Gerald Fink promotes a new definition of a gene

This is the 2019 Killian lecture at MIT, delivered in April 2019 by Gerald Fink. Fink is an eminent scientist who has done excellent work on the molecular biology of yeast. He was director of the prestigious Whitehead Institute at MIT from 1990-2001. With those credentials you would expect to watch a well-informed presentation of the latest discoveries in molecular genetics. Wouldn't you?

What do they mean when they say they want to extend the Modern Synthesis?

As far as I'm concerned, the "Modern Synthesis" has been replaced by modern evolutionary theory that incorporates Nearly-Neutral Theory and random genetic drift as an important mechanism of evolution [see Is the "Modern Synthesis" effectively dead? ]. This extension, and replacement, of the 1940s version of evolutionary theory took place in mainly in the 1970s.

If I'm correct, then why all the fuss in the 21st century about extending the Modern Synthesis?

I think there are two things going on here. First, there are a bunch of biologists who want to incorporate their favorite fad into modern evolutionary theory. They think that their ideas are so revolutionary that this requires an extensive revision of evolutionary theory. Second, those biologists seem to have been asleep during the 1970s when the Modern Synthesis died so they are fighting a strawman.

Watch Jonathan Wells Screw Up

Here's Jonathan Wells attacking the concept of junk DNA during a lecture at Biola University in October 2010. It's remarkable because he repeats a false history that he knows is untrue because many people have corrected him. Pay attention to what he says about four minutes into the presentation.


Wells is talking about the history of junk DNA. He begins by falsely describing the Central Dogma of Molecular Biology, which, he says, is "DNA makes RNA, makes protein, makes us." He then quotes Jacques Monod as a supporter of this concept (4 minutes, 23 seconds).

With that, and the understanding of the random physical basis of mutation that molecular biology has provided, the mechanism of Darwinism is at last securely founded, and man has to understand that he is a mere accident.
Jacque Monod (1970) quoted in "The Eight Day of Creation" by Horace Freeland Judson (p. 192)

I looked up this passage and guess what I found? I discovered that when Monod said "with that" he was referring to the real Central Dogma—the one that Crick actually formulated. Only a few sentences earlier Monod is quoted as saying ...

This was what Francis Crick called the Central Dogma: no information goes from protein to DNA.

This is followed by a brief description of Lamarckism and why it conflicts with the Central Dogma. So Monod has it exactly right, the Central Dogma says that information can only flow from nucleic acid to protein and not vice versa. That rules out the inheritance of applied characteristics and makes "the mechanism of Darwinism ... securely founded."

Why is this important? Because Wells immediately follows this by claiming that ...

... biologists discovered that most human DNA does not code for proteins. Based on the Central Dogma that "DNA makes RNA makes protein makes us," this non-protein-coding DNA was dubbed "junk."

This is nonsense. Not only did the concept of junk DNA have nothing to do with the Central Dogma, it also had nothing to do with "non-coding DNA." By 1970, all knowledgeable molecular biologists knew that there was lots of perfectly functional DNA that did not encode protein. It's simply not true that the consensus opinion among the experts at the time was that all noncoding DNA was junk [Junk & Jonathan: Part 3—The Preface].

There are legitimate debates about the quantity of junk DNA in our genome. What I just don't understand is why IDiots feel they have to distort history in order to make their point. Wouldn't they be a lot more credible if they at least got the simple things right?

Are they pathological liars?

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Quantifying the "central dogma"

There was a short article in a recent issue of Science that caught my eye. The title was "Statistics requantitates the central dogma."

As most Sandwalk readers know, The Central Dogma of Molecular Biology says,

... once (sequential) information has passed into protein it cannot get out again (F.H.C. Crick, 1958)

The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred from protein to either protein or nucleic acid. (F.H.C. Crick, 1970)

You might wonder how you can quantify the idea that once information gets into protein it can't flow back to nucleic acids. You can't, of course.

The authors are referring to the standard scheme of information flow from DNA to RNA to protein. This is often mistakenly referred to as the Central Dogma by those scientists who haven't read the original papers. In this case, the authors of the Science article are asking whether the levels of protein in different cells are mostly controlled at the level of transcription, translation, mRNA degradation, or protein degradation.

