The Dark Matter Rises

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.

Other posts about John Mattick.

How Not to Do Science
John Mattick on the Importance of Non-coding RNA
John Mattick Wins Chen Award for Distinguished Academic Achievement in Human Genetic and Genomic Research
International team cracks mammalian gene control code
Greg Laden Gets Suckered by John Mattick
How Much Junk in the Human Genome?
Genome Size, Complexity, and the C-Value Paradox

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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]

What Should We Teach About the "Tree of Life"?

As most of you already know, I think the Three Domain Hypothesis is dead. The history of life is better explained as a net with rampant transfer of genes between species [The Web of Life]. This idea has been widely promoted by Ford Doolittle.

The debate over the tree of life has implications concerning the distinction between "prokaryote" and "eukaryote." I was checking some recent papers and came across one by Doolittle and Zhaxybayeva (2013) that seems particularly relevant. They discuss the evidence for and against the division of life into three domains and the attempt by Norm Pace to ban the word "prokaryote."

The authors point out, once again, that eukaryotic genes are most closely related to genes from cyanobacteria, proteobacteria, and archaebacteria, in that order. The majority, by far, have their closest homologs in bacteria, not archaebacteria. The most likely explanation is that euakryotes are chimeras resulting from fusion of an archaebacterium and a eubacterium plus genes transferred from mitochondria and chloroplast to the nuclear genome.

The Trouble with Scientism?

Philip Kitcher is a philosopher who specializes in the philsophy of science. He is a professor at Columbia University in New York, USA. He's well known in the atheist, skeptical community and he's an outspoken critic of creationism.

He just published an article in The New Republic entitled: The Trouble with Scientism: Why history and the humanities are also a form of knowledge.

Many of the debates on the issue of "scientism" depend on how you define "science." As you can see from the subtitle of his essay, it's about the two cultures. Kitcher separate the search for knowledge in the humanities from the search for knowledge in the natural sciences. Here's what he says ...

It is so easy to underrate the impact of the humanities and of the arts. Too many people, some of whom should know better, do it all the time. But understanding why the natural sciences are regarded as the gold standard for human knowledge is not hard. When molecular biologists are able to insert fragments of DNA into bacteria and turn the organisms into factories for churning out medically valuable substances, and when fundamental physics can predict the results of experiments with a precision comparable to measuring the distance across North America to within the thickness of a human hair, their achievements compel respect, and even awe. To derive one’s notion of human knowledge from the most striking accomplishments of the natural sciences easily generates a conviction that other forms of inquiry simply do not measure up. Their accomplishments can come to seem inferior, even worthless, at least until the day when these domains are absorbed within the scope of “real science.”

It's clear the he thinks of "science" as something that only natural scientists do. This is a different definition that the one I prefer. I think of "science" as a way of knowing that involves evidence, skepticism, and rationalism. I agree with Rush Holt [Rush Holt on Science and Critical Thinking] that critical thinking is an important part of science as a way of knowing and I agree with him that the scientific approach can be used everywhere—even in philosophy departments.

Kitcher's view is different. That leads him to define scientism as ...

The problem with scientism—which is of course not the same thing as science—is owed to a number of sources, and they deserve critical scrutiny. The enthusiasm for natural scientific imperialism rests on five observations. First, there is the sense that the humanities and social sciences are doomed to deliver a seemingly directionless sequence of theories and explanations, with no promise of additive progress. Second, there is the contrasting record of extraordinary success in some areas of natural science. Third, there is the explicit articulation of technique and method in the natural sciences, which fosters the conviction that natural scientists are able to acquire and combine evidence in particularly rigorous ways. Fourth, there is the perception that humanists and social scientists are only able to reason cogently when they confine themselves to conclusions of limited generality: insofar as they aim at significant—general—conclusions, their methods and their evidence are unrigorous. Finally, there is the commonplace perception that the humanities and social sciences have been dominated, for long periods of their histories, by spectacularly false theories, grand doctrines that enjoy enormous popularity until fashion changes, as their glaring shortcomings are disclosed.

That's a really stupid definition of scientism. I don't know anyone who actually thinks like that. Do you know any "natural science imperialists" who dismiss the humanities and the social sciences?¹

I believe that people in the humanities and social sciences use the same approach as those in the natural sciences. I call that way of knowing "science" but if someone wants to come up with a better name, I'm all ears. As far as I'm concerned, science (as I define it) is the ONLY way of knowing that has actually been successful in discovering true knowledge. I guess that makes me guilty of "scientism."

It's very easy to refute scientism as I define it. All you have to do is show that there's some other way of knowing that produces universal truths or true knowledge. Perhaps philosophers have discovered truths using some other way of knowing?

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1. I criticize evolutionary psychology. The reason why I'm so critical is precisely because they don't conform to the scientific way of knowing. They are not doing "good science" by any definition of the word "science."

Understanding Mutation Rates and Evolution

The recent article by physician Joseph A. Kuhn contains a lot of errors and misunderstandings [Physicians Can Be IDiots]. Today I want to focus on one paragraph.

The complexity of creating two sequential or simultaneous mutations that would confer improved survival has been studied in the malaria parasite when exposed to chloroquine. The actual incidence of two base-pair mutations leading to two changed amino acids leading to resistance has been shown to be 1 in 10²⁰ cases (42). To better understand this incidence, the likelihood that Homo sapiens would achieve any single mutation of the kind required for malaria to become resistant to chloroquine (a simple shift of two amino acids) would be 100 million times 10 million years (many times the age of the universe). This example has been used to further explain the difficulty in managing more than one mutation to achieve benefit.

The reference is to The Edge of Evolution by Michael Behe. His book was published in 2007 but I never got around to reviewing it thoroughly—partly because it's so difficult to explain where he goes wrong.¹ Here's my take on one part of the book: The Two Binding Sites Rule. This post covers "chloroquine-complexity clusters" (CCC).

The Core Genome

Hundreds of genomes have been sequenced. It should be relatively easy to search all these genomes to identify those genes that are found in every single species. This small class of genes should represent the core genome—the genes that were probably present in the first living cell.

Turns out it's not that easy. For one thing, you have to remove parasitic bacteria from your set of genomes because these species could easily be getting by without some essential genes that are supplied by their hosts. Next you have to make sure you have a huge variety of different species that cover all possible forms of life. In practice, this means that you need about 300 different genomes, mostly bacteria.

I'm reading The Logic of Chance: The Nature and Origin of Biological Evolution, by Eugene Koonin. This is just one of many books that are critical of the most popular views of evolution. Most of these books are written by kooks or religious nutters but some of them are valid scientific critiques of modern evolutionary theory. Koonin's book is one of those and I agree with most of what he has to say. One of his topics is genome evolution.

As Koonin describes it, the first genome comparisons looked at Haemophilus influenzae and Mycoplasma genitalium, two species of bacteria that aren't distantly related. There were about 240 orthologous genes found in both species.¹ The first surprise was that this core set was missing some very important members that should have been there.

Some essential metabolic reactions must have been catalyzed by enzymes in the very first cells but the Haemophilus enzyme isn't present in Mycoplasma and vice versa. It took a bit of digging but eventually the problem was solved with the discovery of different enzymes that carried out the same reaction. The genes for these enzymes are completely unrelated.

