Bastille Day 2024

Today is the Fête Nationale in France known also as "le quatorze juillet" or Bastille Day.

This is the day in 1789 when French citizens stormed and captured the Bastille—a Royalist fortress in Paris. It marks the symbolic beginning of the French revolution although the real beginning is when the Third Estate transformed itself into the National Assembly on June 17, 1789 [Tennis Court Oath].

We visited the site of the Bastille (Place de la Bastille) when we were in Paris a few years ago. There's nothing left of the former castle but the site still resonates with meaning and history.

My wife's 5th great-grandfather is William Playfair (1759-1823), the inventor of pie charts and bar graphs [Bar Graphs, Pie Charts, and Darwin]. His work attracted the attention of the French King so he moved to Paris in 1787 to set up an engineering business. Playfair was present at the storming of the Bastille on July 14, 1789. He is recorded as one of one of about 1000 militia who took part in the action: "William Playfair, ingénieur anglais, petit hôtel de Lamaignon rue Couture Sainte Catherine."

His residence, the Hôtel de Lamaignon, still exists. It was about a kilometer west of the Bastille.

In honor of the French national day I invite you to sing the French national anthem, La Marseillaise. An English translation is provided so you can see that La Marseillaise is truly a revolutionary call to arms. (A much better translation can be found here.)

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Check out Uncertain Principles for another version of La Marseillaise—this is the famous scene in Casablanca.

Reposted and modified from 2017.

My ancestor's house in New Amsterdam (1655)

This is the 400th anniversary of the founding of New Amsterdam by Dutch settlers. The map shows what the city looked like in 1660, a few years before it was taken over by the British and renamed New York. The red oval shows the location of Abraham Rychen's house; he sold it in 1655.

Abraham Rycken was born in 1618 in Nijmegen, Netherlands. He is my 9th great-grandfather. Abraham married Grietje Harmensen, the daughter of settler Harmen Harmensen. Harmen was an armorer for the Dutch army and later retired to a farm on Riker's Island where he made tomahawks for the indigenous people who lived there and on Long Island. Harmen was killed in 1643 by a native using one of his tomahawks.

Jerry Coyne changes his mind about the lab leak conspiracy theory and now rejects it

Jerry Coyne was initially convinced by Alina Chan's arguments in favor of the lab leak conspiracy theory concerning the origin of SARS-CoV-2. His mind was changed by reading Paul Offit's rebuttal [Lab Leak Mania].

Here's how Jerry describes his conversion in an article posted on his website [The lab leak theory for the origin of the Covid virus is once again deep-sixed].

The Scientific Theory of Intelligent Design

Everything that's happening in the world today is very depressing but there's at least one bright spot. The Intelligent Design Creationists have finally come up with a scientific theory of intelligent design. It's described by mathematics professor Ganville Sewell on the Evolution News (sic) website: Introduction to the Scientific Theory of Intelligent Design.

Here's how Sewell desribes this "scientific theory."

Of course, normally if a scientific theory for some observed phenomenon fails, we just look for an alternative “natural” theory. But what has long been obvious to the layman is finally becoming clear to many scientists, that evolution is different. We are not talking now about explaining earthquakes or comets or volcanos, we are talking about explaining hearts and lungs and eyes and ears. How many theories without design can there be for the origin of circulatory systems, nervous systems, and human brains? Design has finally started to be taken seriously by scientists not because there are minor problems with Darwin’s explanation, but because it has become absurdly, blindingly obvious that neither it nor any other theory that ignores design will ever completely explain living things. Contrary to common belief, science really has no reasonable alternative to design to explain either the origin or evolution of life. In fact, we really have no idea how living things are able to pass their current complex structures on to their descendants without significant degradation, generation after generation, much less how they evolve even more complex structures.

That's it? The scientific theory of intelligent design is that evolution has failed and it is now "absurdly, blindingly obvious" that you need design in order to explain the origin of life or the evolution of life.

I'm still depressed. Is this the best they can do after three decades of pushing intelligent design creationism?¹

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1. Yes.

"Cancer Virus Hunters" by Gregory J. Morgan

That seven Nobel Prizes were awarded directly or indirectly for work in tumor virology illustrates the impact of the field on biomedical understanding. (p. 273)

We've entered a new era in the field of molecular biology. Almost all of the emphasis and excitement these days is based on studies of mammals, especially humans. Most of the big bucks are for studying some aspect of medicine so that even if you are interested in basic science you have to slant it toward curing some disease.

"Enlightened" scientist at the University of Colorado busts the myth that all non-coding DNA is junk!

We've known for 60 years that some non-coding DNA has a function but the latest generation of scientists thinks this was only discovered in their lifetime. Writer Kara Mason posts an article on the Department of Biomedical Informatics website at the University of Colorado.

Which first commandment do Louisiana school children have to obey?

The government of the state of Louisiana (USA) has just passed a law that requires ten commandments to be posted in every classroom of every publicly funded elementary, secondary, and postsecondary school [House Bill No. 71]. Here's the first one that's specified in the law.

I AM the LORD thy God. Thou shalt have no other gods before me. Thou shalt not make to thyself any graven images. Thou shalt not take the Name of the Lord thy God in vain.

Fauci claims (incorrectly) that the lab leak conspiracy theory is not a conspiracy theory

Here's Fauci being interviewed on MSNBC as part of his book promotion tour (see below). He's asked about the lab leak conspiracy theory beginning at 10 mins. He points out that there's no evidence that SARS-CoV-2 came from the Wuhan Institute of Virology (WIV) but he's keeping an "open mind" about the possibility that something could be true in the absence of evidence and in the face of considerable evidence for a natural origin.

The most fascinating part of the interview is when he goes out of his way to say that such a possibility doesn't require a conspiracy theory. Really?

David Gorski (Orac) dismantles Alina Chan's lab leak conspiracy theory

This post is just a place-holder for an article that I've already shared on Facebook. I greatly appreciate the fact that Orac referrd to me several times in his article on Respectful Insolence.

The New York Times goes all in on “lab leak”

Earlier this week, the New York Times op-ed page ran an article by Alina Chan, Queen of lab leak conspiracy theories. How is it wrong? Let me count the ways…

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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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Anti-science New York Times doubles down on the lab leak conspiracy theory

On June 3, 2024,the New York Times published an opinion piece by Alina Chan in which she promoted the lab leak conspiracy theory about the origin of COVID-19. Her views are not shared by the scientific community and the newspaper was criticized by many who pointed out the many flaws in Chan's arguments and her lack of objectivity.¹

I suspect that some people at the NYT might have been somewhat embarrassed by the response to their reckless behavior so they prepared a response. It was written by David Leonhardt who identifies himself as "a senior writer at the New York Times who runs "The Morning", our flagship daily newsletter." He published his article on the website that he runs and the title sounds like it might be an objective appraisal of the evidence in favor of a natural origin of COVID-19 originating in the Wuhan market: Two Covid Theories.

Don't be fooled by the title. Leonhardt makes no attempt to summarize the massive amount of evidence in favor of a natural origin. Instead, he treats the scientific view and the lab leak conspiracy theory as equally probable.