ChatGPT won't pass my exams!

Here are a few questions for ChatGPT and its answers. The AI program takes the most common information on the web and spews it back at you. It cannot tell which information is correct or which information is more accurate.

It's easy to recognize that these answers were written by something that's not very good at critical thinking. I agree with other professors that they mimic typical undergraduate answers but I disagree that these answers would get them a passing grade.

ChatGPT shares one very important feature that's common in undergraduate answers to essay questions: it gives you lots of unecessary information that's not directly relevant to the question.

It's important to note that (lol) these ChatGPT answers share another important feature with many of the answers on my exams: they look very much like BS!

The pervasive transcription controversy: 2002

I'm working on a chapter about pervasive transcription and how it relates to the junk DNA debate. I found a short review in Nature from 2002 so I decided to see how much progress we've made in the past 15 years.

Most of our genome is transcribed at some time or another in some tissue. That's a fact we've known about since the late 1960s (King and Jukes, 1969). We didn't know it back then, but it turns out that a lot of that transcription is introns. In fact, the observation of abundant transcription led to the discovery of introns. We have about 20,000 protein-coding genes and the average gene is 37.2 kb in length. Thus, the total amount of the genome devoted to these genes is about 23%. That's the amount that's transcribed to produce primary transcripts and mRNA. There are about 5000 noncoding genes that contribute another 2% so genes occupy about 25% of our genome.

Science misinformation is being spread in the lecture halls of top universities

Should universities remove online courses that contain incorrect or misleading information?

There are lots of scientific controversies where different scientists have conflicting views. Eventually these controversies will be solved by normal scientific means involving evidence and logic but for the time being there isn't enough data to settle a genuine scientific controversy. Many of us are interested in these controversies and some of us have chosen to invest time and effort into defending one side or the other.

But there's a dark side of science that infects these debates—false or misleading information used to support one side of a legitimate controversy. To give just one example, I'm frustrated at the constant reference to junk DNA being defined as non-coding DNA. Many scientists believe that this was the way junk DNA was defined by its earliest proponents and then they go on to say that the recent discovery of functional non-coding DNA refutes junk.

I don't know where this idea came from because there's nothing in the scientific literature from 50 years ago to support such a ridiculous claim. It must be coming from somewhere since the idea is so widespread.

Where does misinformation come from and how is it spread?

James Shapiro Never Learns

One of the remarkable things about kooks is that they are incredibly resistant to learning from their mistakes. James Shapiro gives us a fine example in one of his latest articles on The Huffington Post where he tries to convince us that the old definition of "gene" has outlived its usefulness. According to Shapiro, "DNA and molecular genetics have brought us to a fundamentally new conceptual understanding of genomes, how they are organized and how they function."

Really? While we all can agree that there's no definition of "gene" that doesn't have exceptions, we can surely agree that some definitions work pretty well. I've argued that defining a gene as, "a DNA sequence that is transcribed to produce a functional product" works well in most cases [What Is a Gene?].

Let's see how James Shapiro handles this problem.¹ He says,

The identification of DNA as the key molecule of heredity and Crick's Central Dogma of Molecule Biology [Crick 1970] initially seemed to confirm Beadle and Tatum's "one gene -- one enzyme" hypothesis.

I've already explained that Shapiro doesn't understand the Central Dogma of Molecular Biology even though he quotes the Francis Crick papers that explain it correctly [Revisiting the Central Dogma in the 21st Century]. I also made this point in my review of his book: Evolution: A View from the 21st Century.

What do believers in epigenetics think about junk DNA?

I've been writing some stuff about epigenetics so I've been reading papers on how to define the term [What the heck is epigenetics? ]. Turns out there's no universal definition but I discovered that scientists who write about epigenetics are passionate believers in epigenetics no matter how you define it. Surprisingly (not!), there seems to be a correlation between belief in epigenetics and other misconceptions such as the classic misunderstanding of the Central Dogma of Molecular Biology and rejection of junk DNA [The Extraordinary Human Epigenome]

Here's an illustraton of this correlation from the introduction to a special issue on epigenetics in Philosophical Transactions B.