As more and and more genomes were sequenced, the size of the core genome set shrunk until today it comprises fewer than 100 genes. Most of these genes are genes for the three ribosomal RNAs, about 30 tRNAs, and a few other essential RNA molecules. There are only about 33 protein-encoding genes in the universal core set. They include genes for the three large RNA polymerase subunits and 30 proteins required for translation (mostly ribosomal proteins).

DNA polymerase isn't in the core set because some species of bacteria have unusual DNA polymerases that replicate DNA just fine but are unrelated to the enzymes found in most cells. There are multiple, unrelated, versions of the aminoacyl tRNA synthetases—the enzyme that attaches an amino acid to its cognate tRNA. Some species have one version and other species have the second version. Some species have both. In any case, no single synthetase gene is found in every species so it's not part of the core set.

Koonin refers to this observation as non-orthologous gene displacement (NOGD). He envisages a scenario where a cell with gene X takes up a copy of a non-orthologous gene (gene Y) that catalzyes the same reaction. Over time the newly acquired gene displaces the original version. In this way a non-orthologous version (e.g. gene Y) could have arisen after the formation of the first cell and spread to a variety of different species by horizontal gene transfer. The scenario doesn't rule out the possibility that the two non-orthologous versions could have arisen independently in two separate origins of life but this seems less likely.

Let's look at a couple of examples. Biochemistry textbook writers have known for decades that there are different versions of some common metabolic genes ² The aldolase enzyme in gluconeogenesis & glucolysis is a classic. Some species have the class I enzyme/gene while others have the class II enzyme/gene. Some species have both.

This is an example of convergent evolution. The enzymes have different mechanisms and, as you can see from the figure, completely different structures. It doesn't seem to matter if a species has a class I enzyme or a class II enzyme since both enzymes are very good at catalyzing the fusion of two three-carbon molecules into a six-carbon fructose molecule or cleaving the six-carbon molecule in the reverse reaction.

The pyruvate dehydrogenase complex (PDC) is a huge enzyme that catalyzes an important metabolic reaction making acetyl-CoA—the substrate for the citric acid cycle. It seemed likely that every single species would have the genes for all of the PDC subunits but many species of bacteria were missing the entire complex. They have a different enzyme, pyruvate:ferredoxin oxidoreducatase that catalyzes a similar reaction. The enzymes have completely different mechanisms and are unrelated.

In this case, we have reason to believe that the enzyme requiring ferredoxin is more primitive and the more common pyruvate dehydrogenase complex evolved later. The PDC genes displaced the gene for pyruvate:ferredoxin oxidoreductase in many, but not all, species. That's why the genes for neither enzyme are part of the core set.

We don't know whether the existing core set of 100 genes truly represents genes that were present in the first living cell or whether they completely displaced the original versions. The fact that many of these genes are part of large operons might have made it easier for them to be transferred by horizontal gene transfer. (The selfish operon model.)

The bottom line is that attempts to reconstruct the genome of the first cell have failed because of NOGD and we now have to incorporate that concept into our way of thinking about early evolution. The good news is that the evolution of completely new genes seems to be much easier than we first imagined. We even have examples of three or four completely different enzymes carrying out the same reaction.³

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1. Koonin refers to conserved genes as Clusters of Orthologous Genes or COGs. It actually counts conserved domains rather than entire genes but the differences aren't great so I'll just refer to them as genes.

2. That is, those textbook writers that emphasize comparative biochemistry or an evolutionary approach to biochemistry. Some textbooks just cover human (mammalian) biochemistry so they won't even mention whether bacteria do biochemistry.

3. I'm not sure how the Intelligent Design Creationists explain these observations. Maybe there were several different designers who each came up with their ideal solution to the problem? Maybe there was only one designer who just got a kick out of making different versions of the same enzyme activity but got bored at only two or three?

Martin Rees Explains Accommodationism

 
Martin Rees is the President of the Royal Society in the UK. This is a position of enormous influence. When Rees speaks you can assume that he is representing the position of the Royal Society, or at least it's leaders.

Martin Rees was recently interviewed by The Independent [Martin Rees: 'We shouldn't attach any weight to what Hawking says about god'].

He is equally scathing about Hawking's more recent comments about there being no need for God in order to explain creation. "Stephen Hawking is a remarkable person whom I've know for 40 years and for that reason any oracular statement he makes gets exaggerated publicity. I know Stephen Hawking well enough to know that he has read very little philosophy and even less theology, so I don't think we should attach any weight to his views on this topic," he said.

Unlike many of the Fellows of the Royal Society he has presided over in the past five years, Lord Rees is not a militant atheist who goes out of his way to insult people of belief – Richard Dawkins once called him "a compliant quisling" for his tolerance of religion.

"I would support peaceful co-existence between religion and science because they concern different domains," Lord Rees said. "Anyone who takes theology seriously knows that it's not a matter of using it to explain things that scientists are mystified by."

His next popular science book is about these things that science still cannot explain, such as the origin of life on Earth and the scientific nature of human consciousness. This, he insisted, is what science is really about, and why it has the power to touch everyone of every culture.

I don't have time for a detailed explanation of this particular accommodationist position so I'll just note a few points.

• Hawking said there's no need for God but his views can be dismissed because (unlike Martin Rees?) he's not an expert on philosophy and theology.


• Rees does not go out of his way to insult people of belief. Good for him. Neither do lots of atheists, including Stephen Hawking. What's the point? Sounds to me like Dawkins might have been correct.


• Did Martin Rees just go out of his way to insult atheists like Stephen Hawking? I guess atheists don't deserve the same kid-gloves treatment that we owe to theists.


• Religion and science concern different domains. So they do. Religion is firmly planted in the domain of mythology and superstition. What does that prove?


• Martin Rees is an astronomer. He's writing a book about the origin of life and human consciousness. I wonder if we should bother paying any attention to this book since he's not an expert in biology?

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[Photo Credit: BBC]

AAAS Supports Accommodationism, Illogically

 
Alan I. Leshner is the CEO of the American Association for the Advancement of Science (AAAS) and Executive Publisher of Science. He has written an article for the Huffington Post [Science, Religion and Civil Dialogue]. As usual, this type of accommodationist focuses on the fact that there are religious scientists. In this case, the recent study by Elaine Ecklund gets a prominent mention.

Let's hope that Ecklund's unusually comprehensive assessment will help overturn the myth that scientists reject spirituality, or that science and religion are inherently incompatible.

That myth persists among scientists and religious believers alike. In 2009 study by the Pew Research Center, 61% of Americans said that science poses no conflict with their own faith. Nonetheless, 55% of those same respondents said they view religion and science generally as "often in conflict." Evolution, for instance, has divided Americans since 1859, when Charles Darwin published "On the Origin of Species."

There is a better way, which will be demonstrated June 16 when leading scientists and a respected Christian minister engage in a free, public dialogue at the American Association for the Advancement of Science (AAAS).

There may be a myth that all scientists reject spirituality. I really can't comment on that except to note that I have never, ever, heard anyone make this claim.

