AlphaFold and its predecessors were trained on a database of known protein structures called the Protein Data Bank (PDB). PDB began in 1971 as a collaboration between the Cambridge Crystallographic Centre in the UK and Brookhaven National Laboratory in the US. It utilized standardizing software for collecting and storing atomic coordinates and allowing researchers to search the database from remote locations. It soon became a requirement for researchers to deposit their data in PDB when they published.
More Recent Comments
Thursday, November 14, 2024
The success of protein structure prediction software depended on the solved structures deposited in the Protein Data Bank (PDB)
Wednesday, November 13, 2024
Nobel Laureates Andrew Fire and Craig Mello
The Nobel Prize in Physiology or Medicine 2006
"for their discovery of RNA interference - gene silencing by double-stranded RNA"Craig Mello (left) and Andrew Fire (right) won the Nobel Prize in 2005 for discovering RNA interference in Caenorhabditus elegans. The mechanism involves synthesis of a double-stranded RNA molecule where one of the strands is identical to the coding region of a protein-coding gene and the other strand is a complementary antisense RNA. The double-stranded RNA binds to a protein complex called Dicer, which degrades the "coding" strand RNA leaving a small antisense siRNA. This RNA binds to a RISC complex that seeks out the mRNA that's complementary to the antisense RNA and cleaves the mRNA. (RISC = RNA-induced silencing complex.) The interference mechanism blocks the synthesis of proteins from the target RNA. It is used to block synthesis of viral proteins following infection and to block synthesis of transposon proteins.
Here's part of the Ceremony Speech.
THEME:
Nobel LaureatesFifteen years ago, we thought we knew enough about the flow of genetic information to use it for practical purposes. But we did not achieve the expected results. Attempts to silence a gene in an experimental animal were sometimes fruitless, and attempts to use gene technology for improving the colours of flowers could even cause the plants to lose colour completely. These results perplexed the scientific community. Was there an unknown regulatory step on the way from DNA to protein?
This enigma was solved by the 2006 Nobel Laureates, Andrew Fire and Craig Mello. They suspected that RNA contained the solution to the problem and decided to test it in a simple model organism, the nematode worm Caenorhabditis elegans.
Fire and Mello injected different types of RNA into the worms – and usually nothing happened. But they also made the ingenious decision to mix two RNA molecules in a test tube before injection. One RNA molecule was an exact copy of a messenger RNA and the other a mirror image of the messenger. In the test tube, the two RNA molecules bound to each other and formed a double strand. Injection of that double-stranded RNA led to the silencing of the gene. Fire and Mello had discovered a new mechanism for controlling the flow of genetic information.
In their brilliant paper from 1998, Andrew Fire and Craig Mello demonstrated that double-stranded RNA activates an enzymatic mechanism that leads to gene silencing, with the genetic code in the RNA molecule determining which gene to silence. Today, we call this mechanism RNA interference.
Photo Credit: The figure is from the Nobel Prize press release.
The images of the Nobel Prize medals are registered trademarks of the Nobel Foundation (© The Nobel Foundation). They are used here, with permission, for educational purposes only.
Tuesday, November 12, 2024
Monday's Molecule #245
Today's molecule is the little green ladder-like thing in the figure. You have to name the class of molecule it refers to and give a brief description of its properties. You also have to indicate that you know something about the pink blob.
You can use whatever tricks you want to identify today's molecule. Regular readers will know that it's related to at least one Nobel Prize Laureate who will be revealed on Wednesday. I don't think that's going to help you very much.
Email your answer to me at: Monday's Molecule #245. The first one with the correct answer wins. I will only post the names of winners to avoid embarrassment. The winner will be treated to a free coffee and donut at Tim Hortons if you are ever in Toronto or Mississauga (Ontario, Canada).
There could be two winners. If the first correct answer isn't from an undergraduate student then I'll select a second winner from those undergraduates who post the correct answer. You will need to identify yourself as an undergraduate in order to win. (Put "undergraduate" at the bottom of your email message.)
In order to win you must give your correct name. Anonymous and pseudoanonymous players can't win.
Comments are closed for at least 24 hours.
UPDATE: There was no winner this week.
Winners
#145, Oct. 17, 2011: Bill Chaney, Roger Fan#146, Oct. 24, 2011: DK
#147, Oct. 31, 2011: Joseph C. Somody
#148, Nov. 7, 2011: Jason Oakley
#149, Nov. 15, 2011: Thomas Ferraro, Vipulan Vigneswaran
#150, Nov. 21, 2011: Vipulan Vigneswaran (honorary mention to Raul A. Félix de Sousa)
#151, Nov. 28, 2011: Philip Rodger
#152, Dec. 5, 2011: 凌嘉誠 (Alex Ling)
#153, Dec. 12, 2011: Bill Chaney
#154, Dec. 19, 2011: Joseph C. Somody
#155, Jan. 9, 2012: Dima Klenchin
#156, Jan. 23, 2012: David Schuller
#157, Jan. 30, 2012: Peter Monaghan
#158, Feb. 7, 2012: Thomas Ferraro, Charles Motraghi
#159, Feb. 13, 2012: Joseph C. Somody
#160, March 5, 2012: Albi Celaj
#161, March 12, 2012: Bill Chaney, Raul A. Félix de Sousa
#162, March 19, 2012: no winner
#163, March 26, 2012: John Runnels, Raul A. Félix de Sousa
#164, April 2, 2012: Sean Ridout
#165, April 9, 2012: no winner
#166, April 16, 2012: Raul A. Félix de Sousa
#167, April 23, 2012: Dima Klenchin, Deena Allan
#168, April 30, 2012: Sean Ridout
#169, May 7, 2012: Matt McFarlane
#170, May 14, 2012: no winner
#171, May 21, 2012: no winner
#172, May 29, 2012: Mike Hamilton, Dmitri Tchigvintsev