Ganesan, A. (2018) Epigenetics: the first 25 centuries, Philosophical Transactions B. 373: 20170067. [doi: 10.1098/rstb.2017.0067]

Epigenetics is a natural progression of genetics as it aims to understand how genes and other heritable elements are regulated in eukaryotic organisms. The history of epigenetics is briefly reviewed, together with the key issues in the field today. This themed issue brings together a diverse collection of interdisciplinary reviews and research articles that showcase the tremendous recent advances in epigenetic chemical biology and translational research into epigenetic drug discovery.

In addition to the misconceptions, the text (see below) emphasizes the heritable nature of epigenetic phenomena. This idea of heritablity seems to be a dominant theme among epigenetic believers.

A central dogma became popular in biology that equates life with the sequence DNA → RNA → protein. While the central dogma is fundamentally correct, it is a reductionist statement and clearly there are additional layers of subtlety in ‘how’ it is accomplished. Not surprisingly, the answers have turned out to be far more complex than originally imagined, and we are discovering that the phenotypic diversity of life on Earth is mirrored by an equal diversity of hereditary processes at the molecular level. This lies at the heart of modern day epigenetics, which is classically defined as the study of heritable changes in phenotype that occur without an underlying change in genome sequence. The central dogma's focus on genes obscures the fact that much of the genome does not code for genes and indeed such regions were derogatively lumped together as ‘junk DNA’. In fact, these non-coding regions increase in proportion as we climb up the evolutionary tree and clearly play a critical role in defining what makes us human compared with other species.

At the risk of bearting a dead horse, I'd like to point out that the author is wrong about the Central Dogma and wrong about junk DNA. He's right about the heritablitly of some epigenetic phenomena such as methylation of DNA but that fact has been known for almost five decades and so far it hasn't caused a noticable paradigm shift, unless I missed it [Restriction, Modification, and Epigenetics].

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Do the IDiots Understand Biochemistry and Molecular Biology?

 

We've been discussing whether Intelligent Design Creationists understand enough about biochemistry, molecular biology, and evolution to warrant their criticisms of these fields. The answer is clearly "no" as they demonstrate time and time again.

This time it's an anonymous posting on the premier IDC website, Evolution News & Views [Long Non-coding RNA Punches Another Hole in "Junk Genome" Myth]. The anonymous poster links to a recent paper in Genes & Development that shows a function for a particular long non-coding (lnc) RNA. The paper implies that many of these lncRNAs (up to 400) are expressed in mouse erythroid cells.

Regulatory RNA have been known and studied for at least four decades and various lncRNAs have been characterized over the past twenty years. The IDiot at Evolution News & Views seems to think that this is a new discovery proving that there's no junk in our genome. The facts are quite different.

As I pointed out in my review of The Myth of Junk DNA, the amount of the genome devoted to producing lncRNAs is about 0.1% [Junk & Jonathan: Part 6—Chapter 3]. So, not only have we known about regulatory RNAs for many years, we also know that their genes don't account for very much of the genome, I figure it can't be more than 2% even when you include all of the most optimistic estimates of regulatory RNAs [see What's in Your Genome?].

But the ignorance of the IDiots is much more profound than just being incapable of calculating percentages. The latest posting reveals the depth of their ignorance.

These findings have two important implications. First, non-coding regions of the genome were assumed to be leftover evolutionary relics that no longer play a functional role. The assumption was not due to extensive studies of non-coding regions of the genome, but rather to a commitment to what is known as the central dogma of molecular biology: DNA is transcribed into RNA and RNA is translated into amino acids to make proteins. This was considered the primary purpose of DNA. The non-coding regions were assumed to have no function, and were dismissed as the natural consequence of genetic "junk" accumulating over time. This paper is one among an accumulating corpus of papers discussing new and interesting functions of the non-coding regions of the genome. (See The Myth of Junk DNA by Jonathan Wells for a history of "junk" DNA and additional references describing the function of so-called "junk" DNA. See here for a discussion on the regulatory role of introns.)

