The success of protein structure prediction software depended on the solved structures deposited in the Protein Data Bank (PDB)

The development of protein structure prediction programs began fifty years ago and culminated in the remarkable success of AlphaFold, developed by Google DeepMind. Demis Hassabis and John Jumper of Google DeepMind received the Nobel Prize in Chemistry (2024) for their work on AlphaFold.

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.

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." ...

Jonathan Wells (1942 - 2024)

Johnathan Wells died recently. He was a well-known Intelligent Design Creationist and that's why Evolution News (sic) is eulogizing him by posting multiple tributes and excerpts from his books and essays.

I think it's only fair to post links to my efforts to demonstrate the serious flaws in his arguments. I'm particularly proud of the series of articles I wrote when he published his book The Myth of Junk DNA. I went through every chapter and analyzed his arguments against junk DNA. It won't surprise anyone to learn that I found those arguments lacking in substance and in some cases I discovered that Wells had misrepresented the science.

Here are my posts.

• Jonathan, Moonies, and Junk DNA
• Junk & Jonathan: Part I—Getting the History Correct
• Junk & Jonathan: Part 2— What Did Biologists Really Say About Junk DNA?
• Junk & Jonathan: Part 3—The Preface
• Junk & Jonathan: Part 4—Chapter 1
• Junk & Jonathan: Part 5—Chapter 2
• Junk & Jonathan: Part 6—Chapter 3
• Junk & Jonathan: Part 7—Chapter 4
• Junk & Jonathan: Part 8—Chapter 5
• Junk & Jonathan: Part 9—Chapter 6
• Junk & Jonathan: Part 10—Chapter 7
• Junk & Jonathan: Part 11—Chapter 8
• Junk & Jonathan: Part 12—Chapter 9
• Junk & Jonathan: Part 13—Chapter 10

Jonathan Wells never responded directly to my criticism but he did respond to a comment that Paul McBride made on one of his blog posts. Paul asked him why he didn't respond to my post and here's what Wells said,

Oh, one last thing: “paulmc” referred to an online review of my book by University of Toronto professor Larry Moran—a review that “paulmc” called both extensive and thorough. Well, saturation bombing is extensive and thorough, too. Although “paulmc” admitted to not having read more than the Preface to The Myth of Junk DNA, I have read Mr. Moran’s review, which is so driven by confused thinking and malicious misrepresentations of my work—not to mention personal insults—that addressing it would be like trying to reason with a lynch mob.

This is typical of the attitude of most Intelligent Design Creationists. They are happy to publish lengthy books denegrating science and scientists but couldn't be bothered responding to criticism.

Here's are some other post of mine where I demonstrate the flawed thinking of Jonathan Wells.

• Jonathan Wells talks about junk DNA
• Jonathan Wells illustrates zombie science by revisiting junk DNA
• Brace yourselves, a new "Icons" is coming
• Jonathan Wells proves that life must have been created by gods
• Answering ten questions from the IDiots
• John Mattick vs. Jonathan Wells
• Some Questions for IDiots
• American Loons: #409 Jonathan Wells and #411 John West
• A Dishonest Intelligent Design Proponent?
• We Called Out IDiot Jonathan Wells, and He Folded
• Jonathan Wells Sends His Regrets
• Watch Jonathan Wells Screw Up
• Jonathan Wells Talks About Sequence Conservation
• Ohmygod! These photographs are faked!
• Fossil Horses and Directed Evolution
• Peppered Moths and the Confused IDiots
• Jonathan Wells reviews the Christiane Nüsslein-Volhard and Wieschaus Experiment

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John Mattick's seminar at the University of Toronto

I just learned that John Mattick gave a seminar this morning at the Department of Cell & Systems Biology at the University of Toronto. Unfortunately, I was unable to attend.

Most Sandwalk readers will recognize Mattick as one of the few remaining vocal opponents of junk DNA. He is probably best known for his dog-ass plot but this is only one of the ways he misrepresents science.

