The great junk DNA debate

I've been talking to philosophers lately about the true state of the junk DNA controversy. I imagine what it would be like to stage a great debate on the topic. It's easy to come up with names for the pro-junk side; Dan Graur, Ford Doolittle, Sean Eddy, Ryan Gregory etc. It's hard to think of any experts who could defend the idea that most of our genome is functional. The only scientist I can think of who would accept such a challenge is John Mattick but let's imagine that he could find three others to join him in the great debate.

I claim that the debate would be a rout for the pro-junk side. The data and the theories are all on the side of those who would argue that 90% of our genome is junk. I don't think the functionalists could possibly defend the idea that most of our genome is functional. What do you think?

Assuming that I'm right, why is it that the average scientist doesn't know this? Why do they still believe there's a good case for function when none of the arguments stand up to close scrutiny? And why are philosophers not conveying the true state of the controversy to their readers? I'm told that anti-junk philosophers like Evelyn Fox Keller are held in high regard even though her arguments are easy to refute [When philosophers talk about genomes]. I'm told that John Mattick is highly respected in philosophy circles even though knowledgeable scientists have little use for his writings.

Can readers help me identify papers by philosophers of science that come down on the side of junk DNA and conclude that experts like Graur, Doolittle, etc are almost certainly correct?

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Image Credit: The cartoon is by Tom Gauld and it was published online at the The New York Times Magazine website. I hope they will consider it fair use on an educational blog. See: Junk DNA comments in the New York Times Magazine.

Alternative splicing and the gene concept

I just learned about a workshop scheduled for the end of this month. The topic is: Evolutionary Roles of Transposable Elements and Non-coding DNA: The Science and the Philosophy.

I'd love to attend but it's a just small workshop designed to encourage dialogue between scientists and philosophers who are interested in the topic. Here's a list of the speakers ...

• Ryan Gregory: Junk DNA, genome size, and the onion test.
• Stefan Linquist: Four decades debating junk DNA and the Phenotype Paradigm is (somehow) alive and well.
• Chris Ponting: 92.9% of the human genome evolved neutrally.
• Paul Griffiths: Both adaptation and adaptivity are relevant to diagnosing function.
• Ford Doolittle: Selfish genes and selfish DNA: is there a difference?
• Justin Garson: Biological functions, the liberality problem, and transposable elements.
• Joyce Havstad: Evolutionary Thinking about Critique of Function Talk.
• Guillame Bourque: Impact of transposable elements on human gene regulatory networks.
• Ulrich Stegman: On parity, genetic causation and coding.
• Steven Downes: Understanding non-coding variants as disease risk alleles.
• Alexander Palazzo: How nuclear retention and cytoplasmic export of RNAs reduces the deleteriousness of junk DNA.
• David Haig: Pax somatica
• Cedric Feschotte: Transposable elements as catalysts of genome evolution.

Who wants "A Sad Case: Owen vs Huxley" pamphlet and a possible Darwin letter?

A friend has a neighbor who's in possession of a pamphlet from 1863 on the Owen vs Huxley debate. The text of the pamphlet is here: A Report of A SAD CASE, Recently tried before the Lord Mayor, OWEN versus HUXLEY, In which will be found fully given the Merits of the great Recent BONE CASE. A photocopy of the pamphlet is shown below along with a possible letter from Charles Darwin (I have not authenticated the letter).

The owners are willing to donate the material to a worthy cause, preferably a museum if it's valuable. Does anyone know of a worthy home?

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How many protein-coding genes in the human genome?

The three main human databases (GENCODE/Ensembl, RefSeq, UniProtKB) contain a total of 22,210 protein-coding genes but only 19,446 of these genes are found in all three databases. That leaves 2764 potential genes that may or may not be real. A recent publication suggests that most of them are not real genes (Abascal et al., 2018). The issue is the same problem that I discussed in recent posts [Disappearing genes: a paper is refuted before it is even published] [Nature falls (again) for gene hype].

