An editorial in "Nature Reviews Genetics" misrepresents alternative splicing

The transcripts of some genes can be alternatively spliced to produce more than one biologically functional product (e.g. proteins). There are several well-documented examples in the scientific literature but they are not common. There are probably fewer than 500 human genes (2.5%) that exhibit true alternative splicing where the alternate gene product has been conclusively shown to exist and be biologically functional.

However, it's easy to detect multiple examples of unusually spliced transcripts of humans genes. The vast majority of these splice variants are present at less than one copy per cell, are rapidly degraded, and not conserved in closely related species. That has led to the idea that they are simply the result of splicing errors, a conclusion that's reinforced by solid evidence that splicing is error prone.

It's unfortunate that all these splice variants are assumed to be real examples of alternative splicing leading to the widely held view that more than 90% of human protein-coding genes are alternatively spliced. This false claim is used as a way of getting around the Deflated Ego Problem by assuming that the "shockingly" small number of genes in humans is explained by the fact that humans have evolved mechanisms for producing up to one hundred thousand distinct proteins from only 20,000 protein-coding genes.

In recent years, many scientists have come to realize that the role of alternative splicing has been greatly exaggerated. If you're interested in learning more, I cover the controversy on pages 154-169 in my book and in numerous blog posts (see below).

Unfortunately, there's a Nature editor who didn't get the message so they perpetuated the standard misinformation in a recent (May 21, 2025) editorial in Nature Reviews Genetics.

Anonymous (2025) RNA splicing — a central layer of gene regulation. Nat Rev Genet 26:369–370 [doi: 10.1038/s41576-025-00846-x]

... Splicing is essential for the accurate translation of DNA sequence information and comes with the added perk of generating transcriptomic and proteomic diversity in the form of alternative splicing — that is, the regulated inclusion or exclusion of exons. Alternative splicing greatly expands the coding potential of the genome; more than 95% of human multi-intron genes undergo alternative splicing, producing mRNA isoforms that can differ in coding sequence, regulatory elements or untranslated regions. These isoforms can influence mRNA stability, localization and translation output, thereby modulating cellular function.

... The ability of a single gene to produce several, functionally distinct protein isoforms through alternative splicing could enable organisms to rapidly adapt to changing environments. By enabling the sequencing of full-length transcripts, long-read sequencing data have yielded a more complete picture of alternative splicing. Subsequent comparative transcriptomic studies have revealed striking differences in the extent of alternative splicing between eukaryotes. Indeed, recent studies suggest that heritable variation in patterns of alternative splicing contributes to adaptive evolutionary chang.

Wouldn't it be nice if some leading researchers in the field wrote a scathing letter to Nature about the propagation of such misinformation? Does anyone know who to contact at Nature if you want to register a complaint?

Blog posts on alternative splicing

• The number of splice variants in a species correlates inversely with the population size - what does that mean?
• Splicing errors or alternative splicing?
• Alternative splicing and evolution
• Alternative splicing: function vs noise
• The frequency of splicing errors reflects the balance between selection and drift
• Alternative splicing in the nematode C. elegans
• The persistent myth of alternative splicing
• The textbook view of alternative splicing
• Are splice variants functional or noise?
• Debating alternative splicing (part I)
  
• Debating alternative splicing (part II)
• Debating alternative splicing (Part III)
• Debating alternative splicing (Part IV)

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Is AI really "intelligent"? Here are 13 biology questions to test the latest AI algorithms.

Last night I attended a talk by Chris DiCarlo who warned us about the dangers of AI. I'm sure he's right to be worried but I'm skeptical about some of the hype surrounding AI. For example, Chris said that just a few years ago the best AI algorithms were performing at high school level but now they are at Ph.D. level. The implication is that it won't be long before AI is smarter than humans.

Here's the problem. I can only access the cheap versions of AI such as ChatGPT and Scite Assistant but I can also see the results of Google's Generative AI whenever I do a Google search. Chris has access to more sophisticated versions so that's what he might be referring to when he says they operate at the Ph.D. level of intelligence.