Pentagon ran secret anti-vax campaign to undermine China during pandemic

This is a Reuters report about misinformation spread by the United States military in order to discredit China's Sinovac vaccine. It was directed at the Philippines and other countries who were purchasing the China vaccine.

Reuters suggests that by undermining public trust in government health initiatives the US military might have cost thousands of lives in the Phillippines.

A REUTERS INVESTIGATION: Pentagon ran secret anti-vax campaign to undermine China during pandemic

The U.S. military launched a clandestine program amid the COVID crisis to discredit China’s Sinovac inoculation – payback for Beijing’s efforts to blame Washington for the pandemic. One target: the Filipino public. Health experts say the gambit was indefensible and put innocent lives at risk.

It shouldn't surprise anyone that nations engage in propaganda wars in order to destabilize or demonize their perceived enemies. The world is a complicated multinational environment and meddling in the affairs of other countries is a routine part of modern international relations. It's important to emphasize that it's not only the "bad guys" who do this sort of thing. Your own country and your friends and allies also spread misinformation in order to convince you that you are one of the "good guys" (e.g. defenders of morality, decency, democracy, and freedom).

I emphasize this for two reasons. One, here in Canada there's a lot of pearl-clutchng these days about foreign interference and the main focus is on China and India and how they might have influenced our elections. I think this is pretty minor stuff compared to what else is going on and the foreign influence from other countries, including the United States.

Second, as mentioned above, we all need to be aware of the fact that misinformation is rampant and that doesn't just include misinformation spread by Russia, China, Iran, and Hamas. We also need to be skeptical about information being spread by the governments of Ukraine, Israel, and the United States. Do not assume that everything they say is truthful.

These days, I find that it's almost impossible to hear, read, or watch any "authority" who convinces me that they are critical thinkers without an agenda. Almost all of them seem to be victims of propaganda.

Note: I'm aware of the fact that this report may not be accurate—it may, in fact, be misinformation. I'm mostly using it as a vehicle to point out that you can't trust anyone these days, including your friends. That's very upsetting because I grew up thinking that the mainstream news outlets (TV, radio, newspapers) could be (mostly) trusted.

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

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

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

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

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

Where does misinformation come from and how is it spread?

Older but wiser?

With age comes wisdom, but sometimes age comes alone.

Oscar Wilde

Like many baby boomers, I sometimes forget people's names and other important bits of information. Sometimes I can't find a word that's been in my vocabulary for decades. These lapses are often temporary but very annoying. It's a sign of age. (I am 77 years old.)

We often make fun of these incidents and consol ourselves with the knowledge that we may be old but we are much wiser than we were in our younger days. We have years and years of experience behind us and over the years we've learned a thing or two that we never understood when we were listening to the Beatles on the radio. We've lived through the Cuban Missile crisis, the war in Viet Nam, the assassination of two Kennedys and Martin Luther King, and a host of cultural changes. We've lived in several different countries and we've raised children. All of these experiences have made us wiser, or so we think.

The number of splice variants in a species correlates inversely with the population size - what does that mean?

Most of the genes in eukaryotes contain introns that are removed by splicing during processing of the primary transcript. In some cases the gene produces two different functional RNAs due to differential splicing of the introns. If the product is mRNA then two different versions of the protein can be made as shown in the figure from my book What's in Your Genome? This mechanism is known as alternative splicing.

True alternative splicing is rare—less than 5% of all genes are alternatively spliced.¹ However, when you analyze all of the transcripts in a tissue you will invariably detect many transcripts from junk DNA and many low abundance splice variants. Those transcripts and splice variants are due to transcription errors and splicing errors. Splicing errors arise from the presence of weak splice sites that are occasionally recognized by the normal spliceosome or by the splice factors responsible for true alternative splicing.