There was never a time in the past fifty years when knowledgeable biochemists and molecular biologists thought that all non-coding DNA was nonfunctional junk. This was never an assumption of the Central Dogma of Molecular Biology which states that "... once (sequential) information has passed into protein it cannot get out again" [Basic Concepts: The Central Dogma of Molecular Biology]. There are many scientists who have misconceptions about the Central Dogma [The Central Dogma Strawman] but the IDiots go one step farther by misunderstanding the misconception!

We've known about functions in non-coding DNA since the early 1960s as anyone who has ever glanced at a textbook would know. It's hard to tell whether the IDiots are just butt-ignorant of basic science or whether they are lying. This is an especially tricky problem when the silly strawman argument is popularized by Jonathan Wells because he's supposed to know the science [Junk & Jonathan: Part 1—Getting the History Correct] [Junk & Jonathan: Part 2— What Did Biologists Really Say About Junk DNA?].

We know that most of our genome is junk because we know a great deal about genomes, genes, biochemistry, molecular biology, and evolution. We know which parts are likely to be functional and which parts are likely to be broken genes and other kinds of junk. We know this because we understand the subject, not because we are covering up our ignorance.

The IDiots are ignorant of the science and they assume that everyone else is as well. That's a very bad assumption.

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Three Cheers for October's SEED Magazine

 
One of my pet peeves is the misuse of the term "Central Dogma of Molecular Biology" [Basic Concepts: The Central Dogma of Molecular Biology]. Most people define it as the flow of information from DNA to RNA to protein. Many then go on to declare that the Central Dogma has been overthrown because of reverse transcriptase, alternative splicing, microRNA, epigenetics, or whatever.

This month's issue of SEED has a tear-out summary (cribsheet) of "Genetics." In one of the boxes titled "The Central Dogma of Molecular Biology" there's a drawing of the major pathways of information flow. The caption says.

There are nine ways information can theoretically flow between DNA, RNA, and protein. Of these, three are seen throughout nature, DNA to DNA (replication), DNA to RNA (transcription), and RNA to protein (translation). Three more are known to occur in special circumstances like viruses or laboratory experiments (RNA to RNA, RNA to DNA, and DNA to protein). Flows of information from protein have not been observed. The trend is clear: information flow from DNA or RNA into protein is irreversible. This is known as the "central dogma," and forms the foundation of molecular biology.

Yeah! As far as I know this is the only popular magazine to get it right.

Some Questions for IDiots

Here's a short quiz for proponents of Intelligent Design Creationism. Let's see if you have been paying attention to real science. Please try to answer the questions below. Supporters of evolution should refrain from answering for a few days in order to give the creationists a chance to demonstrate their knowledge of biology and of evolution.

The bloggers at Evolution News & Views (sic) are promoting another creationist book [see Biological Information]. This time it's a collection of papers from a gathering of creationists held in 2011. The title of the book, Biological Information: New Perspectives suggests that these creationists have learned something new about biochemistry and molecular biology.

One of the papers is by Jonathan Wells: Not Junk After All: Non-Protein-Coding DNA Carries Extensive Biological Information. Here's part of the opening paragraphs.

James Watson and Francis Crick’s 1953 discovery that DNA consists of two complementary strands suggested a possible copying mechanism for Mendel’s genes [1,2]. In 1958, Crick argued that “the main function of the genetic material” is to control the synthesis of proteins. According to the “ Sequence Hypothesis,” Crick wrote that the specificity of a segment of DNA “is expressed solely by the sequence of bases,” and “this sequence is a (simple) code for the amino acid sequence of a particular protein.” Crick further proposed that DNA controls protein synthesis through the intermediary of RNA, arguing that “the transfer of information from nucleic acid to nucleic acid, or from nucleic acid to protein may be possible, but transfer from protein to protein, or from protein to nucleic acid, is impossible.” Under some circumstances RNA might transfer sequence information to DNA, but the order of causation is normally “DNA makes RNA makes protein.” Crick called this the “ Central Dogma” of molecular biology [3], and it is sometimes stated more generally as “DNA makes RNA makes protein makes us.”