#173, June 4, 2012: Bill Chaney, Matt McFarlane
#174, June 18, 2012: Raul A. Félix de Sousa
#175, June 25, 2012: Raul A. Félix de Sousa
#176, July 2, 2012: Raul A. Félix de Sousa
#177, July 16, 2012: Sean Ridout, William Grecia
#178, July 23, 2012: Raul A. Félix de Sousa
#179, July 30, 2012: Bill Chaney and Raul A. Félix de Sousa
#180, Aug. 7, 2012: Raul A. Félix de Sousa
#181, Aug. 13, 2012: Matt McFarlane
#182, Aug. 20, 2012: Stephen Spiro
#183, Aug. 27, 2012: Raul A. Félix de Sousa
#184, Sept. 3, 2012: Matt McFarlane
#185, Sept. 10, 2012: Matt Talarico
#186, Sept. 17, 2012: no winner
#187, Sept. 24, 2012: Mikkel Rasmussen
#188, Oct. 1, 2012: John Runnels
#189, Oct. 8, 2012: Raúl Mancera
#190, Oct. 15, 2012: Raul A. Félix de Sousa
#191, Oct. 22, 2012: Mikkel Rasmussen
#192, Nov. 12, 2012: Seth Kasowitz, Bill Gunn
#193, Nov. 19, 2012: Michael Rasmussen
#194, Dec. 4, 2012: Paul Clapham, Jacob Toth
#195, Dec. 10, 2012: Jacob Toth
#196, Dec. 17, 2012: Bill Chaney, Dima Klenchin, Bill Gunn
#197, Jan. 14, 2013: Evey Salara
#198, Jan. 21, 2013: Piotr Gasiorowski
#199, March 11, 2013: Bill Gunn, River Jiang
#200, March 18, 2013: Bill Gunn
#201, April 8, 2013: Michael Florea
#202, April 15, 2013: no winner
#203, April 29, 2013: Anders Ernberg
#204, May 6, 2013: Alex Ling, Michael Florea
#205, May 13, 2013: Bill Chaney
#206, June 24, 2013: Michael Florea
#207, July 2, 2013: Matt McFarlane
#208, July 8, 2013: no winner
#209, July 15, 2013: Rosie Redfield, Thuc Quyen Huynh
#210, July 22, 2013: Jacob Toth
#211, July 29, 2013: Alex Ling, Matt McFarlane
#212, August 5, 2013: Brian Shewchuk
#213, Sept. 2, 2013: no winner
#214, Sept. 9, 2013: Bill Chaney
#215, Sept. 16, 2013: Zhimeng Yu
#216, Sept. 23, 2013: Mark Sturtevant, Jacob Toth
#217, Sept. 30, 2013: Susan Heaphy
#218, Oct. 7, 2013: Piotr Gasiorowski, Jacob Troth
#219, Oct. 14, 2013: Jean-Marc Neuhaus
#220, Oct. 21, 2013: Jean-Marc Neuhaus
#221, Oct. 28, 2013: Zhimeng Yu
#222, Nov. 10, 2013: Caroline Josefsson, Andrew Wallace
#223, Nov. 18, 2013: Dean Bruce, Ariel Gershon
#224, Nov. 25, 2013: Jon Nuelle, Ariel Gershon
#225, Dec. 2, 2013: Jean-Marc Neuhaus
#226, Dec. 9, 2013: Bill Gunn
#227, Dec. 16, 2013: Piotr Gasiorowski
#228, Jan. 13, 2014: Tom Mueller
#229, Jan. 20, 2014: Tommy Stuleanu
#230, Jan. 27, 2014: Bill Gunn, Ariel Gershon
#231; March 3, 2014: Keith Conover, Nevraj Kejiou
#232, March 10, 2014: Philip Johnson
#233, March 17, 2014: Jean-Marc Neuhaus
#234, March 24, 2014: Frank Schmidt, Raul Félix de Sousa
#235, March 31, 2014: Jon Binkley
#236, April 7, 2014: no winner
#237, April 21, 2014: Dean Bruce
#238, April 28, 2014: Dean Bruce
#239, May 5, 2014: Piotr Gąsiorowski
#240, May 12, 2014: James Wagstaff
#241, May 19, 2014: no winner
#242, Oct. 7, 2024: Elie Huvier
#243, Oct. 14, 2024: Mikkel Rasmussen
#244, Oct. 21, 2024: Santi Garcia-Vallve
#245, Nov. 12, 2024: no winner
The figure is modified from Hung and Slotkin (2021) The initiation of RNA interference (RNAi) in plants. Current Opinion in Plant Biology 61:102014 [doi: 10.1016/j.pbi.2021.102014] -
Monday, November 11, 2024
Lance Corporal Robert Alexander Hood (1895 - 1917)
Robert Alexander Hood1 was born in 1895 in a small village north-west of Waterloo, Ontario, Canada. He went to France in 1916 when he was only 21 years old. Robert fought with the 73rd Battalion and he was killed in action at Vimy Ridge on April 12, 1917.
Canadians remember the battle of Vimy Ridge as a great Canadian victory. It was part of the larger Battle of Arras, which in turn was a diversionary attack in support of the larger Nivelle Offensive carried out by the French Army. About 3,600 young Canadian men were killed during the four day battle and 7,000 more were wounded. This is just a small fraction of the casualties on both sides during World War I.
We visited the Canadian War memorial at Vimy Ridge with our granddaughter and found Corporal Hood's name engraved at the base.
1. He was a cousin of Ms. Sandwalk's grandfather.
Sunday, November 10, 2024
Bringing down inflation
Managing the national economy is complicated and I don't pretend to understand it. All I know is that practically the entire world suffered from inflation during and after the COVID-19 pandemic. Various governments have struggled to get inflation under control and some have been more successful that others. For example, here's what the inflation rate for the USA looks like over the past five years. The current inflation rate is about 2.4%.
I just heard a couple of Republican pundits claim that one of the priorities of the new Trump administration is to bring down inflation. Does anyone know what their goal is? Are they aiming at a zero inflation rate or just something below 2.4%? Can someone explain, in simple language, what policies the new administration will use to bring down inflation? Does the general public think that the Trump administration will actually lower the cost of goods by creating a negative inflation rate?
We have a similar situation in Canada. Here's the inflation rate over the past ten years. The current inflation rate is 1.6% (September 2024).
The Canadian opposition parties are blaming the current government for inflation and they are promising to do better. Does anyone in Canada know what their inflation rate goals are and how they hope to achieve them?
Let's assume, for the sake of argument, that my questions are merely rhetorical questions and I actually know the answers. Let's assume that the opposition parties in Canada and the United States (and elsewhere) know full well that current governments have been quite successful at combating inflation. Those opposition parties are deliberately misleading the public by claiming that they would have done better and they will bring down inflation if they are elected. Is is possible to create a society where this kind of rhetoric is not acceptable? Is it possible to create a society where the public is so well educated that opposition parties cannot get away with spreading misinformation?