Chapter 7: Gene Families and the Birth & Death of Genes

This chapter describes gene families in the human genome. I explain how new genes are born by gene duplication and how they die by deletion or by becoming pseudogenes. Our genome is littered with pseudogenes: how do they evolve and are they all junk? What are the consequences of whole genome duplications and what does it teach us about junk DNA? How many real ORFan genes are there and why do some people think there are more? Finally, you will learn why dachshunds have short legs and what "The Bridge on the River Kwai" has to do with the accuracy of the human genome sequence.

Click on this link to see more.

Gene Families and the Birth and Death of Genes

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ENCODE and their current definition of "function"

ENCODE has mostly abandoned it's definition of function based on biochemical activity and replaced it with "candidate" function or "likely" function, but the message isn't getting out.

Back in 2012, the ENCODE Consortium announced that 80% of the human genome was functional and junk DNA was dead [What did the ENCODE Consortium say in 2012?]. This claim was widely disputed, causing the ENCODE Consortium leaders to back down in 2014 and restate their goal (Kellis et al. 2014). The new goal is merely to map all the potential functional elements.

... the Encyclopedia of DNA Elements Project [ENCODE] was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types.

The new goal was repeated when the ENCODE III results were published in 2020, although you had to read carefully to recognize that they were no longer claiming to identify functional elements in the genome and they were raising no objections to junk DNA [ENCODE 3: A lesson in obfuscation and opaqueness].

Splicing errors or alternative splicing?

The most important issue in alternative splicing, in my opinion, is whether splice variants are due to splicing errors (= junk RNA) or whether they reflect real biologically relevant alternative splicing.

Unfortunately, this view is not shared by the majority of scientists who work in this field. They are convinced that the vast majority of splice variant transcripts represent real examples of regulation and the main task is to document the extent of alternative splicing and characterize the various mechanisms.

I've written a lot about this topic over the years (see the list of posts at the bottom of this page). The two most important issues are: (1) the frequency of splicing errors and whether it can account for the splice variants and (2) the number of well-established, genuine, examples of biologically relevant alternative splicing and whether that's consistent with the claims.

I managed to post a summary of the data on the accuracy of splicing on the Intron article on Wikipedia and I urge you to take a look at it before it disappears. The bottom line is that splicing is not terribly accurate so we expect to detect a fairly high level of incorrectly spliced transcripts whenever we look at a collection of RNAs from a particular cell line. The expected number of mispliced transcripts is well within the concentrations of 'alternatively spliced' transcripts reported in most studies.

Alternative splicing and evolution

The important issue is whether alternative splicing is ubiquitous or rare. What are the evolutionary implications?

I believe that almost all of the splice variants that are routinely detected in eukaryotic cells are the product of splicing errors. (I've summarized the data on splicing errors in the Wikipedia article on Intron.) Database annotators have rejected several hundred thousand of these variants so that the typical human gene now lists only a handful of possible splice variants and very few of these have been experimentally confirmed as genuine examples of alternative splicing.

There are excellent examples of biologically relevant alternative splicing but they are confined to a small number of genes (<5%) and in almost all cases there are only a small number of alternatives (usually two) [Alternative splicing: function vs noise].

What do we do with two different human genome reference sequences?

It's going to be extremely difficult, perhaps impossible, to merge the new complete human genome sequence with the current standard reference genome.

The source DNA for the new telomere-to-telomere (T2T) human genome sequence was a cell line derived from a molar pregnancy. This meant that the DNA was essentially haploid, thus avoiding the complications of sequencing diploid DNA which contains two highly similar but different genomes. The cell line, CHM13, lacks a Y chromosome but that's trivial since a complete T2T sequence of a Y chromosome will soon be published and it can be added to the T2T-CHM13 genome sequence [Telomere-to-telomere sequencing of a complete human genome].

Science reviews a creationist book

You can't get much more anti-science than a book about Adam and Eve. Nevertheless, Stephen Schaffner—a computational biologist at the Broad Institute of MIT in Boston—decided that such a book was worthy of a mostly favorable review in one of the most prestigious science journals in the world [Adam. Eve, and the evolution of humankind].