The Sequence Hypothesis and the Central Dogma imply that only protein-coding DNA matters to the organism. Yet by 1970 biologists already knew that much of our DNA does not code for proteins. In fact, less than 2% of human DNA is protein-coding. Although some people suggested that non-protein-coding DNA might help to regulate gene expression, the dominant view was that non-protein-coding regions had no function. In 1972, biologist Susumu Ohno published an article wondering why there is “so much ‘ junk’ DNA in our genome” [4].

1. Crick published a Nature paper on The Central Dogma of Molecular Biology in 1970. Did he and most other molecular biologists actually believe that "only protein-coding DNA matters to the organism?"
2. Did Crick really say that "DNA makes RNA makes protein" is the Central Dogma or did he say that this was the Sequence Hypothesis? Read the paper to get the answer—the link is below).
3. Is it true that, in 1970, the majority of molecular biologists did not believe in repressor and activator binding sites (regulatory DNA)?
4. Is it true that in 1970 molecular biologists knew nothing about the functional importance of non-transcribed DNA sequences such as centromeres and origins of DNA replication?
5. It is true that most molecular biologists in 1970 had never heard of genes for ribosomal RNAs and tRNAs (non-protein-coding genes)?
6. If the answer to any of those questions contradicts what Jonathan Wells is saying then why do you suppose he said it?

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Crick, F. (1970) Central Dogma of Molecular Biology. Nature 227:561-563. [PDF]

John Mattick's paradigm shaft

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.

Subhash Lakhotia: The concept of 'junk DNA' becomes junk

Continuing my survey of recent papers on junk DNA, I stumbled upon a review by Subash Lakhotia that has recently been accepted in The Proceedings of the Indian National Science Academy (Lakhotia, 2018). It illustrates the extent of the publicity campaign mounted by ENCODE and opponents of junk DNA. In the title of this post, I paraphrased a sentence from the abstract that summarizes the point of the paper; namely, that the 'recent' discovery of noncoding RNAs refutes the concept of junk DNA.

Lakhotia claims to have written a review of the history of junk DNA but, in fact, his review perpetuates a false history. He repeats a version of history made popular by John Mattick. It goes like this. Old-fashioned scientists were seduced by Crick's central dogma into thinking that the only important part of the genome was the part encoding proteins. They ignored genes for noncoding RNAs because they didn't fit into their 'dogma.' They assumed that most of the noncoding part of the genome was junk. However, recent new discoveries of huge numbers of noncoding RNAs reveal that those scientists were very stupid. We now know that the genome is chock full of noncoding RNA genes and the concept of junk DNA has been refuted.

The Salzburg sixty discuss a new paradigm in genetic variation

Sixty evolutionary biologists are going to meet next July in Salzburg (Austria)to discuss "a new paradigmatic understanding of genetic novelty" [Evolution – Genetic Novelty/Genomic Variations by RNA Networks and Viruses]. You probably didn't know that a new paradigm is necessary. That's because you didn't know that the old paradigm of random mutations can't explain genetic diversity. (Not!) Here's how the symposium organizers explain it on their website ...

Junk DNA doesn't exist according to "Conceptual Revolutions in Science"

The blog "Conceptual Revolutions in Science" only publishes "evidence-based, paradigm-shifting scientific news" according to their home page.

The man behind the website is Adam B. Dorfman (@DorfmanAdam). He has an MBA from my university and he currently works at a software company. Here's how he describes himself on the website.

The Central Dogma according to Riken

You may never have heard of Riken. Here's what they say on their website [Riken] ...

RIKEN is Japan's largest comprehensive research institution renowned for high-quality research in a diverse range of scientific disciplines. Founded in 1917 as a private research foundation in Tokyo, RIKEN has grown rapidly in size and scope, today encompassing a network of world-class research centers and institutes across Japan.

They've published a video on the Central Dogma. Here's how they describe it ...