Or are we doomed to be controlled by an electorate that is incapable of distinguishing between truth and reality?
Do plants have junk DNA?
Current Opinion in Plant Biology has a special edition devoted to Genome studies and molecular genetics 2024. The only paper (so far) that discusses plant genomes is one devoted to RNAs. Here's the abstract ...
Anyatama, A., Datta, T., Dwivedi, S. and Trivedi, P.K. (2024) Transcriptional junk: Waste or a key regulator in diverse biological processes? Current Opinion in Plant Biology 82:102639. [doi: 10.1016/j.pbi.2024.102639]
Plant genomes, through their evolutionary journey, have developed a complex composition that includes not only protein-coding sequences but also a significant amount of non-coding DNA, repetitive sequences, and transposable elements, traditionally labeled as “junk DNA”. RNA molecules from these regions, labeled as “transcriptional junk,” include non-coding RNAs, alternatively spliced transcripts, untranslated regions (UTRs), and short open reading frames (sORFs). However, recent research shows that this genetic material plays crucial roles in gene regulation, affecting plant growth, development, hormonal balance, and responses to stresses. Additionally, some of these regulatory regions encode small proteins, such as miRNA-encoded peptides (miPEPs) and microProteins (miPs), which interact with DNA or nuclear proteins, leading to chromatin remodeling and modulation of gene expression. This review aims to consolidate our understanding of the diverse roles that these so-called “transcriptional junk” regions play in regulating various physiological processes in plants.
Friday, November 01, 2024
Were you lied to in your genetics class?
A recently posted YouTube video tries to make the case that you were lied to about genetics. I'll get to than in a little while but first let me summarize what I was taught in a university genetics class in 1965.
Thursday, October 31, 2024
Philip Ball's view of alternative splicing
Genomics is a powerful tool that allows you to collect massive amounts of data that can point the way to new understanding. But it can also be abused when the results are overinterpreted. We saw an extraordinary example of this in 2012 when ENCODE made unsubstantiated claims that were quickly challenged.
I'm reminded of the caution from Sydney Brenner who warned us about genomics (Brenner, 2000) and the warning in Dan Graur's harsh critique of the 2012 ENCODE claims (Graur et al., 2013) where they said ...
The Editor-in-Chief of Science, [Bruce Alberts,] has recently expressed concern about the future of "small science," given that ENCODE-style Big Science grabs the headlines that decision makers so dearly love. Actually the main function of Big Science is to generate massive amounts of easily accessible data. The road from data to wisdom is quite long and convoluted. Insight, understanding, and scientific progress are generally achieved by "small science." ...
Tuesday, October 29, 2024
Zach Hancock's 10 most influential papers on evolution
Zach emphasizes that this is a personal list and others might disagree with his choices. He is much more interested than I am in explaining the history of life with an emphasis on animals. I'm much more interested in molecular evolution so I would choose a slightly different list as I explain below. Please add your own choices in the comments.
- Force, A., Lynch, M., Pickett, F. B., Amores, A., Yan, Y. L., and Postlethwait, J. (1999) Preservation of duplicate genes by complementary, degenerative mutations. Genetics, 151(4), 1531-1545. [doi: 10.1093/genetics/151.4.1531]
- Coyne, J. A., and Orr, H. A. (1989) Patterns of speciation in Drosophila. Evolution, 43(2), 362-381. [doi: 10.1111/j.1558-5646.1989.tb04233.x]
- Lande, R., and Arnold, S. J. (1983) The measurement of selection on correlated characters. Evolution, 1210-1226. [doi: 10.2307/2408842]
- Lederberg, J., and Lederberg, E. M. (1952) Replica plating and indirect selection of bacterial mutants. Journal of bacteriology, 63(3), 399-406. [PDF]
- Gould, S.J. and Lewontin, R.C. (1979) The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme. Proceedings of the Royal Society of London. Series B. Biological Sciences 205:581-598. [doi: 10.1098/rspb.1979.0086]
- Maynard Smith, J. M. (1974) The theory of games and the evolution of animal conflicts. Journal of theoretical biology, 47(1), 209-221. [doi: 10.1016/0022-5193(74)90110-6"]
- Fisher, R.A. (1918) The correlation between relatives on the supposition of Mendelian Inheritance. Proceedings of the Royal Society of Edingurgh [PDF]
- Hamilton, W. D. (1964) The genetical evolution of social behaviour. II. Journal of theoretical biology, 7(1), 17-52. [doi: 10.1016/0022-5193(64)90039-6]
- Kimura, M. (1968) Evolutionary rate at the molecular level. Nature, 217(5129), 624-626. [PDF]
- Wright, S. (1931) Evolution in Mendelian populations. Genetics, 16(2), 97. [doi: 10.1093/genetics/16.2.97]
I disagree with Hamilton (1964). I realize that there are many evolutionary biologists who think that kin selection and the evolution of altruistic behavior is extremely important1 but I think it's restricted to a tiny perecentage of characteristics in a tiny percentage of all living things on the planet. I would delete the Hamilton paper and replace it with ...
Margoliash, E. (1963) Primary structure and evolution of cytochrome c. Proceedings of the National Academy of Sciences, 50(4), 672-679. [PDF]
This is the first accessible paper on using the animo acid seqences of proteins to obtain information on evolution. It's the beginning of the field of molecular evolution and the idea of a molecular clock. Surely that deserves to be one of the most important advances in the field of evolution. (Linus Pauling and Emile Zuckerkandl published similar work on globins at about the same time but their original papers were not as accessible as the Margoliash paper. See Emile Zuckerkandl and the 50th anniversary of the birth of molecular evolution.)
I'm not a big fan of John Maynard Smith and game theory. I think it only applies to a small part of the field of evolution. I would delete the Maynard Smith (1974) paper and replace it with ...
Ohta, T. (1973) Slightly deleterious mutant substitutions in evolution. Nature 246:96-98. [doi:10.1038/246096a0]
This is the beginning of the nearly neutral theory. I agree that putting the Kimura paper on the neutral theory at #2 is a good choice but it's the Ohta paper that really drives home the idea that deleterious mutations can also be fixed under some circumstances and made (some) evolutionary biologists understand that natural selection was not the only game in town.