The real issue is whether science and religion are inherently incompatible and that issue is not a "myth" by any stretch of the imagination. It's a perfectly reasonable position, whether you agree with it or not. The existence of scientists who are religious does nothing to decide the issue one way or another. After all, there are scientists who believe in homeopathy but that doesn't mean homeopathy is compatible with science. What Leshner says is illogical and logic is supposed to be one of the hallmarks of good science.¹

If the CEO of AAAS can't distinguish real philosophical issues from "myth" then I suggest that Americans need a new CEO—one who will keep the organization out of domains where it has no mandate to speak for all scientists. If Alan I. Leshner can't keep religion out of the organization then he should resign.²

As you might expect, Jerry Coyne restates the position that many of us hold [The AAAS goes all accommodationist]. Scientific organizations like AAAS have no business making claims about whether science and religion are compatible or not. When they cow-tow to religion they are separating themselves from a great many scientists who hold contrary points of view. The organization does not, cannot, and should not speak for scientists on subjects outside of science.

What Should Scientific Organizations Say about Religion?

How Should Scientific Societies Treat Religion?

Are Science and Religion Compatible? AAAS Says Yes.

AAAS Panel: Communicating Science in a Religious America

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1. I haven't mentioned the other illogical part of the argument; namely, that criticism of religion is "uncivil."

2. Please, let's not have any silly debate over whether Leshner is expressing a personal opinion or speaking for AAAS. Read his article and note how he identifies himself as author.

The "Mutationism" Myth I. The Monk's Lost Code and the Great Confusion

This is the second in a series of postings by a guest blogger, Arlin Stoltzfus. You can read the first part at: Introduction to "The Curious Disconnect". Arlin is challenging the status quo in modern evolutionary theory. He's not alone in this challenge but it's important to distinguish between kooks who don't know what they're talking about and serious thinkers who have something to say. Arlin is going to explain to you why everything you thought you knew about mutationism is wrong. I'm happy to give him a chance to post on Sandwalk.

This will be on the exam.

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The Curious Disconnect

The Curious Disconnect is the blog of evolutionary biologist Arlin Stoltzfus, available at www.molevol.org/cdblog. An updated version of the post below will be maintained at www.molevol.org/cdblog/mutationism_myth1 (Arlin Stoltzfus, ©2010)

The "Mutationism" Myth I. The Monk's Lost Code and the Great Confusion

The mutationism myth tells the story of how, just over a century ago, the scientific community responded to the discovery of Mendelian genetics by discarding Darwinism, and how Darwinism subsequently was restored.Our journey to explore The Curious Disconnect-- the gap between how we think about evolution and how we might think if we were freed from historical baggage-- begins with the Mutationism Myth. In this, the first of four parts, we are not going to confront any tough scientific or conceptual issues. Instead, we are just going to review an odd story about our intellectual history.

The Mutationism Story

While "myth" has the connotation of falsehood, the story that a myth tells isn't necessarily a false one. The mutationism myth, at least, is anchored in historical events.¹

The mutationism myth tells the story of how, just over a century ago, the scientific community responded to the discovery of Mendelian genetics by discarding Darwinism, and how Darwinism subsequently was restored. The villains of the story are the influential early geneticists or "Mendelians" who saw genetics as a refutation of Darwinism; the heroes are first, the founders of population genetics, theoreticians who sorted everything out in favor of Darwinism by about 1930, and second, the architects of the Modern Synthesis, activists who popularized and institutionalized what we're calling "Darwinism 2.0".

This story has been re-told in secondary sources for nearly 50 years, though I sense that the frequency is decreasing as this episode passes into ancient history. To find examples, try looking up "mutationism" (sometimes "Mendelism" or even "saltationism") in the index of a book about evolution.

I encourage you to consult whatever sources you have and to share the stories that you find. Note that you won't always be successful. A quick survey of several dozen contemporary books on my shelf reveals that most don't address this episode specifically (a notable absence, in some cases ²); some tell the mutationism myth with varying degrees of panache; and a few provide a historical account rather than a myth. The few historical accounts that I found were in Gould's 2002 The Structure of Evolutionary Theory, Strickberger's 1990 textbook Evolution, and the Wikipedia entry on "Mutationism".

Sample stories

Lets look at a few examples of the mutationism story. Readers who want to check out a freely available online source from the scholarly literature may refer to Ayala and Fitch, 1997 (http://www.ncbi.nlm.nih.gov/pubmed/9223250?dopt=Citation). One example that really caught my eye is not from scientific literature, but from the 2005 obituary for Ernst Mayr in The Economist:

It was not that biologists had given up on evolution by the 1940s-quite the contrary. But they had got very confused about its mechanism. . . . The geneticists of the early 20th century did not help. They rediscovered the laws of inheritance first developed 40 years earlier by Gregor Mendel, an unsung Moravian monk. They also discovered the idea of genetic mutation. But instead of linking these things to natural selection, they came up with the idea of "saltation"-in other words, sudden mutational shifts from one well-adapted species to another. Nor, the geneticists complained, had there been enough time for natural selection to do its work, given what they had discovered about the rate at which mutations occur, and the fact that most mutations are deleterious. It was all a bit of a mess. . .Mr Mayr's advantage over the laboratory-bound biologists who had hijacked and diluted Darwin's legacy was that, like Darwin, he was a naturalist-and a good one. (anonymous, 2005)

Of course, this is a magazine article, written by anonymous staff writers-- typically one doesn't see such florid language in the scholarly literature. But did the staff writers of the Economist (representing elite opinion) really originate this story, based on their own personal recollections of the 1930's? Of course not. Mayr himself popularized the image of geneticists as laboratory-bound geeks lacking the organic insight of "naturalists". This disdain for the geneticists who "hijacked" Darwin's legacy is readily apparent when evolutionary writers depict geneticists as fools holding "beliefs" that have "obvious inadequacies", unable to understand or "grasp" their own scientific findings:

"It is hard for us to comprehend but, in the early years of this century when the phenomenon of mutation was first named, it was regarded not as a necessary part of Darwinian theory but as an alternative theory of evolution! There was a school of geneticists called the mutationists, which included such famous names as Hugo de Vries and William Bateson among the early rediscoverers of Mendel's principles of heredity, Wilhelm Johannsen the inventor of the word gene, and Thomas Hunt Morgan the father of the chromosome theory of heredity. . . Mendelian genetics was thought of, not as the central plank of Darwinism that it is today, but as antithetical to Darwinism. . . It is extremely hard for the modern mind to respond to this idea with anything but mirth" (Dawkins, 1987, p. 305)

"According to mutationism, random changes in the hereditary material are sufficient for adaptation without much, or any, selection at all. Mutations just somehow happen to be adaptive, the right changes simply manage to occur. The inadequacies of this view are obvious" (Cronin, 1991, p. 47).

"Darwin knew nothing of this [i.e., genetics] but as it turned out, his ignorance was sublimely irrelevant to the problem he was really interested in tackling: evolution. This point was not fully grasped by biologists. Many early geneticists at the dawn of the 20th century, thought their discoveries of the fundamental principles of genetics somehow cast doubt [on], or rendered obsolete, the concept of natural selection. It took several decades of experimentation and theoretical (including mathematical) analysis to show not only that there was no conflict inherent between the emerging results of genetics and the older Darwinian notion of natural selection, but that the two operate in different domains." (Eldredge, 2001, p. 67)

"Mendelian particulate inheritance (today, we call the "particles" genes) was originally identified with De Vries's "mutation theory", according to which new variations or species originated in large jumps, or macromutations, and evolution was exclusively explained by mutation pressure. Darwinian naturalists, believing that Mendelism was synonymous with mutation theory, held on to theories of soft inheritance, while they considered selection a weak force at best. They did not know of the new findings in genetics that would have supported Darwinism. (SegerstrŒle, 2002)

Notice how, in every version of the story above, the position taken by early geneticists just doesn't make sense. This isn't a story of theory versus theory, its a story of confusion ultimately yielding to reason.