Do you find both explanations plausible? I do.

As I’ve followed this debate over the past few years, I have gone back and forth about which is more likely. Today, I’m close to 50-50. I have heard similar sentiments from some experts.

“No one has proof,” Julian Barnes, who covers intelligence agencies for The Times, told me. “Everyone is using logic.” Julian’s advice to the rest of us: “Be wary, keep an open mind, rule nothing out.”

Let's be clear about what's necessary in order for the lab leak conspiracy theory to be probable.

1. There has to be evidence that SARS-CoV-2 was present in the Wuhan Institute of Virology (WIV) before the pandemic started. There is none.
2. The graduate students, post-docs, scientists, and research technicians at WIV all deny that they were working with SARS-CoV-2 or any closely-related virus before the pandemic started. In order for the lab leak conspiracy theory to be true they must be lying and engaging in a massive coverup. This is totally inconsistent with their behavior over the past two decades. (The woman in the photo is Shi Zhengli, an internationally renowned scientist who Alina Chan accuses of lying—a claim that David Leonhardt thinks is quite possible.)

The latest opinion piece looks to me like an attempt to defend the NYT against accusations that it is anti-science. You would think that in such a defense, the author would be able to present good scientific evidence for the lab leak conspiracy theory, right? Here's the three arguments advanced by David Leonhardt in support of this massive conspiracy.

1. COVID-19 was first detected near the market in Wuhan and the Wuhan Virolgy Institute is in Wuhan.
2. Leaks happen.
3. China controls the evidence (i.e. conspiracy).

I think we are fully justified in claiming that the NYT is anti-science. I think the newspaper owes the scientific community an apology for ignoring the evidence of a natural origin and disparaging the reputations of reputable scientists who reject the lab leak conspiracy theory in favor of a natural origin.

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1. [The New York Times promotes the lab leak conspiracy theory] [Real scientists destroy the Alina Chan lab leak conspiracy theory] [The New York Times goes all in on “lab leak”] [No, gain of function research did not cause COVID-19]

Tom Cech writes about the "dark matter" of the genome

Tom Cech won a Nobel Prize for discovering one example of a catalytic RNA. He recently published an article in the New York Times extolling the virtues of RNA and non-coding genes [The Long-Overlooked Molecule That Will Define a Generation of Science]. There's a fair amount of hype in the article but the main point is quite valid—over the past fifty years we have learned about dozens of important non-coding RNAs that we didn't know about at the beginning of molecular biology [see: Non-coding RNA, Non-coding DNA].

The main issue in this field concerns the number of non-coding genes in the human genome. I cover the available data in my book and conclude that there are fewer than 1000 (p.214). Those scientists who promote the importance of RNA (e.g. Tom Cech) would like you to believe that there are many more non-coding genes; indeed, most of those scientists believe that there are more non-coding genes than coding genes (i.e. > 20,000). They rarely present evidence for such a claim beyond noting that much of our genome is transcribed.

Tom Cech is wise enough to avoid publishing an estimate of the number of non-coding genes but his bias is evident in the following paragraph from near the end of his article.

Although most scientists now agree on RNA's bright promise, we are still only beginning to unlock its potential. Consider, for instance, that some 75 percent of the human genome consists of dark matter that is copied into RNAs of unknown function. While some researchers have dismissed this dark matter as junk or noise, I expect it will be the source of even more exciting breakthroughs.

Let's dissect this to see where the bias lies. The first thing you note is the use of the term "dark matter" to make it sound like there's a lot of mysterious DNA in our genome. This is not true. We know a heck of a lot about our genome, including the fact that it's full of junk DNA. Only 10% of the genome is under purifying selection and assumed to be functional. The rest is full of introns, pseudogenes, and various classes of repetitive sequences made up mostly of degraded transposons and viruses. The entire genome has been sequenced—there's not much mystery there. I don't know why anyone refers to this as "dark matter" unless they have a hidden agenda.

The second thing you notice is the statement that 75% of the genome is transcribed at some time or another and, according to Tom Cech, these transcripts have an unknown function. That's strange since protein-coding genes take up roughly 40% of our genome and we know a great deal about coding DNA, UTRs, and introns. If you add in the known examples of non-coding genes, this accounts for an additional 2-3% of the genome.¹

Almost all the rest of the transcripts come from non-conserved DNA and those transcripts are present at less than one copy per cell. As the ENCODE researchers noted in 2014, they are likely to be junk RNA resulting from spurious transcription. I'd say we know a great deal about the fraction of the genome that's transcribed and there's not much indication that it's hiding a plethora of undiscovered functional RNAs.

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Photo credit: University of Colorado, Boulder.

1. In my book I make a generous estimate of 5,000 non-coding genes in order to avoid quibbling over a smaller number and in order to demonstrate that even with such a obvious over-estimate the genome is still 90% junk.

June 6, 1944: My father on D-Day

This year is the 80th anniversary of D-Day—the day British, Canadian, and American troops landed on the beaches of Normandy in World War II.¹

For us baby boomers, it has always meant a day of special significance for our parents. In my case, it was my father who took part in the invasions. That's him on the right as he looked in 1944. He was an RAF pilot flying rocket-firing typhoons in close support of the ground troops. His missions were limited to quick strikes and reconnaissance during the first few days of the invasion because Normandy was at the limit of their range from southern England. During the second week of the invasion (June 14th) his squadron landed in Crepon, Normandy and things became very hectic from then on with several close support missions every day [see Hawker Hurricanes and Typhoons in World War II].

The New York Times promotes the lab leak conspiracy theory

Scientists have been actively investigating the origin of SARS-CoV-2 for the past four years. The evidence strongly favors early transmission from infected animals in the Huanan seafood market in Wuhan, China (Worobey et al., 2022; Alwine et al., 2023; Dwyer, 2023; Holmes et al., 2021; Holmes, 2024). The virus probably originated in bats in China or southest asia. [The case for a natural origin of SARS-CoV-2] [Real scientists discuss the lab leak conspiracy theory]

Some people have suggested that the infectious virus, SARS-Cov-2, escaped from a lab in the Wuhan Institute of Virology in spite of the fact that there's not a shred of evidence that the scientists there ever worked with such a strain before the pandemic and all the scientists deny that they had ever seen the pandemic virus before the pandemic began. Such suggestions have all the characteristics of a conspiracy theory (Lewandowsky et al., 2023; Goodrum et al., 2023).¹

The New York Times has just published an opinion piece that promotes the lab leak conspiracy theory. It just happened to coincide with a Republican witch hunt investigation into Dr. Fauci and the origins of SARS-CoV-2. The article is written by Alina Chan who wrote a book on the subject with co-author Matt Ridley [Alina Chan teams up with Matt Ridley to promote the lab leak conspiracy theory].

