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.”

What's In Your Genome? - The Pie Chart

Here's my latest compilation of the composition of the human genome. It's depicted in the form of a pie chart.¹ [UPDATED: March 29, 2018]

What is "dark DNA"?

Some DNA sequencing technologies aren't very good at sequencing and assembling DNA that's rich in GC base pairs. What this means is that some sequenced genomes could be missing stretches of GC-rich DNA if they rely exclusively on those techniques. This difficult-to-sequence DNA was called "dark DNA" in a paper published last summer (July 2017).

The paper looked at some missing genes in the genome of the sand rat Psammomys obesus. The authors initially used a standard shotgun strategy in order to sequence the sand rat genome. They combined millions of short reads (&lt200 bp) to assemble a complete genome. A large block of genes seemed to be missing—genes that were conserved and present in the genomes of related species (Hargraves et al., 2017). They knew the genes were present because they could detect the mRNAs corresponding to those genes.

Making Sense of Genes by Kostas Kampourakis

Kostas Kampourakis is a specialist in science education at the University of Geneva, Geneva (Switzerland). Most of his book is an argument against genetic determinism in the style of Richard Lewontin. You should read this book if you are interested in that argument. The best way to describe the main thesis is to quote from the last chapter.

Here is the take-home message of this book: Genes were initially conceived as immaterial factors with heuristic values for research, but along the way they acquired a parallel identity as DNA segments. The two identities never converged completely, and therefore the best we can do so far is to think of genes as DNA segments that encode functional products. There are neither 'genes for' characters nor 'genes for' diseases. Genes do nothing on their own, but are important resources for our self-regulated organism. If we insist in asking what genes do, we can accept that they are implicated in the development of characters and disease, and that they account for variation in characters in particular populations. Beyond that, we should remember that genes are part of an interactive genome that we have just begun to understand, the study of which has various limitations. Genes are not our essences, they do not determine who we are, and they are not the explanation of who we are and what we do. Therefore we are not the prisoners of any genetic fate. This is what the present book has aimed to explain.

Is evolutionary psychology a deeply flawed enterprise?

We were discussing the field of evolutionary psychology at our local cafe scientific meeting last week. The discussion was prompted by watching a video of Steven Pinker in conversation with Stephen Fry. I pointed out that the field of evolutionary psychology is a mess and many scientists and philosophers think it is fundamentally flawed. The purpose of this post is to provide links to back up my claim.

Can the Dunning-Kruger effect be reversed?

The Dunning-Kruger Effect was first proposed in a classic 1999 paper (Kruger and Dunning, 1999).¹ People suffering from this effect show one of two characteristics. If they are not knowledgeable about a subject they tend to overestimate their ability. If they are experts in a subject they tend to underestimate their ability (see figure).

The phenomenon is more significant in people who overestimate their ability because it includes a large number of people who are making decisions on subjects that they know little about. Because of the Dunning-Kruger effect, they are confident that their decisions are based on facts and evidence. That's bad enough, but there's another aspect to this problem—why do these people seem to be incapable of recognizing that they are suffering from the Dunning-Kruger effect? Here's how Kruger and Dunning explain this ...

Junk DNA and selfish DNA

Selfish DNA is a term that became popular with the publication of a series of papers in Nature in 1980. The authors were referring to viruses and transposons that insert themselves into a genome where they exist solely for the purposes of propagating themselves. These selfish DNA sequences are often thought, incorrectly, to be the same as the Selfish Genes of Richard Dawkins¹ [Selfish genes and transposons]. In fact, "selfish genes" refers to the idea that some DNAs enhance fitness and the frequency of these genes will increase in a population through their effect on the vehicle that carries them. It's an adaptationist view of evolution. The selfish DNA of transposons and viruses is quite different. These sequences only propagate themselves—the fitness of the organism is largely irrelevant. These elements do not contribute directly to the adaptive evolution of the species.

Transposons and integrated viruses are subjected to mutation just like the rest of the genome. Deleterious mutations cannot be purged by natural selection because inactivating a transposon has no effect on the fitness of the organism.² As a result, large genomes are littered with defective transposons and bits and pieces of dead transposons. This is not selfish DNA by any definition. It is junk DNA [What's in Your Genome?].

Human genome books

Theme
Genomes
& Junk DNA

I'm trying to read all the recent books on the human genome and anything related. There are a lot of them. Here's a list with some brief comments. You should buy some of these books. There are others you should not buy under any circumstances.

Test your irony meter

The irony meter was a running joke on the newsgroup talk.origins back in the last century. Our irony meters were supposed to protect us from the craziness of creationists but as soon as we built a really good irony meter a new bit of creationist crazy came along and fried it. Apparently Jesus and Mo have the same problem.

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