Schaffner is reviewing a book by William Lane Craig whom he describes as "a widely published philosopher, theologian, and Christian apologist." There are others who would dispute that laudatory description including Richard Dawkins in a ten-year-old essay published in The Guardian [Why I refuse to debate with William Lane Craig].

I won't bother to mention all of the issues with the review since Jerry Coyne has covered them on his website but I would like to quote part of the second-last paragraph of the review.

Craig’s goal in writing this book, of course, is not a scientific one, and it cannot be judged on scientific grounds. I suspect that for many scientists, including religious ones, the exercise will be seen as misguided or simply incomprehensible.

Having followed Craig's anti-science crusade for several years, I have no difficulty in understanding why he would write such a book. What I find truly misguided and incomprehensible is why Science would publish such a review. Perhaps it's because AAAS, the publisher of Science, has a history of accommodating religion?

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Characteristics of COVID-19 in the United States during 2020

An interesting paper on COVID-19 infections in the USA during 2020 was recently published in Nature. The take-home lessons are:

1. about 78% of infections were probably undocumented so the actual number of people with COVID-19 is almost twice the number that's been reported
2. about 31% of the population was infected during 2020 giving rise to a considerable level of natural immunity
3. by the end of 2020 the case fatality rate (CFR = number of deaths per estimated cases) fell to about 0.30% due to better reporting of cases and better patient care
4. the case fatality rate of 0.30% is about four times higher than that of seasonal influenza (<0.08%)

Sen, P., Yamana, T.K., Kandula, S., Galanti, M. and Shaman, J. (2021) Burden and characteristics of COVID-19 in the United States during 2020. Nature 598:338-341.
[doi: 10.1038/s41586-021-03914-4]

The COVID-19 pandemic disrupted health systems and economies throughout the world during 2020 and was particularly devastating for the United States, which experienced the highest numbers of reported cases and deaths during 2020. Many of the epidemiological features responsible for observed rates of morbidity and mortality have been reported; however, the overall burden and characteristics of COVID-19 in the United States have not been comprehensively quantified. Here we use a data-driven model-inference approach to simulate the pandemic at county-scale in the United States during 2020 and estimate critical, time-varying epidemiological properties underpinning the dynamics of the virus. The pandemic in the United States during 2020 was characterized by national ascertainment rates that increased from 11.3% (95% credible interval (CI): 8.3–15.9%) in March to 24.5% (18.6–32.3%) during December. Population susceptibility at the end of the year was 69.0% (63.6–75.4%), indicating that about one third of the US population had been infected. Community infectious rates, the percentage of people harbouring a contagious infection, increased above 0.8% (0.6–1.0%) before the end of the year, and were as high as 2.4% in some major metropolitan areas. By contrast, the infection fatality rate fell to 0.3% by year’s end.

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I think I'll skip this meeting

I just received an invitation to a meeting ...

On behalf of the international organizing committee, we would like to invite you to a conference to be held in Neve Ilan, near Jerusalem, from 4-8 October 2021, entitled ‘Potential and Limitations of Evolutionary Processes’. The main goal of this interdisciplinary, international conference is to bring together scientists and scholars who hold a range of viewpoints on the potential and possible limitations of various undirected chemical and biological processes.

The conference will include presentations from a broad spectrum of disciplines, including chemistry, biochemistry, biology, origin of life, evolution, mathematics, cosmology and philosophy. Open-floor discussion will be geared towards delineating mechanistic details, with a view to discussing in such a way that speakers and participants feel comfortable expressing different opinions and different interpretations of the data, in the spirit of genuine academic inquiry.

I'm pretty sure I got this invite because I attended the Royal Society Meeting on New trends in evolutionary biology: biological, philosophical and social science perspectives back in 2016. That meeting was a big disappointment because the proponents of extending the modern synthesis didn't have much of a case [Kevin Laland's new view of evolution].