Here's the link to the NYT article: Why the Pandemic Probably Started in a Lab, in 5 Key Points. As you can see from the title, Alina Chan has five reasons why the scientists at the Wuhan Institute of Virology were working on SARS-Cov-2 before the pandemic began and why they are denying that the virus escaped from their lab. All of these five points have been discredited and/or discounted but that didn't stop the newspaper from promoting them.²

1. The SARS-like virus that caused the pandemic emerged in Wuhan, the city where the world’s foremost research lab for SARS-like viruses is located.

   This is just about the only thing in the lab leak conspiracy theory that is true.

2. The year before the outbreak, the Wuhan institute, working with U.S. partners, had proposed creating viruses with SARS‑CoV‑2’s defining feature.

This is extremely misleading. The researchers at WIV worked in collabortion with scientists in other countries, including the United States, on investigating the features of coronaviruses that could lead to infection of humans. That's exactly what you would expect them to do. They never created a virus that could be infectious.

3. The Wuhan lab pursued this type of work under low biosafety conditions that could not have contained an airborne virus as infectious as SARS‑CoV‑2.

   The labs followed all the standard procedures for work of this type and passed an international inspection.

4. The hypothesis that Covid-19 came from an animal at the Huanan Seafood Market in Wuhan is not supported by strong evidence.

   That's a lie. There is strong evidence that the outbreak began in the market.

5. Key evidence that would be expected if the virus had emerged from the wildlife trade is still missing.

   It's true that the exact infectious animal carrying SARS-CoV-2 has not been identified but the circumstantial evidence is strong—just as strong as the circumstantial evidence that sends some people to jail. It's crazy to say that evidence for animal transmission is missing when ALL the evidence for the presence of SARS-CoV-2 at WIT is also missing.

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1. The researchers at WIV are highly respected international experts on virology, especially coronaviruses. They published in the best international journals. Since they all deny that they were working with SARS-CoV-2 before the pandemic, the lab leak hypothesis absolutely requires that several hundred reseachers are lying and covering up the fact that the virus leaked from their labs. In other words, a conspiracy is an essential part of the lab leak conspiracy theory [see Most scientists dismiss the lab leak conspiracy theory].

2. It's amazing how many media personalities have assumed that there must be some element of truth in this opinion piece just because it was published in the New York TImes. It's even more amazing that these media personalities couldn't find any real scientists to interview.

Alwine, J.C., Casadevall, A., Enquist, L.W., Goodrum, F.D. and Imperiale, M.J. (2023) A critical analysis of the evidence for the SARS-CoV-2 origin hypotheses, Am Soc Microbiol. 97: e00365-00323. [doi: 10.1128/jvi.00365-23]

Dwyer, D.E. (2023) The origins of severe acute respiratory syndrome-coronavirus-2. Seminars in Respiratory and Critical Care Medicine, Thieme Medical Publishers, Inc. [doi: 10.1055/s-0042-1759564]

Goodrum, F., Lowen, A.C., Lakdawala, S., Alwine, J., Casadevall, A., Imperiale, M.J., Atwood, W., Avgousti, D., Baines, J. and Banfield, B. (2023) Virology under the microscope—a call for rational discourse. Journal of virology 97:e00089-00023. [doi: 10.1128/jvi.00089-23]

Holmes, E.C., Goldstein, S.A., Rasmussen, A.L., Robertson, D.L., Crits-Christoph, A., Wertheim, J.O., Anthony, S.J., Barclay, W.S., Boni, M.F., Doherty, P.C., Farrar, J., Geoghegan, J.L., Jiang, X., Leibowitz, J.L., Neil, S.J.D., Skern, T., Weiss, S., R, Worobey, M., Anderson, K.G., Garry, R.F. and Rambaut, A. (2021) The origins of SARS-CoV-2: A critical review. Cell 184:4848-4856. [doi: 10.1016/j.cell.2021.08.017]

Holmes, E.C. (2024) The emergence and evolution of SARS-CoV-2. Annual review of virology 11. [doi: 10.1146/annurev-virology-093022-013037]

Lewandowsky, S., Jacobs, P.H. and Neil, S. (2023) Leak or Leap? Evidence and Cognition Surrounding the Origins of the SARS-CoV-2 Virus. Covid Conspiracy Theories in Global Perspective, ed. Michael Butter and Peter Knight:26-39. [PDF]

Worobey, M., Levy, J.I., Malpica Serrano, L., Crits-Christoph, A., Pekar, J.E., Goldstein, S.A., Rasmussen, A.L., Kraemer, M.U., Newman, C. and Koopmans, M.P. (2022) The Huanan Seafood Wholesale Market in Wuhan was the early epicenter of the COVID-19 pandemic. Science 377:951-959. [doi: 10.1126/science.abp8715]

Telomere length in humans

Telomeres are repetitive DNA sequences at the ends of chromosomes. In humans, the repeat sequence is TTAGGG. The purpose of telomeres is to protect the ends of the chromosomes from shortening after DNA replication [Telomeres].

Telomeres are just one of many functional DNA elements in the human genome. The average length of human telomeres was long thought to be about 10 kb and since there are 24 distinct chromosomes in the human genome this amounts to about 480 kb of telomere sequence or about 0.015% of the human genome. With the advent of new sequencng technology it is now possible to generate long reads of DNA sequence and this has led to a somewhat shorter estimate of telomere length (Karimian et al., 2024). The figure from thier paper shows that the average length of telomeres gets shorter with age but the starting length in newborns (cord DNA) is about 8 kb instead of 10 kb. The authors explain why their sequencing technique is likely to give more accurate results than the earlier estimates.

This doesn't make much difference to the previous estimate but I thought I'd post an update since I overestimated the contribution of telomeres in my book and I made a calculation error in a previous post [Telomeres].

If we use 8 kb as the average length, then that means a total of 8 × 2 × 24 = 384 kb or 0.012% of the standard human genome, which includes 22 autosomes and both sex chromsomes.

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Image Credit: The image shows human chromosomes (blue) labelled with a telomere probe (yellow), from Christopher Counter at Duke University.

Karimian, K., Groot, A., Huso, V., Kahidi, R., Tan, K.-T., Sholes, S., Keener, R., McDyer, J.F., Alder, J.K., Li, H., Rechtsteiner, A. and Greider, C. (2024) Human telomere length is chromosome end–specific and conserved across individuals. Science 384:533-539. [doi: 10.1126/science.ado0431]

University of Toronto President explains why the Occupy for Palestine demands are unreasonable and unacceptable

The Occupy for Palestine protestors have occupied part of the campus of the University of Toronto. The protestors are making two demands on the university.

• “terminate all partnerships with Israeli academic institutions that operate in the Occupied Palestinian Territories, or sustain the apartheid policies, occupation and illegal settlement of these territories.”
• “divest its endowment, pension fund, and other financial holdings from all companies that provide Israel with military goods or services which sustain the Israeli apartheid, occupation and illegal settlement of the Palestinian Territories, as well as the ongoing attacks on Gaza.”

The President of the University of Toronto, Meric Gertler, has responded to these demands with a letter sent to the members of Occupy for Palestine [President Meric Gertler’s response to members of Occupy for Palestine].