Nature falls (again) for gene hype

Nature is arguably the most prestigious science journal. Articles published in Nature are widely perceived to be correct, unbiased, and factual. This perception is certainly true of articles that appear in the News section of the journal since these article are presumably written by expert science writers who have evaluated the new study and decided that it's worth reporting.

Sandwalk readers know that this perception is false (fake news). It turns out that science writers who publish in Nature are not very much better than science writers in general and that's not good.

I recently published a post about an extraordinary claim concerning the number of human genes [Disappearing genes: a paper is refuted before it is even published ]. It concerns a paper posted on an archive site claiming to have found 4,998 new genes of which 1,178 are new protein-coding genes (Pertea et. al., 2018). About five weeks later another paper was posted that effectively refuted the claim of new protein-coding genes (Jungreis et al., 2018). In between publication of those two papers, a freelance science writer, Cassandra Willyard, wrote an article for Nature News that covered the original claim of 4,998 new genes [New human gene tally reignites debate].

Let's see how she handled the controversy.

Disappearing genes: a paper is refuted before it is even published

Several readers alerted me to a paper that was posted on bioRxiv a few weeks ago (May 28, 2018). The paper claimed that the human genome contains 43,162 genes consisting of 21,306 protein-coding genes and 21,856 noncoding genes. The authors reported that they had discovered 3,819 new noncoding genes and 1,178 new protein-coding genes. In addition, they claim to have discovered 97,511 new splice variants raising the total number of splice variants to 12.5 per protein-coding gene although they seem to suggest that almost one-third of these splice variants are non-functional splicing errors. The most striking result, according to the authors, is that 95% of all transcripts are just transcriptional noise.

Here's the paper ...

Press release from the Francis Crick Institute misrepresents junk DNA

Press releases have become a serious problem. I'm frequently upset whenever I read a press release covering a field I'm familiar with. They rarely do a good job of explaining what's actually in the paper and putting it into the proper context. The people who write press releases are more concerned with sensationalizing the work than they are with teaching the general public about how science works. They often do this with the blessing and participation of the scientists who did the work.

Let me illustrate the problem using a recent examples from the Francis Crick Institute in London, UK [Non-coding DNA changes the genitals you're born with]. The press release covers a recent Science paper from the Lovell-Badge lab ....

Is lateral gene transfer (LGT) Lamarckian?

There's an interesting discussion going on about lateral gene transfer (LGT) in eukaryotes. LGT is the process by which DNA from one species invades the genome of another species. It was apparently very common among primitive bacteria several billion years ago and it's still quite common in modern bacteria.

There are many reports of LGT in eukaryotes but some of them seem to be due to contamination from bacteria rather than true LGT. Many scientists are skeptical of these reports; notably Bill Martin (Heinrich Heine Universität, Düsseldorf, Germany) who suggests that almost all of them are artifacts and lateral gene transfer in eukaryotes is extremely rare [see Lateral gene transfer in eukaryotes - where's the evidence?].

Fixing carbon by reversing the citric acid cycle

The citric acid cycle¹ is usually taught as depicted in the diagram on the right.² A four-carbon compound called oxaloaceate is joined to a two-carbon compound called acetyl-CoA to produce a six-carbon tricarboxylic acid called citrate. In subsequent reactions, two carbons are released in the form of carbon dioxide to regenerate the original oxaloacetate. The cycle then repeats. The reactions produce one ATP equivalent (ATP or GTP), three NADH molecules, and one QH₂ molecule.

The GTP/ATP molecule and the reduced coenzymes (NADH and QH₂) are used up in a variety of other reactions. In the case of NADH and QH₂, one of the many pathways to oxidation is the membrane-associated electron transport system that creates a proton gradient across a membrane. The electron transport complexes are buried in membranes—plasma and internal membranes in bacteria and the inner mitochondrial membrane in eukaryotes. Students are often taught that this is the only fate of NADH and QH₂ but that's not true.

