subcellular locations.
The figure is supposed to show that by 2020 junk DNA had been eliminated and almost all of the mammalian genome is devoted to functional DNA—mostly in the form of noncoding genes. There's only one very tiny problem with this picture—it's not supported by any evidence that all those functional noncoding genes exist. This is still a paradigm shaft of the third kind (false paradigm, false overthrow, false data).
1. There are 124 references; Dawkins and ENCODE make the list along with 14 of his own papers. Most of the papers in my list of Required reading for the junk DNA debate are missing. The absence of Palazzo and Gregory (2023) is particularly noteworthy.
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.
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.