With respect to the first demand, President Gertler points out that the university has a history of opposition to academic boycotts.

Such demands are antithetical to the University’s firm conviction that the best way to protect human rights is by staunchly defending and promoting academic freedom, freedom of expression, and the unfettered circulation of ideas within the global scholarly community. We have consistently emphasized that it is both inappropriate and, ultimately, counterproductive to single out academics working or studying in a particular country, and to hold them accountable for the actions or policies of their country’s government. Faculty and students are often among the most trenchant critics of their own government’s policies or actions. Events over the past year confirm that Israeli academics – as well as university leaders – have been amongst the most vociferous critics of the current government and its policies.

For this reason, the university rejects the Occupy for Palestine's first demand.

The second demand is unreasonable because the University does not directly control the pension fund; those investments are controlled by a Board of Trustees, some of whom are appointed by staff and faculty because a large percentage of the pension fund is their money. Also, the pension fund is a joint fund with the University of Guelph and Queen's University. Similarly, with respect to the endowment fund, the University does not directly control direct investments in companies so it cannot comply with the demand even if it wished to.

However, notwithstanding those practicalities, there are fundamental principles at stake that need to be addressed.

... the University’s Policy on Social and Political Issues with Respect to University Divestment notes in its opening Preamble that “As a general matter, the University does not take positions on social or political issues apart from those directly pertinent to higher education and academic research.” Accordingly, “the University will not consider proposals for restrictions on its investments that require the institution to take sides in matters that are properly the subject of ongoing academic inquiry and debate.” It further notes, as a corollary, that the University’s response to any requests for divestment “must be governed by the fundamental place of diversity of opinion within its community. Except in those situations in which the University must settle on an answer to controversial questions about how best to achieve its academic mission, the University risks abandoning its core values if it takes sides in ongoing debates and is perceived to be advancing a specific political or social position.”

This is consistent with the Chicago Principles on free expression and the Kalven Report on the University's role in political and social action. Meric Gertler does not specifically mention the Kalven Report from the University of Chicago but it's clear that it forms the basis of the University of Toronto's position. For that reason, and because that position is not widely understood, I quote from the report.

A university has a great and unique role to play in fostering the development of social and political values in a society. The role is defined by the distinctive mission of the university and defined too by the distinctive characteristics of the university as a community. It is a role for the long term.

The mission of the university is the discovery, improvement, and dissemination of knowledge. Its domain of inquiry and scrutiny includes all aspects and all values of society. A university faithful to its mission will provide enduring challenges to social values, policies, practices, and institutions. By design and by effect, it is the institution which creates discontent with the existing social arrangements and proposes new ones. In brief, a good university, like Socrates, will be upsetting.

The instrument of dissent and criticism is the individual faculty member or the individual student. The university is the home and sponsor of critics; it is not itself the critic. It is, to go back once again to the classic phrase, a community of scholars. To perform its mission in the society, a university must sustain an extraordinary environment of freedom of inquiry and maintain an independence from political fashions, passions, and pressures. A university, if it is to be true to its faith in intellectual inquiry, must embrace, be hospitable to, and encourage the widest diversity of views within its own community. It is a community but only for the limited, albeit great, purposes of teaching and research. It is not a club, it is not a trade association, it is not a lobby.

Since the university is a community only for these limited and distinctive purposes, it is a community which cannot take collective action on the issues of the day without endangering the conditions for its existence and effectiveness. There is no mechanism by which it can reach a collective position without inhibiting that full freedom of dissent on which it thrives. It cannot insist that all of its members favor a given view of social policy; if it takes collective action, therefore, it does so at the price of censuring any minority who do not agree with the view adopted. In brief, it is a community which cannot resort to majority vote to reach positions on public issues.

I am a University of Toronto retired professor and I fully support the position of the University President. The university cannot and should not take a position on social issues. I fully support the rights of students and faculty to express their personal views on such issues. For example, we may protest the behavior of the Israel government, of Hamas, the governments of Russia or Ukraine, and even, especially, our own government. Those are all legitimate targets of protest. The university is not a legitimate target. The university is not our enemy.

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Junk DNA debate: Casey Luskin vs Dan Stern Cardinale

Here's a link to the junk DNA debate between Dan Stern Cardinale and Casey Luskin. The debate took place on May 2, 2024.

I mentioned in a previous post that Luskin should have been called out on his repeated attempts to equate junk DNA with non-coding DNA. This allowed him to portray all non-coding functions as evidence against junk DNA. [Casey Luskin posts misleading quotes about junk DNA].

There are several other things that I would have done differently. I would have made it clear that 10% of the genome is functional and we don't know the function of some of that fraction. Thus, all newly discovered functional regions could still fit into the 10% and 90% of the genome is still junk. Every time Casey mentions a new function he should have been challenged to specify exactly what percentage of the genome he is referring to. (Dan tried to do this but he was too nice, and let Casey off the hook.)

The idea here is to make it clear to viewers that recent discoveries of functional regions do not affect the idea that most of our genome is junk.

I would also attempt to get Casey to admit that there's a scientific controversy over junk DNA so there are many papers defending junk DNA and criticizing the arguments of junk DNA opponents. For every quotation from a scientist who opposes junk, there's an equally significant quotation from one who supports junk. Why does Casey only quote scientists who agree with him? Is this cherry-picking? Is selectively rattling off quotations and references from people who agree with you a reasonable way to have a serious scientific debate?

I think the arguments over transcripts should begin with presenting all the scientific evidence that spurious transcripts exist - for example, random DNA sequences inserted into a cell nucleus are transcribed and spurious transcription is easily documented in well-studied organisms such as bacteria and yeast. The characteristics of spurious transcription are that the transcripts are present in very small amounts, that they are rapidly degraded, that they come from regions of the genome that are not under purifying selection, and they are cell/tissue specific. So what is the most reasonable explanation when you look at such transcripts?

Casey Luskin's attempt to avoid the best explanation (spurius transcription) is a classic example ad hoc rescue and it might have been useful to point this out to viewers.

Regulation is not new. There was serious discussion and debate over the amount of the genome devoted to regulation back in the late 1960s when the concept of junk DNA was first proposed. Casey should have been challenged to state what percentage of the genome is devoted to regulation and if he comes up with an unreasonable number he should have to give examples of many well-studied genes that have been shown to have that level of regulation. (Hint: There aren't any.) All of the detailed work on the regulation of dozens of specific human genes has shown that you don't need more than a few transcription factor binding sites to control expression. Is there any reason to suppose that the other genes require ten or a hundred times more regulatory sequences to control expression?

What is the trend line? Ever since the ENCODE publicity disaster of 2012 there has been a flood of papers defending junk DNA and the data supporting junk DNA is now stronger that it has ever been because we now know from hundreds of thousands of human genome sequences that only about 10% is under purifying selection. There have also been a lot of papers fleshing out the 10% of the genome that's functional. There have only been a handful of papers published in the past ten years that seriously attempt to present evidence that most of our genome is functional. I would have challenged Casey to come up with a single scientific publication in the past ten years claiming, with supporting data, that most of the genome is functional.