Finally, I'd like to see one of David Raup's papers in the top ten list but I don't know enough about the other papers to pick one to delete. (I'm skeptical of Lande and Arnold (1983) but I know they have fierce defenders.) Here's a candidate Raup paper that includes Sepkoski.
Raup, David M.; Sepkoski, J. John Jr. (1982) Mass extinctions in the marine fossil record. Science. 215 (4539). [doi:10.1126/science.215.4539.1501]
I'm waiting for the list of the top nine books on evolution—we all know what #1 is going to be.
Image credit: The photo is from Zach's personal website.
1. Richard Dawkins thinks Hamilton is "the greatist Darwinina of my lifetime" [quoted in W.D. Hamilton]
Saturday, October 26, 2024
Three lungfish species have huge genomes
This relationship (lungfish-tetrapods) was firmly established recently by comparing the genome of the Australian lungfish (Neoceratodus forsteri) with that of tetrapods (Meyer et al., 2021). The other possibility had been ceolacanth-tetrapods. Coelacanths and lungfish are related—they form the class Sarcopterygii (lobe-finned fish).
Wednesday, October 23, 2024
Santi Garcia-Vallvé reviews my book
Santi Garcia-Vallvé has reviewed my book in the journal Mètode. It's written in Catalan but Santi was kind enough to send me a translation.
OUR GENOME HAS NOT YET SPOKEN ITS LAST WORDWhat's in Your Genome? 90% of Your Genome Is Junk. Laurence A. Moran. Aevo University of Toronto Press (UTP). May 2023. 392 pages.
What's in Your Genome? exposes a variety of topics and concepts in molecular biology, genetics, and evolution that have been misunderstood by scientists and the general public. Many of these concepts are widely accepted, despite ongoing debate about them. Although the author, Larry Moran, has exhaustively discussed most of these issues on his blog "Sandwalk: Strolling with a sceptical biochemist", discussing them in a book allows for a more in-depth investigation.
One of these recurring themes is Francis Crick 's 1957 proposal of the Central Dogma of Molecular Biology. In his book Molecular Biology of the gene, James Watson adapted this concept by summarizing in a figure the flow of genetic information from DNA to RNA and then to proteins. This version was widely adopted, and many scientists now assume that it was the original definition. However, Crick claimed that once the information had been transferred to the proteins, it could not be returned to nucleic acids. Other controversial topics discussed in the book include the number of genes encoded in the human genome, the concept of Junk DNA and the prevalence of alternative splicing in the transcription of the human genome. Larry takes a certain viewpoint on all these problems, as evidenced by the title of the book, but he also presents arguments from all sides. Throughout the book, he argues that scientists must present evidence in support of and against their findings, as well as contextualise their discoveries in light of the knowledge of the subject. Thus, the first chapters of the book describe in depth the basic ideas of genetics, genetics and evolution that are required to understand the arguments that he will present later, showing also when and how they were discovered.
This is a highly recommendable book that pushed us to think about how research findings are explained and the importance of placing them in their proper context. The media frequently looks for stunning headlines and there is growing demand to assess the social impact of a project, article or scientific project. However, if we exaggerate our findings, we risk exacerbating further diminishing the general lack of interest in scientific news. Everyone is responsible that this does not happen.
Santi Garcia-Vallvé is an associate professor in the Department of Biochemistry and Biotechnology at Rovira i Virgili University (URV) in Tarragona, Spain, and a member of the Chemoinformatics and Nutrition research group."
Philip Ball doesn't understand sloppy genomes
... anything found to be true of E.coli must also be true of Elephants.This version of the famous statement by Jacques Monod comes from 1961 but he said similar things much earlier and other scientists even predate Monod's earliest use of the phrase (Friedman, 2004). He echoed this same idea in Chance and Necessity (p. 102)
Jacques Monod (1961)
The diversity of types remained even so, and there was no getting around the fact that a great many macroscopic structural patterns, radically unlike one another, coexist in the biosphere. A blue alga, an infusorium, an octopus, and a human being—what had they in common? With the discovery of the cell and the advent of cellular theory a new unity could be seen under this diversity. But it was some time before advances in biochemistry, mainly during the second quarter of this century, revealed the profound and strict oneness, on the microscopic level, of the whole of the living world. Today we know that from a bacterium to man the chemical machinery is essentially the same, in both its structure and its functioning.
Monod was making a case for life as a chemical process and he reflected the view of the 'phage group who were studying bacteria and bacteriophage. He argued that all living things would consist of the same basic chemicals such as lipids, nucleic acids, proteins, and carbohydrates. He also assumed that all living things would have similar networks of metabolic enzymes and contain similar pathways. These enzymes would be regulated by similar mechanisms, such as allosteric regulation, and they would be composed of the same 20 amino acids. He expected all living cells would have similar mechanisms for capturing energy and they would obey the fundamental laws of thermodynamics.
He assumed that the genetic code would be universal and that the process of protein synthesis would be essentially the same in all species. He assumed that the fundamentals of transcription and DNA replication would be the same in all species. He imagined that the basic principles of gene regulation that were worked out in bacteria would apply to eukaryotes. This included the action of transcription factors and more unusual regulatory molecules such as the regulatory RNAs discovered in 'phage and bacteria. He expected that genes, regulatory sequences, origins of replication, and other important genetic elements would be found in the DNA molecules of the genome.
This theme of unity of life at the microscopic level was very important but it did not mean that all living things would be identical. Monod was a firm proponent of evolution and since evolution depended on the random occurrence of mutations the actual history of life is unpredictable. There's nothing profoundly upsetting about the fact that elephants have trunks and E. coli doesn't because that's not the point.I'm sure that Monod was not upset to learn that some genes had introns or that eukarotic chromatin is more complicated than the DNA-protein complexes found in bacteria. He would not have been shocked to learn that many eukaryotes have more functional RNAs than E. coli or bacteriophage λ. Junk DNA was not a problem for someone who understood evolution.
I think Monod reflected the dominant view of most knowledgeable biochemists and molecular biologists of the 1960s and 1970s.
Over the next 50 years we learned a lot more about complex eukaryotes and the dominant theme at the molecular level is that they contain lots of junk DNA and lots of overly complex structures that only make sense in light of evolution. There's a lot of sloppiness in eukaryotes, including genomes full of transposon fossils, aberrant transcription, pseudogenes, inefficient splicing, and promiscuous enzymes. A lot of this sloppiness was apparent in the 1970s, including the fact that junk DNA must contain thousands of ineffective transcription factor binding sites. We learned in the 1980s that some structures, such as the spliceosome, could only have arisen by evolution since no designer in their right mind would have built such a thing.