If de Vries and the other geneticists are playing the role of the pied piper in this story, the "naturalists" are like the children lured away from their Darwinian home. Ultimately the innocents are returned, and order restored, by (oddly enough) mathematicians:

"Between 1918 and 1932 Fisher, Haldane, and Wright showed that Mendelian genetics is consistent with natural selection. Only then, more than 60 years after the publication of The Origin of Species, was the genetic objection to natural selection finally removed. Modern molecular and developmental genetics have confirmed in exquisite chemical detail the key aspects of genetics necessary for Darwin's ideas to work: that the genetic material is DNA, that DNA has a sequence, . . . mutates . . . contains information . . " (p. 16 of Stearns and Hoekstra, 2005)

Anatomy of a Myth

In a subsequent post, we will look at original sources to see what the "mutationists" actually believed, and why. And eventually we will integrate this into the bigger picture of how evolutionary theory developed. But for now, lets just summarize the pattern that is apparent in the literature.

First, the mutationism story is clearly a story or myth, and not an ordinary scientific truth claim. We can see this because the story-tellers are not using ordinary scientific conventions to convince us that the story is true. If you or I were making an ordinary scientific argument (for instance) for an effect of "translational selection" on codon usage, we would mention a correlation between codon frequencies and the abundance of corresponding tRNAs, citing the classic work of Ikemura (1981), and we might even repeat a figure showing this correlation, to impress this point upon the minds of readers (e.g., just as in Ch. 7 of Freeman & Herron, 1998).

When I see instances of the mutationism story, typically I don't find quotations illustrating what the mutationists believed, nor facts & figures to refute their views, but only vague attributions and generalized claims. Apropos, the following quotation from Ernst Mayr never fails to make me laugh:

The genetic work of the last four decades has refuted mutationism (saltationism) so thoroughly that it is not necessary to repeat once more all the genetic evidence against it. (Mayr, 1960)

And the puissant Dr. Mayr proceeds on, not boring the reader with any tiresome "genetic evidence", nor citing sources that might allow the reader to evaluate the truth of his statement. Its a story, after all.

By contrast, the 3 sources that I mentioned above as providing scientific history, rather than myth, all make reference to specific experimental and theoretical results, and reveal knowledge of specific historically important scientific works. For instance, Strickberger's reference list includes Johannsen, 1903, as well as the 1902 paper by Yule that reconciled Mendelian genetics with quantitative variation (in neo-Darwinian mythology, credit for Yule's work is given to little Ronny Fisher, who was 11 at the time).

Second, every story has a plot or "action", and the main action of the mutationism story is a turn of fate in which power is temporarily in the hands of the wrong people or ideas. In archetypal terms, its a story of usurpation and restoration: the throne is usurped, and the kingdom falls into darkness and confusion until the throne is restored to the king's rightful heirs. The mutationism episode didn't have to be told that way: it might have been presented as a period of reform (in which old ideas were abandoned) or discovery (when new territory was mapped out). Instead, its presented as a mistake, an interlude of confusion, a collective delusion.

Indeed, another way to look at the mythic action is that the Mendelians are wizards or false prophets who place the kingdom under a spell, leading folks astray and causing them to believe things that they just shouldn't have believed.

What delusional spell did the Mendelians cast? In the story by Eldredge, or by Stearns & Hoekstra above, the spell is that Mendelian genetics is inconsistent with "the concept of natural selection" (Eldredge). In the story told by SegerstrŒle, Cronin, Mayr and The Economist, the delusional spell is a bit different: the principle of selection is irrelevant because mutational jumps alone explain evolution.

Third, the key to restoring Darwin's kingdom was to add the missing piece of genetics. Ultimately, after the period of darkness ended, the discovery of genetics "provided the missing link in Darwin's theory" (SegerstrŒle, 2002), or "The missing link in Darwin's argument was provided by Mendelian genetics" (Ayala & Fitch, 1997). Darwinism was restored, not by taking away the power of genetics, but by redirecting it to support Darwinism. Clearly, genetics is the key to ruling the kingdom, like the One Ring that Rules them All in Tolkien's world. The ones who have the ring have the power.

The story is made more fascinating by the fact that the key to power is literally a code of rules developed by a monk that remained lost for nearly half a century. The usurpers who discover The Monk's Code misinterpret it, and use it to overthrow the true king, establishing a reign of error. But when The Founders decipher the true meaning of the Monk's Code, The Architects campaign throughout the kingdom, spreading the news: the Monk's Code proves that Darwin is the true king. Darwin's rule is re-established, all opposition ceases, and the kingdom is unified.

Homework

If you would like to contribute a mutationism story, I would be happy to start a collection if you make it easy for me by providing a complete and well formed text item. Be sure to provide a quoted passage with a source, citing exact page numbers. If we get enough stories, lets try to recruit a sociologist or historian to study this further.

Summary

To summarize, the mutationism story is a myth that is retold in secondary sources. The basic story is simple: the discoverers of genetics misinterpreted their discovery, thinking it incompatible with Darwinism; Darwinism went into disfavor; population geneticists came along and showed that genetics was the missing key to Darwinism; Darwinism was restored and once again reigned supreme.

Next time on the The Curious Disconnect, we'll start pulling on some of the loose threads of this story.

For now, note how the writers quoted above are genuinely baffled by our scientific history. It just doesn't make sense to them. A century ago, most of an entire generation of scientists thought of genetics as a contradiction of Darwinism. This is a historical fact, and presumably it has an explanation that rational folks can understand by examining what scientists of the time wrote. But this historical fact mystifies Dawkins, Eldredge, Cronin, and others.

References

Anonymous. 2005. Ernst Mayr, evolutionary biologist, died on February 3rd, aged 100. The Economist, February.

Ayala, F. J., and W. M. Fitch. 1997. Genetics and the origin of species: an introduction. Proc Natl Acad Sci U S A 94:7691-7697.

Cronin, H. 1991. The Ant and the Peacock. Cambridge University Presss, Cambridge.

Dawkins, R. 1987. The Blind Watchmaker. W.W. Norton and Company, New York.

Eldredge, N. 2001. The Triumph of Evolution and the Failure of Creationism. W H Freeman & Co.

Freeman, S., and J. C. Herron. 1998. Evolutionary Analysis. Prentice-Hall, Upper Saddle River, New Jersey.

Gould, S. J. 2002. The Structure of Evolutionary Theory. Harvard University Press, Cambridge, Massachusetts.

Ikemura, T. 1981. Correlation between the abundance of Escherichia coli transfer RNAs and the occurrence of the respective codons in its protein genes: a proposal for a synonymous codon choice that is optimal for the E. coli translational system. J Mol Biol 151:389-409.

Mayr, E. 1960. The Emergence of Evolutionary Novelties. Pp. 349-380 in S. Tax, and C. Callender, eds. Evolution After Darwin: The University of Chicago Centennial. University of Chicago Press, Chicago.

SegerstrŒle, U. 2002. Neo-Darwinism. Pp. 807-810 inM. Pagel, ed. Encyclopedia of Evolution. Oxford University Press, New York.