One of the other common misconceptions is that the citric acid cycle runs exclusively in one direction; namely, the direction shown in the diagram. That's also not true. The reactions of the citric acid cycle are near-equilibrium reactions like most reactions in the cell. What this means is that the concentrations of the reactants and products are close to the equilibrium values so that a slight increase in one of them will lead to a rapid equilibration. The reactions can run in either direction.³

Philosophers talking about genes

It's important to define what you mean when you use the word "gene." I use the molecular definition since most of what I write refers to DNA sequences. There's no perfect definition but, for most purposes, a good working definition is: A gene is a DNA sequence that is transcribed to produce a functional product. [What Is a Gene?].

There are two types of genes: protein-coding genes and those that specify a functional noncoding RNA (i.e ribosomal RNA, lincRNA). The gene is the part of the DNA that's transcribed so it includes introns. Transcription is controlled by regulatory sequences such as promoters, operators, and enhancers but these are not part of the gene.

In addition to genes, there are many other functional parts of the genome. In the case of eukaryotic genomes, these include centromeres, telomeres, origins of replication, SARs, and some other bits. None of this is new ... these functions have been known for decades and the working definition I use has been common among knowledgeable experts for half-a-century. Scientists know what they are talking about when they say that the human genome contains about 20,000 protein-coding genes and at least 5,000 genes for non-coding RNAs. They are comfortable with the idea that our genome has lots of other functional regions that lie outside of the genes.

Non-experts may not be familiar with the topic and they may have many misconceptions about genes and DNA sequences but we don't base our science on the views of non-experts.

Because of my interest in this topic, I was intrigued by the title of a new book, The Gene: from Genetics to Postgenomics. I ordered it a soon as I heard about it and I've just finished reading it. The version I read has been translated from German by Adam Bostanci.

Required reading for the junk DNA debate

This is a list of scientific papers on junk DNA that you need to read (and understand) in order to participate in the junk DNA debate. It's not a comprehensive list because it's mostly papers that defend junk DNA and refute arguments for massive amounts of function. The only exception is the paper by Mattick and Dinger (2013).¹ It's the only anti-junk paper that attempts to deal with the main evidence for junk DNA. If you know of any other papers that make a good case against junk DNA then I'd be happy to include them in the list.

If you come across a publication that argues against junk DNA, then you should immediately check the reference list. If you do not see some of these references in the list, then don't bother reading the paper because you know the author is not knowledgeable about the subject.

Brenner, S. (1998) Refuge of spandrels. Current Biology, 8:R669-R669. [PDF]

Brunet, T.D., and Doolittle, W.F. (2014) Getting “function” right. Proceedings of the National Academy of Sciences, 111:E3365-E3365. [doi: 10.1073/pnas.1409762111]

Casane, D., Fumey, J., et Laurenti, P. (2015) L’apophénie d’ENCODE ou Pangloss examine le génome humain. Med. Sci. (Paris) 31: 680-686. [doi: 10.1051/medsci/20153106023] [The apophenia of ENCODE or Pangloss looks at the human genome]

Cavalier-Smith, T. (1978) Nuclear volume control by nucleoskeletal DNA, selection for cell volume and cell growth rate, and the solution of the DNA C-value paradox. Journal of Cell Science, 34(1), 247-278. [doi: PDF]

Doolittle, W.F. (2013) Is junk DNA bunk? A critique of ENCODE. Proc. Natl. Acad. Sci. (USA) published online March 11, 2013. [PubMed] [doi: 10.1073/pnas.1221376110]

Doolittle, W.F., Brunet, T.D., Linquist, S., and Gregory, T.R. (2014) Distinguishing between “function” and “effect” in genome biology. Genome biology and evolution 6, 1234-1237. [doi: 10.1093/gbe/evu098]

Doolittle, W.F., and Brunet, T.D. (2017) On causal roles and selected effects: our genome is mostly junk. BMC biology, 15:116. [doi: 10.1186/s12915-017-0460-9]

Eddy, S.R. (2012) The C-value paradox, junk DNA and ENCODE. Current Biology, 22:R898. [doi: 10.1016/j.cub.2012.10.002]

Eddy, S.R. (2013) The ENCODE project: missteps overshadowing a success. Current Biology, 23:R259-R261. [10.1016/j.cub.2013.03.023]