I would be quite proud to have served on the committee that designed the E. coli genome. There is, however, no way that I would admit to serving on a committee that designed the human genome. Not even a university committee could botch something that badly. David Penny
I got this quote from Dan Graur who credits it to David Penny as a personal communication. Graur used it in his scathing criticism of ENCODE researchers after they declared the death of junk DNA (Graur et al., 2013). The meaning is clear. The E. coli genome is compact and carries all the information needed to ensure the survival and evolution of the bacterium. It has one copy of most protein-coding genes, two copies of ribosomal RNA genes, and a minimal number of tRNA genes. The regulatory sequences are just big enough for efficient transcription under the appropriate conditions. Many genes are clustered in operons to save space. There's only one origin of replication and one terminator sequence. There's only one chromosome and it is efficiently segregated to each daughter cell after DNA replication and cell division. There are only a small number of regulatory RNA genes in E. coli.
The human genome is a mess. 90% of it is junk and it requires complicated features like centromeres and telomeres. There are 100,000 origins of replication and tens of thousands of pseudogenes. The protein-coding genes are full of useless introns and they take up 40% of the genome even though the functional parts only occupy 1%. Every cell has thousands of incorrectly spliced transcripts. The genome is littered with fossil transposons and viruses and many of them still have partially active promoters churning out junk RNA. Useless transcription factor binding sites and chromatin alterations are ubiquitous. The abundance of junk DNA means that you need tens of thousands of copies of every transcription factor just to make sure the right genes are regulated. A large part of the genome is transcribed but the vast majority of those transcripts are useless junk.This is why David Penny would not be proud to have served on the committee that designed the human genome. Neither would I, and that's why I spent so much time explaining sloppy genomes in my book. The idea of a sloppy genome is a difficult concept to grasp so I devoted the final chapter (Chapter 11) to the art of coping with this issue.
Now let's look at how Philip Ball handles this information on pages 116-117 of his book How Life Works.
These differences in the relative proportions of coding and non-coding DNA for simpler and more complex organisms reflect fundamental distinctions in how these organisms work. The problem has been delightfully, if inadvertently, stated by theoretical biologist David Penny. "I would be quite proud to have served on the committee that designed the E. coli genome" he has said. "There is, however, no way that I would admit to serving on a committee that designed the human genome. Not even a university committee could botch something that badly."I'd suggest that can be rephrased: "I can understand how the E. coli genome works. I cannot make any sense of how the human genome works." So the corollary of Penny's comment is rather profound: how E. coli works is not how humans work. But his quip betrays an understandable frustration that the workings of the human genome are inscrutable to us. And I fear that the remark carries the same bias as that which leads us to insist that a foreign language we find difficult to learn is unnecessarily perverse and even absurd.
This shift in perspective challenges a famous statement by Jacques Monod: "What is true for E. coli is true for the elephant." In fairness, Monod had in mind here the notion of how DNA encodes proteins—for indeed it does so in (roughly) the same way in bacteria as in pachyderms, insofar as it uses the same genetic code. But the implication in Monod's comment is that this is what really matters in the same spirit as Crick's Central Dogma. We can now see that Monod's quote is misleading in an important sense, because what matters for E. coli is not the same as what matters for an elephant. The bacterium has a genome dedicated mostly to making proteins. The elephant has a genome dedicated mostly to making noncoding RNAs with regulatory functions. To truly understand how the elephant—and the human—works, we need to untangle the mechanisms governing this regulation.
As Morris and Mattick say,
It appears that we may have fundamentally misunderstood the nature of the genetic programming in complex organisms because of the assumption that most genetic information is transacted by proteins. This may be largely true in simpler organisms, but is turning out not to be the case in more complex organisms, whose genomes appear to be progressively dominated by regulatory RNAs that orchestrate the epigenetic trajectories of differentiation and development.Or as biochemist Danny Licatalosi and neuroscientist Robert Darnell put it, biological complexity "has RNA at its core."
I think this is an excellent illustration of the differing viewpoints of Philip Ball and many biochemists and molecular biologists. David Penny and the rest of us don't disparage the human genome because we don't understand it. Quite the contrary. We think we DO understand evolution and the basic principles of molecular biology and that's why we recognize a sloppy genome when we see it. Philip Ball just can't get his head around the fact that we aren't ignorant of functional non-coding RNAs ... we just don't believe Mattick and ENCODE when they claim, without evidence, that the human genome is full of non-coding genes modulating some sophisticated regulation of the protein-coding genes.
Not only does such a model lack support but it doesn't make any sense. Why would all the 10,000 or so housekeeping genes require such regulation in humans and not in yeast? Why would evolution have selected for regulatory RNAs acting on the genes for the glycolytic enzymes? What kind of selective advantage would there have to be in order to evolve a regulatory RNA gene that could tweek expression by a few percent?
"Ball is one of the most meticulous, precise science writers out there. He is the antithesis of hypey, "dumb-it-down" reporting. He is MUCH more credible than you are, Laurence."
John Horgan July, 2024Philip Ball even wants to twist the Monod quote to fit his agenda on the importance of proteins. That's not what Monod meant. But let's think about this for a minute. The biochemists of the last century discovered a complex network of metabolic pathways with reactions that were catalyzed almost exclusively by protein enzymes. That hasn't changed. It's true of E. coli and it's true of elephants.
They also discovered that the expression of genes, especially at the level of transcription, was mostly controlled and regulated by proteins; namely, RNA polymerase and transcription factors. That hasn't changed. The expression of elephant and human genes is also regulated by transcription factors and RNA polymerase. Hundreds of studies of particular mammalian genes have demonstrated beyond a doubt that we can explain most regulation by such a model.
That doesn't mean that proteins are the only players in regulation. Over the past several decades we've discovered a variety of regulatory RNAs and we now know that there are more of these non-coding genes in humans than in bacteria. We don't know how many but so far the number of well-characterized examples amounts to fewer than 2000 genes and probably less than 1000. Note that I said "well-characterized" examples and that means that the individual RNA molecule has been studied and its biologically relevant function has been confirmed. That's not the same as a genomics study that simply identifies candidate transcripts that may or may not have a function.