Stearns, S. C., and R. F. Hoekstra. 2005. Evolution: an introduction. Oxford University Press, New York.

Strickberger, M.W. 1990. Evolution (1st edition).

Notes
¹ The defining characteristic of a myth is not that it isn't literally true, but that it isn't told for reason of being literally true, but for reason of being meaningful or poignant: a myth is a story with a cultural value, not necessarily a literal-truth value. The connection between myths and untruths, then, has to do with discoverability: when we find a pattern P = { X people are repeating story Y }, where X is a large number, this pattern by itself does not prove that Y is a myth because X people might have all discovered or verified Y independently; but if Y has diverse elements that are untrue (or unverifiable), then we can conclude that its repetition does not signify independent verification, suggesting that its a myth.



²The Oxford Encyclopedia of Evolution does not have an article on mutationism; the article on Morgan says nothing of his views on evolution; there is no article on Bateson; mutationism is only addressed peripherally in Hull's article on the history of evolutionary theory; it is mainly addressed in SegerstrŒle's article on neo-Darwinism.

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The Last Universal Common Ancestor

 
Jeffrey Wong is a former member of our Department¹ and the author of the best theory on the origin of the genetic code [see: Amino Acids and the Racemization "Problem"]

LUCA, LECA and LBACA--Root of Life and Roots of the Biological Domains

Dr. Jeffrey Wong
Department of Biochemistry
Hong Kong University of Science and Technology

4:30 pm, September 10
Medical Sciences Building room 4171

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His mother's photograph is on the wall of graduates on the first floor of our building. She graduated from medical school in 1929.

Decoding the Structure of the HIV Genome

 
The title of the press release on Biology News Net caught my eye: UNC researchers decode structure of an entire HIV genome. I clicked the link on my aggregator and read the first two paragraphs.

The structure of an entire HIV genome has been decoded for the first time by researchers at the University of North Carolina at Chapel Hill. The results have widespread implications for understanding the strategies that viruses, like the one that causes AIDS, use to infect humans.

The study, the cover story in the Aug. 6, 2009, issue of the journal Nature, also opens the door for further research which could accelerate the development of antiviral drugs.

By the time I finished the article I thought I had a pretty good idea of what they were talking about but, just to be sure, I visited the Nature website to read the actual scientific paper.

Watts, J.M., Dang, K.K., Gorelick, R.J., Leonard, C.W., Bess Jr., J.W., Swanstrom, R., Burch, C.L. and Weeks, K.M. (2009) Architecture and secondary structure of an entire HIV-1 RNA genome. Nature 460:705-710 [doi: 10.1038/nature08237]

Single-stranded RNA viruses encompass broad classes of infectious agents and cause the common cold, cancer, AIDS and other serious health threats. Viral replication is regulated at many levels, including the use of conserved genomic RNA structures. Most potential regulatory elements in viral RNA genomes are uncharacterized. Here we report the structure of an entire HIV-1 genome at single nucleotide resolution using SHAPE, a high-throughput RNA analysis technology. The genome encodes protein structure at two levels. In addition to the correspondence between RNA and protein primary sequences, a correlation exists between high levels of RNA structure and sequences that encode inter-domain loops in HIV proteins. This correlation suggests that RNA structure modulates ribosome elongation to promote native protein folding. Some simple genome elements previously shown to be important, including the ribosomal gag-pol frameshift stem-loop, are components of larger RNA motifs. We also identify organizational principles for unstructured RNA regions, including splice site acceptors and hypervariable regions. These results emphasize that the HIV-1 genome and, potentially, many coding RNAs are punctuated by previously unrecognized regulatory motifs and that extensive RNA structure constitutes an important component of the genetic code.

The authors determined the two- and in some cases the three-dimensional structure of the HIV RNA genome. In other words, they figured out the way RNA folds to form regions of secondary structure (double-stranded RNA). This RNA molecule functions as a complex messenger RNA and the secondary structure plays a role in regulating how the molecule is translated.

The press release doesn't really convey this result very well, especially in the opening paragraph. Part of the problem is misue of the word "decode." We're familiar with journalists who use "decode" to mean "nucleotide sequence" as in "Scientists decoded the human genome." This elevates "decode" to an entirely new meaning.

In fairness, this confusion over the word "decode" is exacerbated by the language used by the authors in the paper.

Our discovery that the peptide loops that link independently folded protein domains are encoded by highly structured RNA indicates that these and probably other mRNAs encode protein structure at a second level beyond specifying the amino acid sequence. In this view, higher-order RNA structure directly encodes protein structure, especially at domain junctions. The extraordinary density of information encoded in the structure of large RNA molecules (Figs 1, 2 and 4d) represents another level of the genetic code, one which we understand the least at present. This work makes clear that there is much to be discovered by broad structural analyses of RNA genomes and intact mRNAs.

I'm not sure this language is helpful.

UPDATE: The press release from Scientific American is different: HIV genome structure decoded.

It might not be super high-res, but researchers at the University of North Carolina at Chapel Hill have described the first full structure of the HIV-1 genome.

The paper, published online today in Nature, maps out the virus' genome down to a one-nucleotide resolution with the help of a technique call SHAPE—selective 2'-hydroxyl acylation analyzed by primer extension—to paint the full, previously unknown picture of the virus (Scientific American is part of Nature Publishing Group).

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Religion may have evolved because of its ability to help people exercise self-control

 
Here's an example of evolutionary thinking by a psychologist at the University of Miami. Read the press release (below) and watch the video. It's only when you watch the video that you realize where Professor McCullough is coming from on this issue. He uses the word "evolution" to talk about cultural phenomena without necessarily including genetic changes. In other words, he is not talking about biological evolution.

This can be very confusing and I recommend that evolutionary psychologists change their practice. They should refer to "cultural evolution" and distinguish it from "biological evolution" whenever possible.

Religion may have evolved because of its ability to help people exercise self-control

A study by a University of Miami psychologist reveals that religion facilitates the exercise of self-control and attainment of long-term goals

CORAL GABLES, FL (December 30, 2008)—Self-control is critical for success in life, and a new study by University of Miami professor of Psychology Michael McCullough finds that religious people have more self-control than do their less religious counterparts. These findings imply that religious people may be better at pursuing and achieving long-term goals that are important to them and their religious groups. This, in turn, might help explain why religious people tend to have lower rates of substance abuse, better school achievement, less delinquency, better health behaviors, less depression, and longer lives.

In this research project, McCullough evaluated 8 decades worth of research on religion, which has been conducted in diverse samples of people from around the world. He found persuasive evidence from a variety of domains within the social sciences, including neuroscience, economics, psychology, and sociology, that religious beliefs and religious behaviors are capable of encouraging people to exercise self-control and to more effectively regulate their emotions and behaviors, so that they can pursue valued goals. The research paper, which summarizes the results of their review of the existing science, will be published in the January 2009 issue of Psychological Bulletin.