The 'Central Dogma' of molecular biology is that 'DNA makes RNA makes protein'. This anime shows how molecular machines transcribe the genes in the DNA of every cell into portable RNA messages, how those messenger RNA are modified and exported from the nucleus, and finally how the RNA code is read to build proteins.

The video was made by RIKEN Omics Science Center (RIKEN OSC) for the exhibition titled 'Beyond DNA' held at National Science Museum of Japan. RIKEN OSC has published in Nature Genetics on the regulation of RNA expression in human cancer cells.

Most of you know that I have a different view of The Central Dogma of Molecular Biology but that's not what I want to discuss here. Watch the video. Do you think it's a good idea to show this process as well-designed little machines and ships? It sure gets the IDiots excited {RIKEN’s 10-minute antidote to atheism: see for yourself].

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Better Biochemistry

This is a "Theme" post where I collect all previous posts on teaching biochemistry and molecular biology.

March 22, 2015
On the handedness of DNA

March 5, 2015
Don't misuse the word "homology"

January 28, 2015
Vision and Change

January 28, 2015
Evidence-based teaching

January 15, 2015
The Nature of Science (NOS)

January 11, 2015
Why can't we teach properly?

January 8, 2015
Evolutionary biochemistry and the importance of random genetic drift

January 3, 2015
Thinking critically about the Central Dogma of Molecular Biology

December 9, 2014
On the meaning of pH optima for enzyme activity

December 9, 2014
On the specificity of enzymes

December 4, 2014
How to revolutionize education

October 20, 2014
How not to teach biochemistry

October 3, 2014
Metabolism first and the origin of life

September 11, 2014
The mystery of Maud Menten

August 8, 2014
Historical contingency and the evolution of the glucocorticoid receptor

July 28, 2014
Finding the "perfect" enzyme

Jun 2, 2014
"Flipping the classroom": what does that mean?

April 25, 2014
ASBMB Core Concepts in Biochemistry and Molecular Biology: Molecular Structure and Function

April 24, 2014
ASBMB Core Concepts in Biochemistry and Molecular Biology: Biological Information

March 21, 2014
ASBMB Core Concepts in Biochemistry and Molecular Biology: Homeostasis

March 5, 2014
The crystal structure of E. coli RNA polymearse σ70 holoenzyme

January 10, 2014
How not to teach biochemistry at memorize.com

December 9, 2013
Monday's Molecule #226

December 6, 2013
Die, selfish gene, die!

December 6, 2013
Do you understand this Nature paper on transcription factor binding in different mouse strains?

December 2, 2013
Monday's Molecule #225

November 12, 2013
David Evans Says, "Teach What the Vast Majority of Scientists Affirm as Settled Science"

November 5, 2013
Stop Using the Term "Noncoding DNA:" It Doesn't Mean What You Think It Means

October 30, 2013
Time to Re-Write the Textbooks! Nature Publishes a New Version of the Citric Acid Cycle

October 29, 2013
The Khan Academy and AAMC Teach Evolution in Preparation for the MCAT

October 29, 2013
The Khan Academy and AAMC Teach the Central Dogma of Molecular Biology in Preparation for the MCAT

October 29, 2013
The Khan Academy and the Association of American Medical Colleges (AAMC) Team Up to Teach Evolution and Biochemistry for the New MCAT

October 24, 2013
ASBMB Core Concepts in Biochemistry and Molecular Biology: Matter and Energy Transformation

October 15, 2013
ASBMB Core Concepts in Biochemistry and Molecular Biology: Evolution

October 14, 2013
Fundamental Concepts in Biochemistry and Molecular Biology

October 11, 2013
ASBMB Promotes Concept Driven Teaching Strategies in Biochemistry and Molecular Biology

Another curious aspect of the theory of evolution is that everybody thinks he understands it. I mean philosophers, social scientists, and so on. While in fact very few people understand it, actually, as it stands, even as it stood when Darwin expressed it, and even less as we now may be able to understand it in biology. Jacques Monod (1974)October 8, 2013
On the Importance of Defining Evolution

October 6, 2013
Teaching Biochemistry from an Intelligent Design Creationist Perspective

October 1, 2013
The Many Definitions of Evolution

September 30. 2013
The Problems With The Selfish Gene

September 18, 2013
Breaking News!!! Wikipedia Is Wrong! (about the Central Dogma)

September 13, 2013
Sean Carroll: 'What Is Science?"

