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Saturday, February 25, 2023

How Intelligent Design Creationists try to deal with the similarity between human and chimp genomes

The initial measurement of the difference between the human and chimp genomes was based on aligning 2.4 billion base pairs in the two genomes. This gave a difference of 1.23% by counting base pair substitutions and small deletions and insertions (indels). However, if you look at larger indels, including genes, you can come up with bigger values because you can count the total number of base pairs in each indel; for example, a deletion of 1,000 bp will be equivalent to 1,000 SNPs.

Thursday, February 16, 2023

What are the best Nobel Prizes in biochemistry & molecular biology since 1945?

The 2022 Nobel Prize in Physiology or Medicne went to Svante Pääbo “for his discoveries concerning the genomes of extinct hominins and human evolution”. It's one of a long list of Nobel Prizes awarded for technological achievement. It most cases, the new techniques led to a better understanding of science and medicine.

Since World War II, there have been significant advances in our understanding of biology but most of these have come about by the slow and steady accumulation of knowledge and not by paradigm-shifting breakthroughs. These advances don't often get recognized by the Nobel Prize committees because it's difficult to single out any one individual or any single experiment that merits a Nobel Prize. In some cases the Nobel Prize committees have tried to recognize major advances by picking out leaders that have made important contributions over a number of years but their choices don't always satisfy others in the field. One of the notable successes is the awarding of Nobel Prizes to Max Delbrück, Alfred D. Hershey and Salvador E. Luria “for their discoveries concerning the replication mechanism and the genetic structure of viruses” (Nobel Prize in Physiology or Medicine 1969). Another is Edward B. Lewis, Christiane Nüsslein-Volhard and Eric F. Wieschaus “for their discoveries concerning the genetic control of early embryonic development” (Nobel Prize in Physiology or Medicine 1995)

Birds of a feather: epigenetics and opposition to junk DNA

There's an old saying that birds of a feather flock together. It means that people with the same interests tend to associate with each other. It's extended meaning refers to the fact that people who believe in one thing (X) tend to also believe in another (Y). It usually means that X and Y are both questionable beliefs and it's not clear why they should be associated.

I've noticed an association between those who promote epigenetics far beyond it's reasonable limits and those who reject junk DNA in favor of a genome that's mostly functional. There's no obvious reason why these two beliefs should be associated with each other but they are. I assume it's related to the idea that both beliefs are presumed to be radical departures from the standard dogma so they reinforce the idea that the author is a revolutionary.

Or maybe it's just that sloppy thinking in one field means that sloppy thinking is the common thread.

Here's an example from Chapter 4 of a 2023 edition of the Handbook of Epigenetics (Third Edition).

The central dogma of life had clearly established the importance of the RNA molecule in the flow of genetic information. The understanding of transcription and translation processes further elucidated three distinct classes of RNA: mRNA, tRNA and rRNA. mRNA carries the information from DNA and gets translated to structural or functional proteins; hence, they are referred to as the coding RNA (RNA which codes for proteins). tRNA and rRNA help in the process of translation among other functions. A major part of the DNA, however, does not code for proteins and was previously referred to as junk DNA. The scientists started realizing the role of the junk DNA in the late 1990s and the ENCODE project, initiated in 2003, proved the significance of junk DNA beyond any doubt. Many RNA types are now known to be transcribed from DNA in the same way as mRNA, but unlike mRNA they do not get translated into any protein; hence, they are collectively referred to as noncoding RNA (ncRNA). The studies have revealed that up to 90% of the eukaryotic genome is transcribed but only 1%–2% of these transcripts code for proteins, the rest all are ncRNAs. The ncRNAs less than 200 nucleotides are called small noncoding RNAs and greater than 200 nucleotides are called long noncoding RNAs (lncRNAs).

In case you haven't been following my blog posts for the past 17 years, allow me to briefly summarize the flaws in that paragraph.

  • The central dogma has nothing to do with whether most of our genome is junk
  • There was never, ever, a time when knowledgeable scientists defended the idea that all noncoding DNA is junk
  • ENCODE did not "prove the significance of junk DNA beyond any doubt"
  • Not all transcripts are functional; most of them are junk RNA transcribed from junk DNA

So, I ask the same question that I've been asking for decades. How does this stuff get published?