"The importance of self-control and self-regulation for understanding human behavior are well known to social scientists, but the possibility that the links of religiosity to self-control might explain the links of religiosity to health and behavior has not received much explicit attention," said McCullough. "We hope our paper will correct this oversight in the scientific literature." Among the most interesting conclusions that the research team drew were the following:

• Religious rituals such as prayer and meditation affect the parts of the human brain that are most important for self-regulation and self-control;
• When people view their goals as "sacred," they put more energy and effort into pursuing those goals, and therefore, are probably more effective at attaining them;
• Religious lifestyles may contribute to self-control by providing people with clear standards for their behavior, by causing people to monitor their own behavior more closely, and by giving people the sense that God is watching their behavior;
• The fact that religious people tend to be higher in self-control helps explain why religious people are less likely to misuse drugs and alcohol and experience problems with crime and delinquency.

McCullough's review of the research on religion and self-control contributes to a better understanding of "how the same social force that motivates acts of charity and generosity can also motivate people to strap bomb belts around their waists and then blow themselves up in crowded city buses," he explained. "By thinking of religion as a social force that provides people with resources for controlling their impulses (including the impulse for self-preservation, in some cases) in the service of higher goals, religion can motivate people to do just about anything."

Among the study's more practical implications is that religious people may have at their disposal a set of unique psychological resources for adhering to their New Year's Resolutions in the year to come.

I leave it up to you, dear readers, to decide whether non-religious people (atheists) tend to have higher rates of substance abuse, worse school achievement, more delinquency, worse health behaviors, more depression, and shorter lives. It would imply that countries like Sweden, where half the population is non-religious, are in much worse shape than America, where more than 80% is religious. It would imply that extremely religious countries like Saudi Arabia must be near-perfect societies full of very old people.

Incidentally, the idea of "self-control" is not well explained. If you behave in a certain way because you fear punishment from your god or your priests, then this isn't exactly what I think of when I use the term "self-control."

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On the Origin of Eukaryotes

 
Theme

The Three Domain Hypothesis
If all you do is read the textbooks, you would think that the origin of eukaryotic cells has been discovered. Most textbooks describe the Three Domain Hypothesis as a done deal. Eukaryotes and archaebacteria share a more recent common ancestor than either group does with the remaining groups of bacteria. Thus, eukaryotes arose from archaebacteria.

The scientific literature does not reflect this confidence. In fact, there is general agreement that the classic Three Domain Hypothesis is no longer viable as a complete explanation for the origin of eukaryotic cells. The current consensus favors a more confused picture of early life with lots of gene swapping—the so-called web of life. It is not clear that eukaryotes as a group arose from any particular prokaryotic clade. It is likely that in addition to horizontal gene transfer, there were probably one or more fusion events where the cells from two separate lineages united to form a hybrid.¹

This week's issue of the Proceedings of the National Acedemy of Sciences (USA) has a paper that addresses the problem, one more time. Cox et al. (2008) ask whether there is phylogenetic support for the Three Domain Hypothesis by analyzing 53 well conserved genes. The answer is no. But is there support for one of the alternatives, the Eocyte Hypothesis? The answer is, maybe.²

The commentary by John Archibald is worth reading. Here's an excerpt.

Evolving Views on the Tree of Life

Next to life itself, the origin of complex cells is one of the most fundamental, and intractable, problems in evolutionary biology. Progress in this area relies heavily on an understanding of the relationships between present-day organisms, yet despite tremendous advances over the last half-century scientists remain firmly divided on how to best classify cellular life. Many adhere to the textbook concept of 2 basic types of cells, prokaryotes and eukaryotes, as championed by Stanier and van Niel (7). Others posit that at its deepest level life is not a dichotomy but a trichotomy comprised of cells belonging to the domains Bacteria, Archaea, and Eukarya, each monophyletic and sufficiently distinct from one another to warrant equal status (5, 8). The conceptual and practical challenges associated with establishing a genealogy-based classification scheme for microbes have been fiercely debated for decades (see ref. 9 for recent review), and the literature is rich in philosophy and rhetoric.

The genomics revolution of the 1990s brought tremendous optimism to the field of microbial systematics: if enough genomes from diverse organisms could be sequenced and compared, definitive answers to questions about evolutionary relationships within and between eubacteria, archaebacteria, and eukaryotes would surely emerge. More specifically, it should be possible to discern how eukaryotes evolved from prokaryotes (if indeed that is what happened), and perhaps even who among modern-day prokaryotic lineages is our closest ancestor. Unfortunately, with the sequences of hundreds of eubacterial, archaebacterial, and eukaryotic genomes has come the realization that the number of universally distributed genes suitable for global phylogenetic analysis is frustratingly small (10). Lateral (or horizontal) gene transfer has shown itself to be a pervasive force in the evolution of both prokaryotic and eukaryotic genomes, and even if a “core” set of genes can be identified (and there is much debate on this issue), how confident are we that the phylogenetic signal in these genes reflects the vertical history of cells? How meaningful are sequence alignment-independent, gene content-based approaches to resolving the “tree of life” (11)? To what extent is a “net of life” a more accurate and useful metaphor for describing the full spectrum of life on Earth (10, 12–14)?

The bottom line is that the earliest stages of evolution are still very much open questions. It is wrong to assume that the Three Domain Hypothesis is correct and scientists, as well as textbooks writers, should stop making this assumption.

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1. Most workers make the unstated assumption that eukaryotic cells are more recent than prokaryotic cells. The idea that archaebacteria could have arisen by a fusion of an early eukaryote with an early prokaryote is just as consistent with most of the data yet this possibility is almost never discussed.

2. Cox et al. use very "sophisticated" techniques for analyzing their sequence data. Much of the controversy in this field involves disputes over which computer programs give the most accurate results. What's really going on, in my opinion, is that the data isn't good enough to justify the kinds of manipulations that are being done. The trees give you a good approximation of the true phylogeny but subjecting the data to over-analysis isn't helpful.

Archibald, J.M. (2008) The eocyte hypothesis and the origin of eukaryotic cells. Proc. Natl. Acad. Sci. (USA) 105:20049-20050. [doi:10.1073/pnas.0811118106]

Cox, C.J., Foster, P.G., Hirt, R.P., Harris, S.R., and Embley, T.M. (2008) The archaebacterial origin of eukaryotes. Proc. Natl. Acad. Sci. (USA) 105:20356-20361. [doi:10.1073/pnas.0810647105].

Two Examples of "Alternative Splicing"

THEME:
Transcription
Last week I bumped into a colleague who teaches in our third year molecular biology course. I was lamenting about the sad state of science these days and we got to talking about alternative splicing. I repeated my complaint that much of the predicted alternative splice variants are artifacts. It makes no sense that conserved genes would be producing alternative protein variants that are species specific. I am convinced that the EST databases are full of artifacts and that most predicted splice variants do not exist.

My colleague was shocked. He is firmly convinced that most human genes express a number of different protein products that are produced as the result of alternatively spliced mRNA precursors. I asked him if he had ever looked at his favorite genes to see if the predicted variants make any sense. The ones that I've looked at certainly don't. (Join in the fun: see the challenge below.)

My colleague is very knowledgeable about the genes for the major subunits of eukaryotic RNA polymerase since it was his lab that cloned the first one. I suggested that he look at the predicted alternative splice variants of the two human genes and let me know if he is still convinced that these variants make biological sense. I'm not sure he will do it so let's take a look ourselves.

Eukaryotic RNA polymerase is a complex protein machine consisting of ten different subunits. Two of the subunits, Rpb1 and Rbp2, are more commonly known as A and B. In the human genome they are encoded by the genes POLR2A and POLR2B respectively [RNA Polymerase Genes in the Human Genome].