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Casey Luskin posts misleading quotes about junk DNA

On Thursday May 2, 2024, Casey Luskin and Dan Stern Cardinale debated junk DNA on the YouTube channel "The NonSequitor Show." David Klinghoffer thinks that this debate went very well for the ID side [Debate: Casey Luskin Versus Rutgers Biologist Dan Cardinale, Thursday, May 2]. I agree with Klinghoffer; Luskin did an excellent job of promoting his case because many of his statements and claims were not challenged effectively.

I'll be putting up a separate post on the debate but for now I'd like to address an article by Casey Luskin that he posted before the debate as preparation for what he was going to say. The article consists of a bunch of quotes from prominent scientists about junk DNA [“Junk DNA” from Three Perspectives: Some Key Quotes]. Here are the three perspectives, according to Luskin.

Category 1: Quotes from evolutionists claiming (or repeating the widespread belief) that non-coding DNA is “junk” and has no function.

Some of the quotes represent the actual position of junk DNA proponents but Luskin has also picked out stupid quotes from scientists who think, incorrectly, that all non-coding DNA is junk. This is deliberate as we will see below.

Category 2: Early quotes from intelligent design theorists predicting function for non-coding “junk” DNA.

Luskin builds the case for function in non-coding DNA by quoting religious scientists who "predict" that there will be functional DNA in non-coding regions of the genome. This is disingenuous at best because Luskin knows full well that from the very beginning of the scientific debate we knew about functional non-coding DNA. It was never the case that all non-coding DNA was assumed to be junk.

Category 3: Quotes from mainstream scientific sources saying that we’ve experienced a shift in our thinking that junk DNA actually has function.

Many of these quotes are from scientists announcing that some non-coding DNA has a function. They support Luskin's false claim that all non-coding DNA was thought to be junk and the discovery of functional regions of non-coding DNA has resulted in a "paradigm shift" in our view of the human genome.

Casey Luskin should not have been allowed to get away with equating junk DNA and non-coding DNA in the debate. He should have been challenged to retract that false claim at the very beginning of the debate and called out whenever he used the term "non-coding DNA" during the debate.

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Why do Intelligent Design Creationists still lie about junk DNA?

Intelligent Design Creationists are heavily invested in refuting junk DNA because it casts doubt on their model of an intelligently designed human. Over the years they have advanced all kinds of arguments against junk DNA and some ID supporters actually address the real scientific issues (e.g. Jonathan Wells). However, most Intelligent Design Creationists are as ignorant about the scientific dispute over junk DNA as they are about evolution and lots of other science issues that conflict with their underlying religious beliefs.

A few days ago (March 26, 2024), the Discovery Institute's Center for Science and Culture published a short video on "The MYTH of Junk DNA" where they ignored most of the science and appealed to the majority of creationists who don't care about the truth. We have enough data to conclude that the Discovery Institute isn't just ignorant of the real science but is actually lying in this video. We know this because there are prominent Senior Fellows of the Center for Science and Culture who know that the material in this video is wrong and/or mispleading.

Thesis defense: 50th anniversary

Today is the 50th anniversary of my Ph.D. oral defense. The event took place in the Department of Biochemical Sciences at Princeton University back in 1974. It began with a departmental seminar. When the seminar was over I retired with my committee to a small classroom for the oral exam.

I don't remember everyone who was on my committee. My Ph.D. supervisor (Bruce Alberts) was there, as was my second reader, Abe Worcel. I know Uli Laemmli was there and so was Arnie Levine. I'm pretty sure the external member of the committee was Nancy Nossal from NIH in Bethesda, MD (USA). It's a bit of a blur after all these years.

I remember being fairly confident about the exam. After five and a half years I was pretty sure that everyone on my committee wanted to get rid of me and the easiest way to do that was to let me pass. Bruce stood to gain $3000 per year of research money and Uli was going to get back the basement of his house where I had been living for the past month after getting kicked out of the married graduate students housing project for taking too long to complete my thesis.

The toughest questions were from Uli Laemmli, which should not come as a surprise to anyone who knows him. He has this annoying habit of expecting people to understand the basic physics and chemistry behind the biochemical sciences. Fortunately, my inability to answer most of his questions didn't deter him from voting to pass me.

More genomes, more variation

The "All of Us Research Program" is an American effort to sequence one million genomes. The stated goal is to study human genetic variants and link them to genetic diseases. The study is complimentary to similar studies in Great Britain, Iceland, and Japan but the American team hopes to include more diversity in their study by recruiting people from different ethnic backgrounds.

All of Us published the results from almost 250,000 genome sequences in a recent issue of Nature (All of Us Research Program Investigators, 2024). They found one billion variants of which 275 million had not been seen before.

Recall that the UK study (UK Biobank) emphasized the importance of variation in determining whether a given region of DNA was functional or not. They noted that regions that were constrained (i.e. fewer variants) were likely under purifying selection whereas regions that accumulated variants were likely junk [Identifying functional DNA (and junk) by purifying selection]. Their results indicated that only about 10% of the genome was constrained and that's consistent with the view that 90% of our genome is junk. The American study did not address this issue so we don't know how it related to the junk DNA controversy.

Note that if 90% of our genome is junk then that represents 2.8 billion base pairs and the potential for more than 8 billion variants in the human population.¹ Some of these will be quite frequent in different groups just by chance but most of them will be quite rare. We'll have to wait and see how this all pans out when more genomes are sequenced. The idea of increasing the detection of unusual variants by sequencing more diverse populations is a good one but the real key is just more genome sequences.

One of the things you can do with this data is to cluster the variants according to the self-identified ethnic group of the participants and All of Us didn't hesitate to do this. They even identified the clusters as races, proving once again that there are clear genetic diffences between these groups, just as you would expect. Given the sensitive nature of this fact, you would also expect a lot of criticism on the internet and that's what happened.

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1. I'm defining a "variant" as a difference from the reference genome sequence. I'm aware of the terminology issue but it's not important here. There will also be a large number of variants in the functional regions.

All of Us Research Program Investigators (2024) Genomic data in the All of Us Research Program. Nature 627:340. [doi: 10.1038/s41586-023-06957-x].

Toronto is number 3 in health sciences!

I'm a retired member of the Faculty of Medicine at the University of Toronto. For many decades researchers here have been complaining that they don't get the recognition they deserve. They were convinced that the University of Toronto and its associated hospital research insitutes were among the top health science research centers in the world.

That seems to be changing. In the March 14, 2024 issue of Nature we rank #3 in the world, ahead of many American health science centers that you might think are better [Leading 200 institutions in health sciences]. The University of Toronto is the only non-American institution in the top ten and one of only four in the top 20.

I expect to see the Chinese institutions move up in the next few years.

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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?

Western scientists should continue to cooperate with Chinese scientists

China has become a science powerhouse and it achieved this goal, in part, by sending its young scientitsts abroad to train in universities in Canada, Australia, United States, and Europe. Many of these countries have signed scientific cooperation agreements with China but some of those agreements are in danger of lapsing as China is increasingly seen as an untrustworthy enemy.