Proteins still play the most important functional roles in metabolism and gene expression but they are not the only players. We've known that for 50 years. The only thing that's changed is that there may be as many as two thousand non-coding genes in humans and only a dozen or so in E. coli and the human genome may be a lot more sloppy than bacterial genomes. That's not a paradigm shift.
Note: Philip Ball was an editor at Nature and that's ironic because it's the failure of Nature editors to do their job in 2012 that got us into the mess we're in today. The editors not only allowed ENCODE researchers to make exaggerated claims about junk DNA but they actively supported and participated in the publicity campaign that sold those false claims to the general public. Nature editors have never apologized for their behavior in 2012; in fact, one of them, Magdalena Skipper, has been promoted to editor-in-chief. [The 10th anniversary of the ENCODE publicity campaign fiasco]
Friedman, H.C. (2004) From Butyribacterium to E. coli: An Essay on Unity in Biochemistry. Perspectives in Biology and Medicine 47:47-66. doi: 10.1353/pbm.2004.0007
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 5:578-590. doi: doi: 10.1093/gbe/evt028
Nobel Laureate: Vincent du Vigneaud
The Nobel Prize in Chemistry 1955
"for his work on biochemically important sulphur compounds, especially for the first synthesis of a polypeptide hormone" Vincent du Vigneaud (1901-1978) was an American biochemist who was awarded the Nobel Prize in Chemistry in 1955 for his work on biological molecules containing sulfur, especially methionine cystine, and biotin. The prize was for solving the structure of the peptide hormone oxytocin and synthesizing an active molecule. (See Monday's Molecule #244.) From 1938 to 1967 Vigneaud's lab was at Cornell Medical College in New York City.Here's part of the Presentation Speech.
THEME:
Nobel LaureatesUnderneath the brain, there is a small, well-protected gland, the pituitary gland. In man it is about as big as a bean. There are secreted several hormones, that is, substances which regulate important physiological functions. spite of its small size, the pituitary gland is made up of several distinct parts with different functions. We are interested here in the posterior lobe, which contains two substances called oxytocin and vasopressin. The former stimulates the contractions of the uterus and also the lactation, the latter raises the blood pressure and regulates the function of the kidneys. As early as in 1933, when rather impure preparations from the posterior lobe were used in experiments, du Vigneaud found a high percentage of sulphur, which seemed to be correlated to the physiological activity.
Using the experimental methods, which the development of science has put at his disposal and making the best of his own intimate knowledge of the organic chemistry of sulphur, du Vigneaud has step by step forced his way. Both hormones were isolated in a state of purity, and it was found that they are built up from amino acids in the same way as proteins, but with a far lower molecular weight. Such compounds are, as distinguished from real proteins, called polypeptides. The nature of the amino acids and their positions in the molecule could be determined. The sulphur is present in cystine. The two hormones have a very similar structure; both contain eight amino acids, connected to a chain, which at one point is closed to a ring. The molecule has some resemblance to a figure six or nine, where the loop contains five amino acids and the “tail” three. Two sulphur atoms, linked to each other, form a part of the ring.
The design of the molecule was thus known. It remained to build it up by synthesis and check the correctness of the design. That was perhaps the most difficult part of the work. The interest was first concentrated on the synthesis of oxytocin. Step by step the amino-acid chain was built up with the two sulphur atoms in the proper positions, one at the end of the chain and the other near the middle. At last the ring was closed by formation of a bond between the sulphur atoms. Now followed the most thrilling moment, the testing of the chemical properties and the physiological activity; perhaps there had been some mistake after all. It turned out, however, that the synthetic polypeptide was identical with the natural product.
The images of the Nobel Prize medals are registered trademarks of the Nobel Foundation (© The Nobel Foundation). They are used here, with permission, for educational purposes only.
Monday, October 21, 2024
Monday's Molecule #244
Email your answer to me at: Monday's Molecule #244. The first one with the correct answer wins. I will only post the names of winners to avoid embarrassment. The winner will be treated to a free coffee and donut at Tim Hortons if you are ever in Toronto or Mississauga (Ontario, Canada).
There could be two winners. If the first correct answer isn't from an undergraduate student then I'll select a second winner from those undergraduates who post the correct answer. You will need to identify yourself as an undergraduate in order to win. (Put "undergraduate" at the bottom of your email message.)
In order to win you must give your correct name. Anonymous and pseudoanonymous players can't win.
Comments are closed for at least 24 hours.
UPDATE: The winner is Santi Garcia-Vallve who correctly guessed that the molecule is the peptide hormone oxytocin. Santi lives in Spain so he won't be able to collect his coffee and donut anytime soon.