If you click on the Entrez Gene URLs you will end up at a page that summarizes what is known about the gene. Down the right-hand side of the page there are links to several other webpages, including a link to AceView, a database of alternative splice variants. Before following this link to the POLR1A variants, let's note that on the annotated Entrez Gene website there are no alternative splice variants listed. Apparently someone has decided that the predicted variants are probably artifacts.

Go to the AceView page for AceView POLR2A. The first thing you see is a short explanation.

RefSeq annotates one representative transcript (NM included in AceView variant.a), but Homo sapiens cDNA sequences in GenBank, filtered against clone rearrangements, coaligned on the genome and clustered in a minimal non-redundant way by the manually supervised AceView program, support at least 11 spliced variants.

AceView summary
Note that this locus is complex: it appears to produce several proteins with no sequence overlap.
Expression: According to AceView, this gene is expressed at very high level, 4.8 times the average gene in this release. The sequence of this gene is defined by 537 GenBank accessions from 518 cDNA clones, some from breast (seen 40 times), marrow (29), head neck (19), brain (18), eye (18), leukopheresis (18), lung tumor (18) and 132 other tissues. We annotate structural defects or features in 13 cDNA clones.
Alternative mRNA variants and regulation: The gene contains 29 different introns (28 gt-ag, 1 gc-ag). Transcription produces 13 different mRNAs, 11 alternatively spliced variants and 2 unspliced forms. There are 7 probable alternative promotors and 5 non overlapping alternative last exons (see the diagram). The mRNAs appear to differ by truncation of the 5' end, truncation of the 3' end, overlapping exons with different boundaries, alternative splicing or retention of 4 introns. 337 bp of this gene are antisense to spliced gene pluvu, raising the possibility of regulated alternate expression.
Protein coding potential: 10 spliced and the unspliced mRNAs putatively encode good proteins, altogether 11 different isoforms (3 complete, 4 COOH complete, 4 partial), some containing domains RNA polymerase Rpb1, domain 1, RNA polymerase, alpha subunit, RNA polymerase Rpb1, domain 3, RNA polymerase Rpb1, domain 4, RNA polymerase Rpb1, domain 5, RNA polymerase Rpb1, domain 6, RNA polymerase Rpb1, domain 7, Eukaryotic RNA polymerase II heptapeptide repeat [Pfam]. The remaining 2 mRNA variants (1 spliced, 1 unspliced) appear not to encode good proteins.

Here's the figure showing the various predicted alternatively spliced transcripts and the various different proteins.


It's really difficult to imagine that any of these are biologically relevant. How could a small bit of the large RNA polymerase subunit ever be part of the RNA polymerase protein complex? It's not a surprise that the Entrez Gene annotators have ignored these predictions.

If, as I believe, most of the small ESTs on which these predictions are based are artifacts, then the overall pattern makes sense. What you see are examples of splicing errors where an intron has not been correctly removed. These extremely rare splicing errors are copied into cDNA during construction of EST libraries and specifically selected by screening out all the correctly spliced mRNAs. (That's how you make most EST libraries.)

Here's what AceView says about the gene for the other large subbunit [AceView: POLR2B].

RefSeq annotates one representative transcript (NM included in AceView variant.a), but Homo sapiens cDNA sequences in GenBank, filtered against clone rearrangements, coaligned on the genome and clustered in a minimal non-redundant way by the manually supervised AceView program, support at least 9 spliced variants.

One again, AceView notes that the annotated human genome has ignored the predicted alternative plice variants but maintains that there are at least nine of them.

Here's the figure, decide for yourself whether this is credible.


There are several well-known examples of human genes producing different protein variants due to alternative splicing. The ones I can think of off the top of my head are the genes for class I antigens, α-tropomyosin, and calcitonin. I'm sure there are half a dozen others.

Here's the challenge. See if you can find a human gene for a well-studied protein where the structure of the protein is known and there are multiple protein variants derived by alternative splicing. I bet that readers of Sandwalk can't find very many where the predicted variants many any sense and are likely to be biologically significant.

What does this mean? Whenever you look at your favorite well-studied gene you see that the predictions of alternative splicing are silly. So why should we believe the genome wide analyses? Is it just a coincidence that the more we learn about a given gene the most we become willing to reject the ESTs as artifacts? Or is it possible that alternative splicing is mostly confined to those genes that have not been well studied?

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Monday's Molecule #93

 
What's going on here? Your task is to identify the experiment that led to this result. It's a short step from there to this week's Nobel Laureate(s). You just need to switch species.

Here's a hint: This week's Nobel Laureate(s) and last week's Nobel Laureates have something in common.

You need to describe what you see in the figure as accurately as possible. Then identify the Nobel Laureate(s).

The first one to correctly identify the figure and name the Nobel Laureate(s), wins a free lunch at the Faculty Club. Previous winners are ineligible for one month from the time they first collected the prize. There are four ineligible candidates for this week's reward: Brad Hersh of Clemsen University, Alex Ling of the University of Toronto, Haruhiko Ishii, and Bill Chaney of the University of Nebraska.

THEME:

Nobel Laureates
Send your guess to Sandwalk (sandwalk (at) bioinfo.med.utoronto.ca) and I'll pick the first email message that correctly identifies the molecule and names the Nobel Laureate(s). Note that I'm not going to repeat Nobel Laureate(s) so you might want to check the list of previous Sandwalk postings by clicking on the link in the theme box.

Correct responses will be posted tomorrow. I reserve the right to select multiple winners if several people get it right.

Comments will be blocked for 24 hours. Comments are now open.

UPDATE:The figure shows the result of an experiment where human cells in culture were irradiated with X-rays (Scherthan et al. 2008). There are two obvious chromosomal rearrangements. Breaks and deletions are common in X-ray treated cells. The Nobel Laureate is Hermann Muller who won the prize for creating mutants using X-rays. He worked with Drosophila melanogaster. Only one person got this one right and that person is ineligible.

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[Figure Credit: The figure is from Scherthan et al. (2008)]

Scherthana, H., Hieberb, L., Braselmannb, H., Meinekea, V., and Zitzelsberger, H. (2008) Accumulation of DSBs in γ-H2AX domains fuel chromosomal aberrations. Biochemical and Biophysical Research Communications 371:694-697. [doi:10.1016/j.bbrc.2008.04.127]

Into the Textbooks It Goes

 
This week's issue of Science contains an important paper.

Maier, T,, Leibundgut, M. and B. Nenad (2008) The Crystal Structure of a Mammalian Fatty Acid Synthase. Science 321:1315-1322.

We've known for a long time that this is a very important enzyme and that it's a classic example of a little protein machine combining the activities of may different enzymes in order to carry out the complex reactions of fatty acid synthesis. Here's how I described it in the last edition of my book ...

In bacteria, each reaction in fatty acid synthesis is catalyzed by a discrete monofunctional enzyme. This type of pathway is known as a type II fatty acid synthesis system (FAS II). In animals, the various enzymatic activities are localized to individual domains in a large multifunctional enzyme and the complex is described as a type I fatty acid synthesis system (FAS I). The large animal polypeptide contains the activities of malonyl/acetyl transferase, 3-ketoacyl-ACP synthase, 3-ketoacyl–ACP reductase, 3-hydroxyacyl–ACP dehydratase, enoyl–ACP reductase, and thioesterase. It also contains a phosphopantetheine prosthetic group (ACP) to which the fatty acid chain is attached. Note that the malonyl CoA:ACP transacylase enzyme shown in Figure 16.3 is replaced by a transferase activity in the FAS I complex. This transferase catalyzes a substrate loading reaction where malonyl CoA is covalently attached to the ACP-like domain on the multienzyme polypeptide chain. The eukaryotic enzyme is called fatty acid synthase.