Graur, D. (2017) Rubbish DNA: The functionless fraction of the human genome Evolution of the Human Genome I (pp. 19-60): Springer. [doi: 10.1007/978-4-431-56603-8_2 (book)] [PDF]

Graur, D. (2017) An upper limit on the functional fraction of the human genome. Genome Biology and Evolution, 9:1880-1885. [doi: 10.1093/gbe/evx121]

Graur, D., Zheng, Y., Price, N., Azevedo, R. B., Zufall, R. A., and Elhaik, E. (2013) On the immortality of television sets: "function" in the human genome according to the evolution-free gospel of ENCODE. Genome Biology and Evolution published online: February 20, 2013 [doi: 10.1093/gbe/evt028

Graur, D., Zheng, Y., and Azevedo, R.B. (2015) An evolutionary classification of genomic function. Genome Biology and Evolution, 7:642-645. [doi: 10.1093/gbe/evv021]

Gregory, T. R. (2005) Synergy between sequence and size in large-scale genomics. Nature Reviews Genetics, 6:699-708. [doi: 10.1038/nrg1674]

Haerty, W., and Ponting, C.P. (2014) No Gene in the Genome Makes Sense Except in the Light of Evolution. Annual review of genomics and human genetics, 15:71-92. [doi:10.1146/annurev-genom-090413-025621]

Hurst, L.D. (2013) Open questions: A logic (or lack thereof) of genome organization. BMC biology, 11:58. [doi:10.1186/1741-7007-11-58]

Kellis, M., Wold, B., Snyder, M.P., Bernstein, B.E., Kundaje, A., Marinov, G.K., Ward, L.D., Birney, E., Crawford, G. E., and Dekker, J. (2014) Defining functional DNA elements in the human genome. Proc. Natl. Acad. Sci. (USA) 111:6131-6138. [doi: 10.1073/pnas.1318948111]

Mattick, J. S., and Dinger, M. E. (2013) The extent of functionality in the human genome. The HUGO Journal, 7:2. [doi: 10.1186/1877-6566-7-2]

Five Things You Should Know if You Want to Participate in the Junk DNA DebateMorange, M. (2014) Genome as a Multipurpose Structure Built by Evolution. Perspectives in biology and medicine, 57:162-171. [doi: 10.1353/pbm.2014.000]

Niu, D. K., and Jiang, L. (2012) Can ENCODE tell us how much junk DNA we carry in our genome?. Biochemical and biophysical research communications 430:1340-1343. [doi: 10.1016/j.bbrc.2012.12.074]

Ohno, S. (1972) An argument for the genetic simplicity of man and other mammals. Journal of Human Evolution, 1:651-662. [doi: 10.1016/0047-2484(72)90011-5]

Ohno, S. (1972) So much "junk" in our genome. In H. H. Smith (Ed.), Evolution of genetic systems (Vol. 23, pp. 366-370): Brookhaven symposia in biology.

Palazzo, A.F., and Gregory, T.R. (2014) The Case for Junk DNA. PLoS Genetics, 10:e1004351. [doi: 10.1371/journal.pgen.1004351]

Rands, C. M., Meader, S., Ponting, C. P., and Lunter, G. (2014) 8.2% of the Human Genome Is Constrained: Variation in Rates of Turnover across Functional Element Classes in the Human Lineage. PLOS Genetics, 10:e1004525. [doi: 10.1371/journal.pgen.1004525]

Thomas Jr, C.A. (1971) The genetic organization of chromosomes. Annual review of genetics, 5:237-256. [doi: annurev.ge.05.120171.001321]

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1. The paper by Kellis et al. (2014) is ambiguous. It's clear that most of the ENCODE authors are still opposed to junk DNA even though the paper is mostly a retraction of their original claim that 80% of the genome is functional.

I'm going to a birthday party!

It's Bruce Alberts' 80th birthday party in San Francisco. There will be food, wine, cake, and (probably) dancing but first you go to the symposium on education.