Intelligent design creationists think junk DNA is a placeholder for ignorance

Paul Nelson is a Senior Fellow of the Discovery Institute—the most important source of intelligent design propaganda. Paul and I have been disagreeing about science for many years. He is prone to interpret anything he finds in the scientific literature as support for the idea that scientists have misunderstood their subject matter and failed to recognize that science supports intelligent design. My goal has always been to try and explain the actual science and why his interpretations are misguided. I have not been very successful.

The photo was taken in London (UK) in 2016 at a meeting on evolution. It looks like I'm holding my breath because I'm beside a creationist but I assure you that's not what was happening. We actually get along quite well in spite of the fact that he's wrong about everything. :-)

Happy St. Patrick's Day 2024

Happy St. Patrick's Day! These are my great-grandparents Thomas Keys Foster, born in County Tyrone on September 5, 1852 and Eliza Ann Job, born in Fintona, County Tyrone on August 18, 1852. Thomas came to Canada in 1876 to join his older brother, George, on his farm near London, Ontario, Canada. Eliza came the following year and worked on the same farm. Thomas and Eliza decided to move out west where they got married in 1882 in Winnipeg, Manitoba, Canada.

The couple obtained a land grant near Salcoats, Saskatchewan, a few miles south of Yorkton, where they build a sod house and later on a wood frame house that they named "Fairview" after a hill in Ireland overlooking the house where Eliza was born. That's where my grandmother, Ella, was born.

Other ancestors in this line came from the nearby counties of Donegal (surname Foster) and Fermanagh (surnames Keys, Emerson, Moore) and possibly Londonderry (surname Job).

One of the cool things about studying your genealogy is that you can find connections to almost everyone. This means you can celebrate dozens of special days. In my case it was easy to find other ancestors from England, Scotland, Netherlands, Germany, France, Spain, Poland, Lithuania, Belgium, Ukraine, Russia, and the United States. Today, we will be celebrating St. Patrick's Day. It's rather hectic keeping up with all the national holidays but somebody has to keep the traditions alive!

It's nice to have an excuse to celebrate, especially when it means you can drink beer. However, I would be remiss if I didn't mention one little (tiny, actually) problem. Since my maternal grandmother is pure Irish, I should be 25% Irish but my DNA results indicate that I'm only 8% Irish. That's probably because my Irish ancestors were Anglicans and were undoubtedly the descendants of settlers from England, Wales, and Scotland who moved to Ireland in the 1600s. This explains why they don't have very Irish-sounding names.

I don't mention this when I'm in an Irish pub. Instead, I focus on my mother's maiden name, which was Doherty, and her ancestors on her father's side who were O'Doughertys. The O'Doughertys were a prominent Irish clan from Donegal and they were fierce enemies of the English invaders. Unfortunately, my ancestor was Donald O'Dougherty (1760 - 1810) who came to Canada in 1803 from the Isle of Skye in Scotland where his family had been for several generatons after fleeing Ireland in the 1600s. His wife was Anne Stewart and she wasn't Irish.

I don't mention that part either.

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How do proteins move around amidst the jumble of molecules inside a living cell?

I've been reading Philip Ball's book on "How Life Works" and I find it increasingly frustrating because he consistently describes things that he's "discovered" that biochemists like me must have missed. Here's an example from pages 231-232.

He presents a cartoon image of a cell showing that it's full of all kinds of molecules packed closely together, then he says,

Nils Walter disputes junk DNA: (9) Reconciliation

I'm discussing a recent paper published by Nils Walter (Walter, 2024). He is arguing against junk DNA by claiming that the human genome contains large numbers of non-coding genes.

This is the ninth and last post in the series. I'm going to discuss Walker's view on how to tone down the dispute over the amount of junk in the human genome. Here's a list of the previous posts.

• Nils Walter disputes junk DNA: (1) The surprise
• Nils Walter disputes junk DNA: (2) The paradigm shaft
• Nils Walter disputes junk DNA: (3) Defining 'gene' and 'function'
• Nils Walter disputes junk DNA: (4) Different views of non-functional transcripts
• Nils Walter disputes junk DNA: (5) What does the number of transcripts per cell tell us about function?
• Nils Walter disputes junk DNA: (6) The C-value paradox
• Nils Walter disputes junk DNA: (7) Conservation of transcribed DNA
• Nils Walter disputes junk DNA: (8) Transcription factors and their binding sites

"Conclusion: How to Reconcile Scientific Fields"

Walter concludes his paper with some thoughts on how to deal with the controversy going forward. I'm using the title that he choose. As you can see from the title, he views this as a squabble between two different scientific fields, which he usually identifies as geneticists and evolutionary biologists versus biochemists and molecular biologists. I don't agree with this distinction. I'm a biochemist and molecular biologist, not a geneticist or an evolutionary biologist, and still I think that many of his arguments are flawed.

Let's see what he has to say about reconciliation.

Science thrives from integrating diverse viewpoints—the more diverse the team, the better the science.[107] Previous attempts at reconciling the divergent assessments about the functional significance of the large number of ncRNAs transcribed from most of the human genome by pointing out that the scientific approaches of geneticists, evolutionary biologists and molecular biologists/biochemists provide complementary information[42] was met with further skepticism.[74] Perhaps a first step toward reconciliation, now that ncRNAs appear to increasingly leave the junkyard,[35] would be to substitute the needlessly categorical and derogative word RNA (or DNA) “junk” for the more agnostic and neutral term “ncRNA of unknown phenotypic function”, or “ncRNAupf”. After all, everyone seems to agree that the controversy mostly stems from divergent definitions of the term “function”,[42, 74] which each scientific field necessarily defines based on its own need for understanding the molecular and mechanistic details of a system (Figure 3). In addition, “of unknown phenotypic function” honors the null hypothesis that no function manifesting in a phenotype is currently known, but may still be discovered. It also allows for the possibility that, in the end, some transcribed ncRNAs may never be assigned a bona fide function.

First, let's take note of the fact that this is a discussion about whether a large percentage of transcripts are functional or not. It is not about the bigger picture of whether most of the genome is junk in spite of the fact that Nils Walter frames it in that manner. This becomes clear when you stop and consider the implications of Walter's claim. Let's assume that there really are 200,000 functional non-coding genes in the human genome. If we assume that each one is about 1000 bp long then this amounts to 6.5% of the genome—a value that can easily be accommodated within the 10% of the genome that's conserved and functional.

Now let's look at how he frames the actual disagreement. He says that the groups on both sides of the argument provide "complementary information." Really? One group says that if you can delete a given region of DNA with no effect on the survival of the individual or the species then it's junk and the other group says that it still could have a function as long as it's doing something like being transcribed or binding a transcription factor. Those don't look like "complimentary" opinions to me.