The structure (shown below) will be going right into the textbooks.

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Postmodernism and the Two Cultures

John Wilkins at Evolving Thoughts has some comments about the "two cultures" debate [see Cocktail Parties and the Two Cultures].

While most scientists see the problem as a lack of respect for science, John examines the other side of the coin. Noting that the Sokal Affair often comes up in these discussion, John reacts to the criticism of postmodernism implicit in that reference. It's true that most scientists agree with Alan Sokal that the worst form of postmodernism is an embarrassment to all disciplines, not just the humanities. However, it's also true that humanities (e.g. English, Sociology, Psychology) have been far more lax than the sciences when it comes to intellectual rigor. In that sense, the humanities have lost respect.

John attempts to explain the good things about postmodernism. I understand his point, although I think might be protesting just a bit too much. He concludes with,

There is a cultural divide between the humanities and the sciences, but it is not a simple one. It has to do, ultimately, with respect. The division is between those who respect science, and those who respect the humanities (and the other human-related subjects, like social science, political science and so on). Yes, we in the humanities treat science like a text. This is because, as we are not doing science, we interface with that vibrant tradition via the texts of science, mostly. And we are being, as philosophers, very "meta" about science - that is, we are discussing its discussions, and reflecting upon its reflections. Textualisation is impossible to avoid, although one can correct for it. But some of us respect science. We respect it for the same reason that Locke, Hume, Kant and Mill respected science - it is where the knowledge is gathered (or made, or constructed out of data, etc.), so it is the single most important part of human cognition and social organisation to a philosopher.

Anyone who has spent much time wading through the pious, obscurantist, jargon-filled cant that now passes for 'advanced' thought in the humanities knew it was bound to happen sooner or later: some clever academic, armed with the not-so-secret passwords ('hermeneutics,' 'transgressive,' 'Lacanian,' 'hegemony,' to name but a few) would write a completely bogus paper, submit it to an au courant journal, and have it accepted . . . Sokal's piece uses all the right terms. It cites all the best people. It whacks sinners (white men, the 'real world'), applauds the virtuous (women, general metaphysical lunacy) . . . And it is complete, unadulterated bullshit – a fact that somehow escaped the attention of the high-powered editors of Social Text, who must now be experiencing that queasy sensation that afflicted the Trojans the morning after they pulled that nice big gift horse into their city.

Gary KamiyaYes, it's all about respect. However, I still think scientists are feeling more like Rodney Dangerfield¹ than the average sociologist or philosopher. The way I see it, philosophers and others in the humanities often have a very narrow view of science. It's not that they treat science as just another human endeavor, which is bad enough, it's that they treat science as something that's not a part of their disciplines. This exact point is addressed in a lecture Alan Sokal gave earlier this year [What is science and why should we care?]. "Science" is not just about rocket ships and natural selection, it's a way of thinking. A way of thinking that people in the humanities would be wise to adopt. Sokal says,

At a superficial level you could say that my topic is the relation between science and society; but as I hope will become clear, my deeper theme is the importance, not so much of science, but of the scientific worldview—a concept that Ishall define more precisely in a moment, and which goes far beyond the specific disciplines that we usually think of as "science"—in humanity's collective decision making. I want to argue that clear thinking, combined with a respect for evidence—especially inconvenient and unwanted evidence that challenges our preconceptions—are of the utmost importance to the survival of the human race in the twenty-first century.

Of course, you might think that calling for clear thinking and a respect for evidence is a bit like advocating Motherhood and Aple Pie (if you'll pardon this Americanism)—and in a sense you'd be right. Hardly anyone will openly defend muddled thinking or disrespect for evidence. Rather, what people do is to surround these practices with a fog of verbiage designed to conceal from their listeners—and in most cases, I would imagine, from themselves as well—the true implications of their reasoning.

Sokal has it right, as far as I'm concerned. The war between the two cultures is not just about whether you've read Shakespeare or Einstein, it's about how you think. Either you adopt the scientific worldview that values evidence and rationality, or you practice some form of superstition. In this sense, the humanities are just a part of science and not a separate way of knowing.

Sokal emphasizes this point again and again.

I stress that my use of the term "science" is not limited to the natural sciences, but includes investigations aimed at acquiring accurate knowledge of factual matters relating to any aspect of the world by using rational empirical methods analogous to those employed in the natural sciences.

I don't think John Wilkins would agree with this perspective since it makes philosophy—and all other humanties—just a part of a scientific worldview.²

John continues with his analysis of the two cultures problem.

Scientists often do not respect humanists, either. It is a running gag that PZ or Larry Moran will tweak me and others for being mere philosophers, but the gag is that most scientists really do think philosophy is a waste of funds and office space. Likewise they think the same thing about literary studies, history, social sciences, and in fact everything that is not their own speciality. It's not hard to see this as special pleading, but if scientists want respect, they had better show some. It's not impossible: Ed Wilson and Stephen Jay Gould are just two examples of scientists who - for all their faults - respect the humanities. Nobody has the time or energy (or mental capacity) to become experts in both fields; there's barely enough time to become expert in one subspeciality of one discipline of one field); but we can respect those who do learn those limited domains even if they are not our own. This is a plea for respect too, between the analytic and continental styles of philosophy. Neither is totally stupid nor totally on track. Rather than reject the other styles, perhaps what we should do is mutually support each other to do what we do well.

For the record, I'm much closer to Gould on this issue that it appears. I have a great deal of respect for philosophy, provided that it's done correctly. I would strongly support making philosophy and the study of logic a mandatory course in every university. Similarly, there is much to be learned about human behavior—and, let's face it, we are all interested in ourselves even if we know that we are just one species out of ten million—by studying sociology, English literature, and art history. The problem isn't lack of respect for the subject matter as much as lack of respect for the way the subjects are studied.

I'd also like to point out that I'm an equal opportunity curmudgeon—the best kind, in my opinion. While I don't hesitate to point out the muddle-headedness of philosophers like Michael Ruse and Daniel Dennett who pretend to be scientists, I also don't hesitate to make fun of scientists like Ken Miller and Francis Collins who abuse science to support religion.

In the war between rationalism and superstition there are many in the humanities who are on the wrong side. But there are lots of scientists who are wrong as well. I still think that, as a general proposition, there's more respect for the humanities out there than for science. Our society is educating an entire generation of scientific illiterates who are not only unknowledgeable about basic concepts in science but, in most cases, still quite proud of their ignorance.

The next time you hear someone say that science or math is way too hard for them, you should express your sympathy by saying, "Gee, I'm sorry you're too stupid to understand these things. What can I do to help?"

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1. or Aretha Franklin

2. To put it even more bluntly. All of the humanities is simply concerned with the behavior of one particular species on this planet. It's just one tiny part of life on this planet, which, in turn, is an infinitesimally small part of the universe. Those who think that the philosophy of Plato is more important than understanding evolution have their priorities all screwed up.