Bruce Alberts’ 80th Birthday Gathering and Symposium
Saturday, April 14
Symposium on Science Education and Science Policy in Honor of Bruce Alberts’ 80th Birthday
(At the Metropolitan Club, 640 Sutter St., San Francisco 94102)

9a Guests arrive and register

10a Introduction by Master of Ceremonies Gregor Eichele

10:10a Session 1 How do we convey the importance of science to the public?
Moderator: Maureen Munn
Panelists: Janet Coffey, Will Colglazier, Janet English, Caroline Kiehle

11:40a Break

12p Buffet Lunch served in the Garden Room

1:30p Session 2 Innovations in Teaching and Learning in Higher Education
Moderators: Doug Kellogg and Kimberly Tanner.
Panelists: Judy Miner, Sally Pasion (one more panelist TBA)

2:30p Coffee and tea break

3p Session 3 Challenges Facing the Next Generation of Scientists
Moderators: Cynthia Fuhrmann and Bill Theurkauf.
Panelists: Marc Kirschner, Barry Selick, Nolan Sigal

4p Break

4:30p Session 4 Science Policy
Moderators: Mary Maxon and Jason Rao
Panelists: Bill Colglazier, Haile Debas, Donna Riordan, Keith Yamamoto

5:30p Elaine Bearer’s Duet for clarinet and viola: “Replication Machine”

6:15p Reception at Metropolitan Club Bar (4th Floor)

7p Buffet Dinner (Metropolitan Club Main Dining Hall — 4th Floor) Ending at 9:30p.

Sunday, April 15

10a - 2p Drop-in Brunch for all hosted at Beth Alberts’ home

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Photo: Bruce Alberts with his first three graduate students: Glenn Herrick (right), Keith Yamamoto (left), Larry Moran (middle right), Bruce Alberts (middle left).

Cafe Scientific Mississauga: The Good, Bad, & Natural

Dan Riskin: The Good, Bad, & Natural: What Mother Nature says
about morality?

Thursday, April 12, 2018
7:30 - 10:00 pm
The Franklin House
263 Queen Street S
Streetsville (Mississauga), Ontario, Canada

"People often act like “natural” is synonymous with “good.” Using heinous examples from the scientific literature, Dan Riskin will blow the hinges off that misconception. Then he’ll give some thoughts about where, if not from nature, the roots of human morality might lie.

Dan Riskin, PhD, is a television personality, scientist, author, and podcaster. He is best known as the co-host of Discovery's flagship science program, Daily Planet, and as the host of Animal Planet's show about parasites, Monsters Inside Me. To make science accessible and interesting to wide audiences, Dan has appeared as a guest on The Tonight Show with Jay Leno, The Late Late Show with Craig Ferguson, The Dr. Oz Show, and on several news outlets, including CP24, CTV, CNN, and CBS. Dan has published more than 20 papers in scientific journals, and his first popular book, Mother Nature is Trying to Kill You was a Canadian bestseller.

IMPORTANT:
This meetup starts 30 minutes later than our regular meeting time to give Dan time to drive to Mississauga from Scarborough.
You are welcome to come at 7 or 7:30, but don't expect the talk to begin before 8 pm. It will definitely be worth it."

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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.

Peter Larsen: "There is no such thing as 'junk DNA'"

The March 2018 issue of Chromosome Research is a Special Issue on Transposable Elements and Genome Function. I found it as I was doing my routine search for papers on junk DNA in order to see whether scientists are finally beginning to understand the issue. Peter Larsen (guest editor) wrote the introduction to the special issue. He says ...

There is no such thing as “junk DNA.” Indeed, a suite of discoveries made over the past few decades have put to rest this misnomer and have identified many important roles that so-called junk DNA provides to both genome structure and function (this special issue; Biémont and Vieira 2006; Jeck et al. 2013; Elbarbary et al. 2016; Akera et al. 2017; Chen and Yang 2017; Chuong et al. 2017). Nevertheless, given the historical focus on coding regions of the genome, our understanding of the biological function of non-coding regions (e.g., repetitive DNA, transposable elements) remains somewhat limited, and therefore, all those enigmatic and poorly studied regions of the genome that were once identified as junk are instead best viewed as genomic “dark matter.”