His first step toward reconciliation starts with "now that ncRNAs appear to increasingly leave the junkyard." That's not a very conciliatory way to start a conversation because it immediately brings up the question of how many ncRNAs we're talking about. Well-characterized non-coding genes include ribosomal RNA genes (~600), tRNA genes (~200), the collection of small non-coding genes (snRNA, snoRNA, microRNA, siRNA, PiWi RNA)(~200), several lncRNAs (<100), and genes for several specialized RNAs such as 7SL and the RNA component of RNAse P (~10). I think that there are no more than 1000 extra non-coding genes falling outside these well-known examples and that's a generous estimate. If he has evidence for large numbers that have left the junkyard then he should have presented it.

Walter goes on to propose that we should divide non-coding transcripts into two categories; those with well-characterized functions and "ncRNA of unknown function." That's ridiculous. That is not a "agnostic and neutral term." It implies that non-conserved transcripts that are present at less that one copy per cell could still have a function in spite of the fact that spurious transcription is well-documented. In fact, he basically admits this interpretation at the end of the paragraph where he says that using this description (ncRNA of unknown function) preserves the possibility that a function might be discovered in the future. He thinks this is the "null hypothesis."

The real null hypothesis is that a transcript has no function until it can be demonstrated. Notice that I use the word "transcript" to describe these RNAs instead of "ncRNA" or "ncRNA of unknown phenotypic function." I don't think we lose anything by using the word "transcript."

Walter also address the meaning of "function" by claiming that different scientific fields use different definitions as though that excuses the conflict. But that's not an accurate portrayal of the problem. All scientists, no matter what field they identify with, are interested in coming up with a way of identifying functional DNA. There are many biochemists and molecular biologists who accept the maintenance definition as the best available definition of function. As scientists, they are more than willing to entertain any reasonable scientific arguments in favor of a different definition but nobody, including Nils Walter, has come up with such arguments.

Now let's look at the final paragraph of Walter's essay.

Most bioscientists will also agree that we need to continue advancing from simply cataloging non-coding regions of the human genome toward characterizing ncRNA functions, both elementally and phenotypically, an endeavor of great challenge that requires everyone's input. Solving the enigma of human gene expression, so intricately linked to the regulatory roles of ncRNAs, holds the key to devising personalized medicines to treat most, if not all, human diseases, rendering the stakes high, and unresolved disputes counterproductive.[108] The fact that newly ascendant RNA therapeutics that directly interface with cellular RNAs seem to finally show us a path to success in this challenge[109] only makes the need for deciphering ncRNA function more urgent. Succeeding in this goal would finally fulfill the promise of the human genome project after it revealed so much non-protein coding sequence (Figure 1). As a side effect, it may make updating Wikipedia and encyclopedia entries less controversial.

I agree that it's time for scientists to start identifying those transcripts that have a true function. I'll go one step further; it's time to stop pretending that there might be hundreds of thousands of functional transcripts until you actually have some data to support such a claim.

I take issue with the phrase "solving the enigma of human gene expression." I think we already have a very good understanding of the fundamental mechanisms of gene expression in eukaryotes, including the transitions between open and closed chromatin domains. There may be a few odd cases that deviate from the norm (e.g. Xist) but that hardly qualifies as an "enigma." He then goes on to say that this "enigma" is "intricately linked to the regulatory roles of ncRNAs" but that's not a fact, it's what's in dispute and why we have to start identifying the true function (if any) of most transcripts. Oh, and by the way, sorting out which parts of the genome contain real non-coding genes may contribute to our understanding of genetic diseases in humans but it won't help solve the big problem of how much of our genome is junk because mutations in junk DNA can cause genetic diseases.

Sorting out which transcripts are functional and which ones are not will help fill in the 10% of the genome that's functional but it will have little effect on the bigger picture of a genome that's 90% junk.

We've known that less than 2% of the genome codes for proteins since the late 1960s—long before the draft sequence of the human genome was published in 2001—and we've known for just as long that lots of non-coding DNA has a function. It would be helpful if these facts were made more widely known instead of implying that they were only dscovered when the human genome was sequenced.

Once we sort out which transcripts are functional, we'll be in a much better position to describe the all the facts when we edit Wikipedia articles. Until that time, I (and others) will continue to resist the attempts by the students in Nils Walter's class to remove all references to junk DNA.

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Walter, N.G. (2024) Are non‐protein coding RNAs junk or treasure? An attempt to explain and reconcile opposing viewpoints of whether the human genome is mostly transcribed into non‐functional or functional RNAs. BioEssays:2300201. [doi: 10.1002/bies.202300201]

Nils Walter disputes junk DNA: (8) Transcription factors and their binding sites

I'm discussing a recent paper published by Nils Walter (Walter, 2024). He is arguing against junk DNA by claiming that the human genome contains large numbers of non-coding genes.

This is the seventh post in the series. The first one outlines the issues that led to the current paper and the second one describes Walter's view of a paradigm shift/shaft. The third post describes the differing views on how to define key terms such as 'gene' and 'function.' In the fourth post I discuss his claim that differing opinions on junk DNA are mainly due to philosophical disagreements. The fifth, sixth, and seventh posts address specific arguments in the junk DNA debate.

• Nils Walter disputes junk DNA: (1) The surprise
• Nils Walter disputes junk DNA: (2) The paradigm shaft
• Nils Walter disputes junk DNA: (3) Defining 'gene' and 'function'
• Nils Walter disputes junk DNA: (4) Different views of non-functional transcripts
• Nils Walter disputes junk DNA: (5) What does the number of transcripts per cell tell us about function?
• Nils Walter disputes junk DNA: (6) The C-value paradox
• Nils Walter disputes junk DNA: (7) Conservation of transcribed DNA

Nils Walter disputes junk DNA: (7) Conservation of transcribed DNA

I'm discussing a recent paper published by Nils Walter (Walter, 2024). He is arguing against junk DNA by claiming that the human genome contains large numbers of non-coding genes.

This is the seventh post in the series. The first one outlines the issues that led to the current paper and the second one describes Walter's view of a paradigm shift/shaft. The third post describes the differing views on how to define key terms such as 'gene' and 'function.' In the fourth post I discuss his claim that differing opinions on junk DNA are mainly due to philosophical disagreements. The fifth and sixth posts address specific arguments in the junk DNA debate.

• Nils Walter disputes junk DNA: (1) The surprise
• Nils Walter disputes junk DNA: (2) The paradigm shaft
• Nils Walter disputes junk DNA: (3) Defining 'gene' and 'function'
• Nils Walter disputes junk DNA: (4) Different views of non-functional transcripts
• Nils Walter disputes junk DNA: (5) What does the number of transcripts per cell tell us about function?
• Nils Walter disputes junk DNA: (6) The C-value paradox

Sequence conservation

If you don't know what a transcript is doing then how are you going to know whether it's a spurious transcript or one with an unknown function? One of the best ways is to check and see whether the DNA sequence is conserved. There's a powerful correlation between sequence conservation and function: as a general rule, functional sequences are conserved and non-conserved sequences can be deleted without consequence.