Winners
#145, Oct. 17, 2011: Bill Chaney, Roger Fan#146, Oct. 24, 2011: DK
#147, Oct. 31, 2011: Joseph C. Somody
#148, Nov. 7, 2011: Jason Oakley
#149, Nov. 15, 2011: Thomas Ferraro, Vipulan Vigneswaran
#150, Nov. 21, 2011: Vipulan Vigneswaran (honorary mention to Raul A. Félix de Sousa)
#151, Nov. 28, 2011: Philip Rodger
#152, Dec. 5, 2011: 凌嘉誠 (Alex Ling)
#153, Dec. 12, 2011: Bill Chaney
#154, Dec. 19, 2011: Joseph C. Somody
#155, Jan. 9, 2012: Dima Klenchin
#156, Jan. 23, 2012: David Schuller
#157, Jan. 30, 2012: Peter Monaghan
#158, Feb. 7, 2012: Thomas Ferraro, Charles Motraghi
#159, Feb. 13, 2012: Joseph C. Somody
#160, March 5, 2012: Albi Celaj
#161, March 12, 2012: Bill Chaney, Raul A. Félix de Sousa
#162, March 19, 2012: no winner
#163, March 26, 2012: John Runnels, Raul A. Félix de Sousa
#164, April 2, 2012: Sean Ridout
#165, April 9, 2012: no winner
#166, April 16, 2012: Raul A. Félix de Sousa
#167, April 23, 2012: Dima Klenchin, Deena Allan
#168, April 30, 2012: Sean Ridout
#169, May 7, 2012: Matt McFarlane
#170, May 14, 2012: no winner
#171, May 21, 2012: no winner
#172, May 29, 2012: Mike Hamilton, Dmitri Tchigvintsev
#173, June 4, 2012: Bill Chaney, Matt McFarlane
#174, June 18, 2012: Raul A. Félix de Sousa
#175, June 25, 2012: Raul A. Félix de Sousa
#176, July 2, 2012: Raul A. Félix de Sousa
#177, July 16, 2012: Sean Ridout, William Grecia
#178, July 23, 2012: Raul A. Félix de Sousa
#179, July 30, 2012: Bill Chaney and Raul A. Félix de Sousa
#180, Aug. 7, 2012: Raul A. Félix de Sousa
#181, Aug. 13, 2012: Matt McFarlane
#182, Aug. 20, 2012: Stephen Spiro
#183, Aug. 27, 2012: Raul A. Félix de Sousa
#184, Sept. 3, 2012: Matt McFarlane
#185, Sept. 10, 2012: Matt Talarico
#186, Sept. 17, 2012: no winner
#187, Sept. 24, 2012: Mikkel Rasmussen
#188, Oct. 1, 2012: John Runnels
#189, Oct. 8, 2012: Raúl Mancera
#190, Oct. 15, 2012: Raul A. Félix de Sousa
#191, Oct. 22, 2012: Mikkel Rasmussen
#192, Nov. 12, 2012: Seth Kasowitz, Bill Gunn
#193, Nov. 19, 2012: Michael Rasmussen
#194, Dec. 4, 2012: Paul Clapham, Jacob Toth
#195, Dec. 10, 2012: Jacob Toth
#196, Dec. 17, 2012: Bill Chaney, Dima Klenchin, Bill Gunn
#197, Jan. 14, 2013: Evey Salara
#198, Jan. 21, 2013: Piotr Gasiorowski
#199, March 11, 2013: Bill Gunn, River Jiang
#200, March 18, 2013: Bill Gunn
#201, April 8, 2013: Michael Florea
#202, April 15, 2013: no winner
#203, April 29, 2013: Anders Ernberg
#204, May 6, 2013: Alex Ling, Michael Florea
#205, May 13, 2013: Bill Chaney
#206, June 24, 2013: Michael Florea
#207, July 2, 2013: Matt McFarlane
#208, July 8, 2013: no winner
#209, July 15, 2013: Rosie Redfield, Thuc Quyen Huynh
#210, July 22, 2013: Jacob Toth
#211, July 29, 2013: Alex Ling, Matt McFarlane
#212, August 5, 2013: Brian Shewchuk
#213, Sept. 2, 2013: no winner
#214, Sept. 9, 2013: Bill Chaney
#215, Sept. 16, 2013: Zhimeng Yu
#216, Sept. 23, 2013: Mark Sturtevant, Jacob Toth
#217, Sept. 30, 2013: Susan Heaphy
#218, Oct. 7, 2013: Piotr Gasiorowski, Jacob Troth
#219, Oct. 14, 2013: Jean-Marc Neuhaus
#220, Oct. 21, 2013: Jean-Marc Neuhaus
#221, Oct. 28, 2013: Zhimeng Yu
#222, Nov. 10, 2013: Caroline Josefsson, Andrew Wallace
#223, Nov. 18, 2013: Dean Bruce, Ariel Gershon
#224, Nov. 25, 2013: Jon Nuelle, Ariel Gershon
#225, Dec. 2, 2013: Jean-Marc Neuhaus
#226, Dec. 9, 2013: Bill Gunn
#227, Dec. 16, 2013: Piotr Gasiorowski
#228, Jan. 13, 2014: Tom Mueller
#229, Jan. 20, 2014: Tommy Stuleanu
#230, Jan. 27, 2014: Bill Gunn, Ariel Gershon
#231; March 3, 2014: Keith Conover, Nevraj Kejiou
#232, March 10, 2014: Philip Johnson
#233, March 17, 2014: Jean-Marc Neuhaus
#234, March 24, 2014: Frank Schmidt, Raul Félix de Sousa
#235, March 31, 2014: Jon Binkley
#236, April 7, 2014: no winner
#237, April 21, 2014: Dean Bruce
#238, April 28, 2014: Dean Bruce
#239, May 5, 2014: Piotr Gąsiorowski
#240, May 12, 2014: James Wagstaff
#241, May 19, 2014: no winner
#242, Oct. 7, 2024: Elie Huvier
#243, Oct. 14, 2024: Mikkel Rasmussen
#244, Oct. 21, 2024: Santi Garcia-Vallve
Philip Ball strikes back
In order to build the case for revolution, he tries to demonstrate a paradigm shift in our view of molecular biology by showing a huge gap between the understanding of previous generations of molecular biologists and the post-genomic view. I believe he is wrong about this for two reasons: first, he misrepresents the views of older molecular biologists and, second he misrepresents the discoveries of the past twenty years. I tried to explain why he was wrong about these two claims in a previous post where I discussed an article he published in Scientific American in May 2024: Philip Ball says RNA may rule our genome.
Philip Ball responded to my criticism in a comment under that article.
Older molecular biologists were really stupid
I said ...
Ball begins with the same old myth that writers like him have been repeating for many years. He claims that before ENCODE most molecular biologists were really stupid. According to Philip Ball, most of us thought that coding DNA was the only functional part of the genome and most of the rest was junk DNA.
In the comment section of my earlier post, Philip Ball says,
I’m sorry to say that Larry’s commentary here is dismayingly inaccurate.
Let’s get this one out of the way first:
“He claims that before ENCODE most molecular biologists were really stupid.”
I have never made this claim and never would – it is a pure fabrication on Larry’s part. I guess this is what John Horgan meant in his comment to Larry: credible writers don’t just make up stuff.
I admit that Philip Ball never said those exact words. I'll leave it to the readers to decide whether my characterization of his position is accurate.
I stand by the statements I made although I admit to a bit of hyperbole. Ball has said repeatedly that the molecular biologists of my generation were wedded to the idea that coding regions were the only important part of the genome and he often connects that to the Central Dogma of Molecular Biology. He also claims that the experts in molecular biology dismissed all non-coding DNA as junk. Here's how he puts it in another article that he published recently in Aeon: We are not machines.
Only around 1-2 per cent of the entire human genome actually consists of protein-coding genes. The remainder was long thought to be mostly junk: meaningless sequences accumulated over the course of evolution. But at least some of that non-coding genome is now known to be involved in regulating genes: altering, activating or suppressing their transcription in RNA and translation into proteins.