September 13, 2013
Better Biochemistry: Teaching ATP Hydrolysis for the MCAT

September 12, 2013
Better Biochemistry: Teaching to the MCAT?

June 27, 2013
The Best Enzyme

April 16, 2013
Where Do Organisms Get Their Energy?

April 10, 2013
Spontaneous Degradation of DNA

March 18, 2013
Estimating the Human Mutation Rate: Biochemical Method

The fuzzy thinking of John Parrington: pervasive transcription

Opponents of junk DNA usually emphasize the point that they were surprised when the draft human genome sequence was published in 2001. They expected about 100,000 genes but the initial results suggested less than 30,000 (the final number is about 25,000¹. The reason they were surprised was because they had not kept up with the literature on the subject and they had not been paying attention when the sequence of chromosome 22 was published in 1999 [see Facts and Myths Concerning the Historical Estimates of the Number of Genes in the Human Genome].

The experts were expecting about 30,000 genes and that's what the genome sequence showed. Normally this wouldn't be such a big deal. Those who were expecting a large number of genes would just admit that they were wrong and they hadn't kept up with the literature over the past 30 years. They should have realized that discoveries in other species and advances in developmental biology had reinforced the idea that mammals only needed about the same number of genes as other multicellular organisms. Most of the differences are due to regulation. There was no good reason to expect that humans would need a huge number of extra genes.

That's not what happened. Instead, opponents of junk DNA insist that the complexity of the human genome cannot be explained by such a low number of genes. There must be some other explanation to account for the the missing genes. This sets the stage for at least seven different hypotheses that might resolve The Deflated Ego Problem. One of them is the idea that the human genome contains thousands and thousands of nonconserved genes for various regulatory RNAs. These are the missing genes and they account for a lot of the "dark matter" of the genome—sequences that were thought to be junk.

Here's how John Parrington describes it on page 91 of his book.

The study [ENCODE] also found that 80 per cent of the genome was generating RNA transcripts having importance, many were found only in specific cellular compartments, indicating that they have fixed addresses where they operate. Surely there could hardly be a greater divergence from Crick's central dogma than this demonstration that RNAs were produced in far greater numbers across the genome than could be expected if they were simply intermediates between DNA and protein. Indeed, some ENCODE researchers argued that the basic unit of transcription should now be considered as the transcript. So Stamatoyannopoulos claimed that 'the project has played an important role in changing our concept of the gene.'

This passage illustrates my difficulty in coming to grips with Parrington's logic in The Deeper genome. Just about every page contains statements that are either wrong or misleading and when he strings them together they lead to a fundamentally flawed conclusion. In order to critique the main point, you have to correct each of the so-called "facts" that he gets wrong. This is very tedious.

I've already explained why Parrington is wrong about the Central Dogma of Molecular Biology [John Avise doesn't understand the Central Dogma of Molecular Biology]. His readers don't know that he's wrong so they think that the discovery of noncoding RNAs is a revolution in our understanding of biochemisty—a revolution led by the likes of John A. Stamatoyannopoulos in 2012.

The reference in the book to the statement by Stamatoyannopoulos is from the infamous Elizabeth Pennisi article on ENCODE Project Writes Eulogy for Junk DNA (Pennisi, 2012). Here's what she said in that article ...

As a result of ENCODE, Gingeras and others argue that the fundamental unit of the genome and the basic unit of heredity should be the transcript—the piece of RNA decoded from DNA—and not the gene. “The project has played an important role in changing our concept of the gene,” Stamatoyannopoulos says.

I'm not sure what concept of a gene these people had before 2012. It appears that John Parrington is under the impression that genes are units that encode proteins and maybe that's what Pennisi and Stamatoyannopoulos thought as well.