There might be an exception to the the conservation criterion in the case of de novo genes. They arise relatively recently so there's no history of conservation. That's why purifying selection is a better criterion. Now that we have the sequences of thousands of human genomes, we can check to see whether a given stretch of DNA is constrained by selection or whether it accumulates mutations at the rate we expect if its sequence were irrelevant junk DNA (neutral rate). The results show that less than 10% of our genome is being preserved by purifying selection. This is consistent with all the other arguments that 90% of our genome is junk and inconsistent with arguments that most of our genome is functional.

This sounds like a problem for the anti-junk crowd. Let's see how it's addressed in Nils Walter's article in BioEssays.

There are several hand-waving objections to using conservation as an indication of function and Walter uses them all plus one unique argument that we'll get to shortly. Let's deal with some of the "facts" that he discusses in his defense of function. He seems to agree that much of the genome is not conserved even though it's transcribed. In spite of this, he says,

"... the estimates of the fraction of the human genome that carries function is still being upward corrected, with the best estimate of confirmed ncRNAs now having surpassed protein-coding genes,[12] although so far only 10%–40% of these ncRNAs have been shown to have a function in, for example, cell morphology and proliferation, under at least one set of defined conditions."

This is typical of the rhetoric in his discussion of sequence conservation. He seems to be saying that there are more than 20,000 "confirmed" non-coding genes but only 10%-40% of them have been shown to have a function! That doesn't make any sense since the whole point of this debate is how to identify function.

Here's another bunch of arguments that Walter advances to demonstrate that a given sequence could be functional but not conserved. I'm going to quote the entire thing to give you a good sense of Walter's opinion.

A second limitation of a sequence-based conservation analysis of function is illustrated by recent insights from the functional probing of riboswitches. RNA structure, and hence dynamics and function, is generally established co-transcriptionally, as evident from, for example, bacterial ncRNAs including riboswitches and ribosomal RNAs, as well as the co-transcriptional alternative splicing of eukaryotic pre-mRNAs, responsible for the important, vast diversification of the human proteome across ∼200 cell types by excision of varying ncRNA introns. In the latter case, it is becoming increasingly clear that splicing regulation involves multiple layers synergistically controlled by the splicing machinery, transcription process, and chromatin structure. In the case of riboswitches, the interactions of the ncRNA with its multiple protein effectors functionally engage essentially all of its nucleotides, sequence-conserved or not, including those responsible for affecting specific distances between other functional elements. Consequently, the expression platform—equally important for the gene regulatory function as the conserved aptamer domain—tends to be far less conserved, because it interacts with the idiosyncratic gene expression machinery of the bacterium. Consequently, taking a riboswitch out of this native environment into a different cell type for synthetic biology purposes has been notoriously challenging. These examples of a holistic functioning of ncRNAs in their species-specific cellular context lay bare the limited power of pure sequence conservation in predicting all functionally relevant nucleotides.

I don't know much about riboswitches so I can't comment on that. As for alternative splicing, I assume he's suggesting that much of the DNA sequence for large introns is required for alternative splicing. That's just not correct. You can have effective alternative splicing with small introns. The only essential parts of introns sequences are the splice sites and a minimum amount of spacer.

Part of what he's getting at is the fact that you can have a functional transcript where the actual nucleotide sequence doesn't matter so it won't look conserved. That's correct. There are such sequences. For example, there seem to be some examples of enhancer RNAs, which are transcripts in the regulatory region of a gene where it's the act of transcription that's important (to maintain an open chromatin conformation, for example) and not the transcript itself. Similarly, not all intron sequences are junk because some spacer sequence in required to maintain a minimum distance between splice sites. All this is covered in Chapter 8 of my book ("Noncoding Genes and Junk RNA").

Are these examples enough to toss out the idea of sequence conservation as a proxy for function and assume that there are tens of thousands of such non-conserved genes in the human genome? I think not. The null hypothesis still holds. If you don't have any evidence of function then the transcript doesn't have a function—you may find a function at some time in the future but right now it doesn't have one. Some of the evidence for function could be sequence conservation but the absence of conservation is not an argument for function. If conservation doesn't work then you have to come up with some other evidence.

It's worth mentioning that, in the broadest sense, purifying selection isn't confined to nucleotide sequence. It can also take into account deletions and insertions. If a given region of the genome is deficient in random insertions and deletions then that's an indication of function in spite of the fact that the nucleotide sequence isn't maintained by purifying selection. The maintenance definition of function isn't restricted to sequence—it also covers bulk DNA and spacer DNA.

(This is a good time to bring up a related point. The absence of conservation (size or sequence) is not evidence of junk. Just because a given stretch of DNA isn't maintained by purifying selection does not prove that it is junk DNA. The evidence for a genome full of junk DNA comes from different sources and that evidence doesn't apply to every little bit of DNA taken individually. On the other hand, the maintenance function argument is about demonstrating whether a particular region has a function or not and it's about the proper null hypothesis when there's no evidence of function. The burden of proof is on those who claim that a transcript is functional.)

This brings us to the main point of Walter's objection to sequence conservation as an indication of function. You can see hints of it in the previous quotation where he talks about "holistic functioning of ncRNAs in their species-specific cellular context," but there's more ...

Some evolutionary biologists and philosophers have suggested that sequence conservation among genomes should be the primary, or perhaps only, criterion to identify functional genetic elements. This line of thinking is based on 50 years of success defining housekeeping and other genes (mostly coding for proteins) based on their sequence conservation. It does not, however, fully acknowledge that evolution does not actually select for sequence conservation. Instead, nature selects for the structure, dynamics and function of a gene, and its transcription and (if protein coding) translation products; as well as for the inertia of the same in pathways in which they are not involved. All that, while residing in the crowded environment of a cell far from equilibrium that is driven primarily by the relative kinetics of all possible interactions. Given the complexity and time dependence of the cellular environment and its environmental exposures, it is currently impossible to fully understand the emergent properties of life based on simple cause-and-effect reasoning.

The way I see it, his most important argument is that life is very complicated and we don't currently understand all of it's emergent properties. This means that he is looking for ways to explain the complexity that he expects to be there. The possibility that there might be several hundred thousand regulatory RNAs seems to fulfil this need so they must exist. According to Nils Walter, the fact that we haven't (yet) proven that they exist is just a temporary lull on the way to rigorous proof.

This seems to be a common theme among those scientists who share this viewpoint. We can see it in John Mattick's writings as well. It's as though the logic of having a genome full of regulatory RNA genes is so powerful that it doesn't require strong supporting evidence and can't be challenged by contradictory evidence. The argument seems somewhat mystical to me. Its proponents are making the a priori assumption that humans just have to be a lot more complicated than what "reductionist" science is indicating and all they have to do is discover what that extra layer of complexity is all about. According to this view, the idea that our genome is full of junk must be wrong because it seems to preclude the possibility that our genome could explain what it's like to be human.

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Walter, N.G. (2024) Are non‐protein coding RNAs junk or treasure? An attempt to explain and reconcile opposing viewpoints of whether the human genome is mostly transcribed into non‐functional or functional RNAs. BioEssays:2300201. [doi: 10.1002/bies.202300201]