A new higher mutation rate in humans includes indels in repetitive DNA regions

Theme

Mutation

-definition
-mutation types
-mutation rates
-phylogeny
-controversies

There are three ways of estimating the human mutation rate. The Biochemical Method is based on the known error rate of DNA replication and the average number of cell divisions between generations. It gives a rate of about 130 mutations per generation.

The Phylogenetic Method assumes that a large fraction of mammalian genomes is evolving at the neutral rate because it is junk DNA. Since we know that the rate of fixation of neutral alleles is equal to the mutation rate, we can estimate the mutation rate if we know the total number of nucleotide difference between two species (e.g. humans and chimpanzees) and the approximate time of divergence from a common ancestor. This gives an estimate of about 112 mutations per generation.

L'ADN poubelle: Junk DNA

This is a podcast in French on the topic of junk DNA. The moderator is Thomas C. Durand of La Tronche en Biais, a YouTube channel that focuses on critical thinking. Durand interviews two scientists from l’Université Paris Cité (City University of Paris), Didier Casane and Patrick Laurenti.

It's a two hour video that discusses all the relevant topics on the human genome and junk DNA. The most exciting part for me comes at 56 mins when the moderator asks Casane and Laurenti to recommend a book on the subject (see screenshot on right). Patrick Laurenti suggests that my book should be translated into French but I don't think that's going to happen.

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Current Trump tariffs

Here's a list of the current Trump tariffs taken from Wikpedia. It's important to remember that there's a 10% tariff on every country and special tariffs that severely affect Canada and Mexico. In Canada's case, it's the 25% tariff on steel, alumium, and autos.

This isn't just about China. Trump has focused much of his attack on Canada.

I don't think anybody understands what it is that Trump wants to negotiate.

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American Society of Human Genetics DNA Day essay contest winners

The American Society of Human Genetics sponsors an annual DNA Day Essay Contest. It's for grade 9-12 students from anywhere in the world.

This year's question is ...

President Trump promotes the lab leak conspiracy theory on the White House website

Knowledgeable scientists agree that the COVID-19 pandemic began when the virus SARS-CoV-2 infected citizens of Wuhan who were visiting the wet market in the late Fall of 2019. The virus probably came from infected live animals that were on sale in the market. There is very little dispute within the (knowledgeable) scientific community, the vast majority of scientists support a natural origin.

Templeton Foundation funds a grant on transposons

The John Templeton Foundation supports "interdisciplinary research and catalyze conversations that enable people to pursue lives of meaning and purpose." Many of these projects have religious themes or religious implications. The foundation is well-known for its support of projects that promote the compatibility of science and religion. You can see a list of recent grants here.

Templeton recently awarded a grant of $607,686 (US) to study the role of transposons in the human genome. The project leader is Stefan Linquist, a philosopher from the University of Guelph (Guelph, Ontario, Canada). Stefan has published a number of papers on junk DNA and he promotes the definition of functional DNA as DNA that is subject to purifying selection [The function wars are over]. Other members of the team include Ryan Gregory and Ford Doolittle who are prominent supporters of junk DNA.

Structure of the mitochondrial respirasome (electron transport complexes)

The membranes of bacterial cells and mitochondria contain a series of complexes that catalyze the oxidation of NADH. A lengthy electron transport chain leads eventually to the reduction of oxygen to water. Electrons lose energy as they pass down the chain and this is coupled to the transport of protons (H⁺) from one side of the membrane to the other. This proton gradient is used to drive ATP synthesis by the ATP synthase complex. The mechanism of making ATP is chemiosmosis but the pathway is often called oxidative phosphorylation or respiration.

The discovery of chemiosmosis (Chemiosmotic Theory) is one the few examples of a genuine paradigm shift. It is largely due to the work of Peter Mitchell [Ode to Peter Mitchell].