I interpret that to mean that older molecular biologists, like me, didn't know about functional non-coding DNAs such as centromeres, telomeres, origins of replication, non-coding genes, SARs, and regulatory sequences in spite of the fact that thousands of papers on these sequences were published in the 30 years that preceded the publication of the first draft of the human genome sequence. This is not true, we did know about those things. I don't think it's too much of an exaggeration to say that Philip Ball thinks we were really stupid.
Here's what he says in his book, "How Life Works" (p. 85) when he's talking about the beginning of the human genome project.
Even at its outset, it faced the somewhat troubling issue that just 2 percent or so of our genome actually accounts for protein-coding genes. The conventional narrative was that our biology was all about proteins, for each of which the genome held the template. ... But we had all this other DNA too! What was it for? The common view was that it was mostly just junk, like the stuff in our attics: meaningless material accumulated during evolution, which our cells had no motivation to clear out.
Again, his claim is that in 1990 at the beginning of the human genome project the experts in molecular biology thought that non-coding DNA was mostly junk (98% of the genome). I have repeatedly refuted this myth and challenged anyone to come up with a single scientific paper arguing that all non-coding DNA is junk. I challenge Philip Ball to find a single molecular biology textbook written before 1990 that fails to discuss regulation, non-coding genes, and other non-coding functional elements in the human genome.
The truth is that the molecular biology experts concluded in the 1970s that we had about 30,000 genes and that 90% of our genome is junk and 10% is functional. That 10% consisted of about 2% coding DNA (now thought to be only 1%) and 8% functional non-coding DNA. So the "conventional narrative" was that there was a lot more functional non-coding DNA than coding DNA.
The human genome is full of genes for regulatory RNAs.
"Ball is one of the most meticulous, precise science writers out there. He is the antithesis of hypey, "dumb-it-down" reporting. He is MUCH more credible than you are, Laurence."
John Horgan July, 2024The title of the article I was discussing is "Revolutionary Genetics Research Shows RNA May Rule Our Genome." In that article Ball says that ENCODE was basically right and there are many more non-coding genes than protein-coding genes. I pointed out that Ball mentions some criticism of this idea but only to dismiss it. I said that "[Ball] wants you to believe that almost of all of those transcripts are functional—that's the revolution that he's promoting." Philip Ball objects to this statement ...
This too is sheer fabrication. I don’t say this in my article, nor in my book. Instead, I say pretty much what Larry seems to want me to say, but for some reason he will not admit it – which is that there is controversy about how many of the transcripts are functional."
Ball states that "ENCODE was basically right" when they claimed that 75% of our genome was transcribed and he goes on to say that ...
Dozens of other research groups, scoping out activity along the human genome, also have found that much of our DNA is churning out 'noncoding' RNA.
He says that ENCODE has identified 37,000 noncoding genes but there may be as many as 96,000. After making these definitive statements, he mentions that there are "still doubters" but then discuss why these discoveries are revolutionary. Later on he quotes John Mattick suspecting that there may be more that 500,000 non-coding genes.
Toward the end of the article, after discussing all kinds of functional RNAs, he brings up the Ponting and Haerty review where they say that most lncRNAs are just noise. He also mentions that the low copy number of non-coding RNAs raises questions about whether they are functional but immediately counters with the standard excuses from his allies.
Ball closes the article with ...
Gingeras says he is perplexed by ongoing claims that ncRNAs are merely noise or junk, as evidence is mounting that they do many things. "It is puzzling why there is such an effort to persuade colleagues to move from a sense of interest and curiosity in the ncRNA field to a more dubious and critical one," he says.
Perhaps the arguments are so intense because they undercut the way we think our biology works. Ever since the epochal discovery about DNA's double helix and how it encodes information, the bedrock idea of molecular biology has been that there are precisely encoded instructions that program specific molecules for particular tasks. But ncRNAs seem to point to a fuzzier, more collective, logic to life. It is a logic that is harder to discern and harder to understand. ut if scientists can learn to live with the fuzziness, this view of life may turn out to be more complete.
What's remarkable about the quote from a leading ENCODE worker (Gingeras) is that he is "puzzled" by scientists who are dubious and critical about claims in the ncRNA field. Isn't that what good scientists are supposed to do? Isn't that exactly what we did when we successfully challenged the dubious claims about junk DNA made in 2012?
There is no doubt in my mind that Philip Ball has fallen hook-line-and-sinker for the ENCODE claims that our genome is buzzing with non-coding genes. He only brings up the counter-arguments to dismiss them and pretend that he is being fair. Nobody who was truly skeptical about the function of transcripts would write an article with the title, "Revolutionary Genetics Research Shows RNA May Rule Our Genome."
However, as Ball points out in other comments, he does have a sentence in his book where he mentions that perhaps only 30% of the genome is functional. He says in the comment that what he believes is that the amount of functional DNA lies somewhere between 10% and 30%. That's not something that he mentions in the Scientific American article but, if he's being honest, it does mean that I was unfair when I said he believes that "almost of all of those transcripts are functional" but I only know that from what he now says, not from the published article.
If I were to take Philip Ball at his word—as expressed in the comment—then he must believe that most of the ENCODE transcripts are junk RNA. That's not a belief that you get from reading his published work.2 Furthermore, if I were to take him at his word, then he must believe that there are some reasonable criteria that must be applied to a transcript in order to decide whether it has a biologically relevant function. So, when he says that ENCODE identified 37,600 non-coding genes he must have these criteria in mind but he doesn't express any serious skepticism about that number. We all know that there's no solid evidence that such a large number of transcripts are functional but that doesn't bother Philip Ball. He thinks we are in the middle of an RNA revolution.
1. In commenting to my previous post, Ball says he believes that somewhere between 70% and 90% of our genome is junk but he doesn't say this in the Scientific American article. Instead, he says that scientists were surprised to learn that 75% of the human genome is transcribed implying that there's a lot of function. He goes on the say that "ENCODE was basically right." But what the ENCODE publicity campaign actually said was that junk DNA is dead and there's practically no junk DNA. If Ball really believes that up to 90% of the genome is junk then to me this means that ENCODE was spectacularly wrong not "basically right."
2. Ball says that 75% of the genome is transcribed. If Ball believes that as little as 10% may be functional then he must believe that less than 10% is transcribed to produce functional RNAs since he has to allow for regulatory sequences and other functional DNA elements. Let's say that 8% is a reasonable number. Ball seems to be willing to admit that 67% of the genome might be transcribed to produce junk RNA.