If so, then perhaps the publicity surrounding ENCODE really did change their concept of a gene but all that proves is that they were remarkably uniformed before 2012. Intelligent biochemists have known for decades that the best definition of a gene is "a DNA sequence that is transcribed to produce a functional product."² In other words, we have been defining a gene in terms of transcripts for 45 years [What Is a Gene?].

This is just another example of wrong and misleading statements that will confuse readers. If I were writing a book I would say, "The human genome sequence confirmed the predictions of the experts that there would be no more than 30,000 genes. There's nothing in the genome sequence or the ENCODE results that has any bearing on the correct understanding of the Central Dogma and there's nothing that changes the correct definition of a gene."

You can see where John Parrington's thinking is headed. Apparently, Parrington is one of those scientists who were completely unaware of the fact that genes could specify functional RNAs and completely unaware of the fact that Crick knew this back in 1970 when he tried to correct people like Parrington. Thus, Parrington and his colleagues were shocked to learn that the human genome only had only 25,000 genes and many of them didn't encode proteins. Instead of realizing that his view was wrong, he thinks that the ENCODE results overthrew those old definitions and changed the way we think about genes. He tries to convince his readers that there was a revolution in 2012.

Parrington seems to be vaguely aware of the idea that most pervasive transcription is due to noise or junk RNA. However, he gives his readers no explanation of the reasoning behind such a claim. Spurious transcription is predicted because we understand the basic concept of transcription initiation. We know that promoter sequences and transcription binding sites are short sequences and we know that they HAVE to occur a high frequency in large genomes just by chance. This is not just speculation. [see The "duon" delusion and why transcription factors MUST bind non-functionally to exon sequences and How RNA Polymerase Binds to DNA]

If our understanding of transcription initiation is correct then all you need is a activator transcription factor binding site near something that's compatible with a promoter sequence. Any given cell type will contain a number of such factors and they must bind to a large number of nonfunctional sites in a large genome. Many of these will cause occasional transcription giving rise to low abundance junk RNA. (Most of the ENCODE transcripts are present at less than one copy per cell.)

Different tissues will have different transcription factors. Thus, the low abundance junk RNAs must exhibit tissue specificity if our prediction is correct. Parrington and the ENCODE workers seem to think that the cell specificity of these low abundance transcripts is evidence of function. It isn't—it's exactly what you expect of spurious transcription. Parrington and the ENCODE leaders don't understand the scientific literature on transription initiation and transcription factors binding sites.

It takes me an entire blog post to explain the flaws in just one paragraph of Parrington's book. The whole book is like this. The only thing it has going for it is that it's better than Nessa Carey's book [Nessa Carey doesn't understand junk DNA].

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1. There are about 20,000 protein-encoding genes and an unknown number of genes specifying functional RNAs. I'm estimating that there are about 5,000 but some people think there are many more.

2. No definition is perfect. My point is that defining a gene as a DNA sequence that encodes a protein is something that should have been purged from textbooks decades ago. Any biochemist who ever thought seriously enough about the definition to bring it up in a scientific paper should be embarrassed to admit that they ever believed such a ridiculous definition.

Pennisi, E. (2012) "ENCODE Project Writes Eulogy for Junk DNA." Science 337: 1159-1161. [doi:10.1126/science.337.6099.1159"]

DNA: Nature Celebrates Ignorance

Some freelance science writer named Philip Ball has published an article in the April 25, 2013 issue of Nature: Celebrate the Unknowns.

The main premise of the article is revealed in the short blurb under the title: "On the 60th anniversary of the double helix, we should admit that we don't fully understand how evolution works at the molecular level, suggests Philip Ball."

What nonsense! We understand a great deal about how evolution works at the molecular level. Perhaps Philip Ball meant to say that we don't understand the historical details of how a particular genome evolved, but even that's misleading.

I've commented before on articles written by Philip Ball. In the past, he appeared to be in competition with Elizabeth Pennisi of Science for some kind of award for misunderstanding the human genome.

SEED and the Central Dogma of Molecular Biology - I Take Back My Praise
Shoddy But Not "Junk"?

Let's look at what the article says ...