Tom Cech rejects junk DNA

A few months ago (June, 2024) I commented on an article by Tom Cech in The New York Times. [Tom Cech writes about the "dark matter" of the genome] In that article he expressed the view that 75% of the human genome consists of "dark matter" that is copied into RNAs of unknown function. He believes that many of these mysterious RNAs will turn out to have exciting functions.

I suspected that Cech is opposed to junk DNA and that suspicion is confirmed in his new book The Catalyst.

Michael Shermer supports Matt Ridley and the lab leak conspiracy theory

Back in 2021 Matt Ridley teamed up with Alina Chan to publish a book promoting the lab leak conspiracy theory about the origin of SARS-CoV-2. (See my summary of a review here.)

Yesterday (March 25, 2025) Michael Shermer interviewed Matt Ridley on The Michael Shermer Show podcast. The reason for the interview was to promote Ridley's new book Birds, Sex and Beauty: The Extraordinary Implications of Charles Darwin's Strangest Idea but Shermer started off the interview by asking about Ridley's previous book with Alina Chan. At 2 mins he asks,

Before we get into the new book, do you want to take a victory lap for your previous book. I mean the lab leak hypothesis is looking more and more like you called it years ago.

It's all downhill from there. I have lost all respect for Michael Shermer. It's a shame that this podcast is hosted on the Skeptic magazine website.

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Zeynep Tufekci writes in the New York Times defending the conspiracy part of the COVID-19 lab leak conspiracy theory

Zeynep Tufekci is Henry G. Bryant Professor of Sociology and Public Affairs at Princeton University (Princeton, NJ, USA). She is often praised for her non-academic writings in the popular press.

Ten days ago (March 16, 2025) she published an opinion piece in the New York Times where she discussed the lab leak conspiracy theory concerning the origin of the SARS-CoV-2 virus that caused the COVID-19 pandemic. As most Sandwalk readers know, there is no evidence to support that claim and plenty of evidence that the virus came from animals in the Wuhan market.

Google's "Generative AI" lies about junk DNA

Every now and then I check Google to see if there's any news about junk DNA. I use "junk DNA" as my search query.

The first thing I see at the top of the results page is a summary of the topic created by Google's Generative AI, which it claims is experimental. The AI summary is different every time you start a new search but all of the responses are similar in that they criticize the idea of junk DNA. Here's an example from today,

The misinformation spread by ENCODE in 2012 is gradually being recognized

I want to draw your attention to an excellent online book on bacterial genomes: Bacterial Genomes:Trees and Networks. The author is Aswin Sai Narain Seshasayee of the National Centre for Biological Sciences at the Tata Institute of Fundamental Research in Bangalore, India. Here's a link to Chapter 3: The genome: how much DNA? where he explains why bacterial genomes don't have very much junk DNA.

The chapter contains an excellent summary of the history of genome sizes in bacteria and eukaryotes and a detailed description of both the c-value paradox and the mutation load arguments. The relationship between junk DNA and population size is described.

I was especially pleased to see that the author didn't pull any punches in describing the ENCODE publicity campaign and their false statements about junk DNA.

In 2012, a post-human-genome project called ENCODE, which aims to experimentally identify regions of the human genome that undergo transcription—or are bound by a set of DNA-binding proteins, or undergo chemical changes called epigenetic modifications—came to a stunning conclusion that at least 80% of the human genome is functional and that it was time to sing a requiem for the concept of junk DNA! However, this conclusion, which has been severely criticised since its publication, ignores decades of well-supported arguments from evolutionary biology arising from the c-value paradox, some of which we have described here or will do so shortly; it does not quite explain why this conclusion—if broadly applied to the genomes of other multicellular eukaryotes—would not imply that a fish needs 100 times as much functional DNA as a human; and plays “fast and loose” with the definition of the term ‘function’. While the ENCODE project, a great success in many ways, has provided an invaluable resource for the study of human molecular biology, we can safely ignore its ill-fated conclusion on what fraction of the human genome is functional.

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Happy St. Patrick's Day! 2025

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.