I was curious to see what kind of followup the organizers of this new meeting were planning so I checked out the website at: Potential and Limitations of Evolutionary Processes. Warning bells went off immediately when I saw the list of topics.

• Fine-Tuning of the Universe
• The Origin of Life
• Origin & Fine-Tuning of the Genetic Code
• Origin of Novel Genes
• Origin of Functional Islands in Protein Sequence Space
• Origin of Multi-Component Molecular Machines
• Fine-Tuning of Molecular Systems
• Fine-Tuning in Complex Biological Systems
• Evolutionary Waiting Times
• History of Life & Comparative Genomics

This is a creationist meeting. A little checking shows that three of the four organizers, Russ Carlson, Anthony Futerman, and Siegfried Scherer, are creationists. (I don't know about the other organizer, Joel Sussman, but in this case guilt by association seems appropriate.)

I don't think I'll book a flight to Israel.

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Alternative splicing: function vs noise

This post is about a recent review of alternative splicing published by my colleague Ben Blencowe in the Dept. of Medical Genetics at the University of Toronto (Toronto, Ontario, Canada). (The other author is Jermej Ule of The Francis Crick Institute in London (UK).) They are strong supporters of the idea that alternative splicing is a common feature of most human genes.

I am a strong supporter of the idea that most splice variants are due to splicing errors and only a few percent of human genes undergo true alternative spicing.

This is a disagreement about the definition of "function." Is the mere existence of multiple splice variants evidence that they are biologically relevant (functional) or should we demand evidence of function—such as conservation—before accepting such a claim?

The frequency of splicing errors reflects the balance between selection and drift

Splice variants are very common in eukaryotes. We know that it's possible to detect dozens of different splice variants for each gene with multiple introns. In the past, these variants were thought to be examples of differential regulation by alternative spicing but we now know that most of them are due to splicing errors. Most of the variants have been removed from the sequence databases but many remain and they are annotated as examples of alternative splicing, which implies that they have a biological function.

I have blogged about splice variants many times, noting that alternative splicing is a very real phenomenon but it's probably restricted to just a small percentage of genes. Most of splice variants that remain in the databases are probably due to splicing errors. They are junk RNA [The persistent myth of alternative splicing].

The ongoing controversy over the origin of splice variants is beginning to attract attention in the scientific literature although it's fair to say that most scientists are still unaware of the controversy. They continue to believe that abundant alternative splicing is a real phenomenon and they don't realize that the data is more compatible with abundant splicing errors.

Some molecular evolution labs have become interested in the controversy and have devised tests of the two possibilities. I draw your attention to a paper that was published 18 months ago.

Alternative splicing in the nematode C. elegans

The importance of alternative splicing is highly controversial. In the case of humans, the competing views are: (a) more than 90% of human protein-coding genes are alternatively spliced to produce multiple protein isoforms, and (b) less than 10% of human genes are alternatively spliced and most of the splice variants detected are due to splicing errors.

In addition to this fundamental difference in how to interpret the data, there's a controversy over the meaning and significance of abundant alternative splicing, assuming that it exists. The consensus view among the workers in the field is that alternative splicing is ubiquitous and it explains why humans are so complex when they have only the same number of genes as "lower" species like the nematode C. elegans. This was the view expressed by Gil Ast in a 2005 Scientific American article on "The Alternative Genome."

The textbook view of alternative splicing

As most of you know, I'm interested in the problem of alternative splicing. I believe that the number of splice variants that have been detected is perfectly consistent with the known rate of splicing errors and that there's no significant evidence to support the claim that alternative splicing leading to the production of biologically relevant protein variants is widespread. In fact, there's plenty of evidence for the opposite view; namely, splicing errors (lack of conservation, low abundance, improbable protein predictions, inability to detect the predicted proteins).

My preferred explanation is definitely the minority view. What puzzles me is not the fact that the majority is wrong () but the fact that they completely ignore any other explanation of the data and consider the case for abundant alternative splicing to be settled.