Wednesday, February 15, 2023

The Maud Menten Center

Several people have commented on Facebook about an interview with Matthew Cobb [Reflections on the Double Helix's Platinum Anniversary]. Cobb has written several books that you all should have read by now. You may also be familiar with his name from Jerry Coyne's website since he is mentioned there quite a lot.

Cobb is currently writing a biography of Francis Crick and it's the reference to Crick that's attracting attention.

Watson and Crick had something that very few of us have, which is a very relaxed relationship that allowed arguing and talking and debating and being prepared to have crazy ideas that the other person could shoot down.

This is something that Crick continued to do with Nobelist Sydney Brenner, PhD, for over 20 years. Every morning, they would just yak at each other for hours on end and talk rubbish. And most of it was rubbish! But every now and again, there would be something really insightful that they had seen in an article that they could develop further.

And that’s not exactly possible in today’s world, which focuses on how many Nature, Science, or Cell articles are on a CV. So, they were living in a very different world that was much more relaxed. But I think if we could reinject a bit of that back into science—more freedom and time to explore—I think everybody would benefit.

I think we need an institute that's similar to the Institute for Advanced Studies in Princeton except that it would be focused on biochemistry and molecular biology, including genomics and molecular evolution. It would be a place for theorists and it would encourage the kind of interactions that Cobb is talking about. I think we should create that institute in Toronto and call it the Maud Menten Center after Maud L. Menten who got her undergraduate medical degree at the University of Toronto in 1907 and later on (1911) was awarded the advanced medical degree equivalent to a Ph.D.1 Most of you will know her from her work on the theory of enzyme kinetics with Leonor Michaelis. Michaelis-Menten kinetics is one of the most important contributions to biochemistry in the 20th century.

The Maud Menten Center should have a permanent staff of several smart scientists and facilities for a large number of visiting scientists who could spend their sabbaticals at the institute. There are major corporations in Toronto that could be encouraged to contribute to supporting research in this field but a lot of the support might come from various levels of government. The Canadian model is the Perimeter Institute for Theoretical Physics in Waterloo, Ontario, Canada.

1. There's a lot of confusion about the various degrees Menten got at the University of Toronto but with the help of a few people in the alumni office we were able to sort it out [The mystery of Maud Menten].

David Allis (1951 - 2023) and the "histone code"

C. David Allis died on January 8, 2023. You can read about his history of awards and accomplishments in the Nature obituary with the provocative subtitle Biologist who revolutionized the chromatin and gene-expression field. This refers to his work on histone acetyltransferases (HATs) and his ideas about the histone code.

The key paper on the histone code is,

Strahl, B. D., and Allis, C. D. (2000) The language of covalent histone modifications. Nature, 403:41-45. [doi: 10.1038/47412]

Histone proteins and the nucleosomes they form with DNA are the fundamental building blocks of eukaryotic chromatin. A diverse array of post-translational modifications that often occur on tail domains of these proteins has been well documented. Although the function of these highly conserved modifications has remained elusive, converging biochemical and genetic evidence suggests functions in several chromatin-based processes. We propose that distinct histone modifications, on one or more tails, act sequentially or in combination to form a ‘histone code’ that is, read by other proteins to bring about distinct downstream events.

They are proposing that the various modifications of histone proteins can be read as a sort of code that's recognized by other factors that bind to nucleosomes and regulation gene expression.

This is an important contribution to our understanding of the relationship between chromatin structure and gene expression. Nobody doubts that transcription is associated with an open form of chromatin that correlates with demethylation of DNA and covalent modifications of histone and nobody doubts that there are proteins that recognize modified histones. However, the key question is what comes first; the binding of transcription factors followed by changes to the DNA and histones, or do the changes to DNA and histones open the chromatin so that transcription factors can bind? These two models are referred to as the histone code model and the recruitment model.

Strahl and Allis did not address this controversy in their original paper; instead, they concentrated on what happens after histones become modified. That's what they mean by "downstream events." Unfortunately, the histone code model has been appropriated by the epigenetics cult and they do not distinguish between cause and effect. For example,

The “histone code” is a hypothesis which states that DNA transcription is largely regulated by post-translational modifications to these histone proteins. Through these mechanisms, a person’s phenotype can change without changing their underlying genetic makeup, controlling gene expression. (Shahid et al. (2022)

The language used by fans of epigenetics strongly implies that it's the modification of DNA and histones that is the primary event in regulating gene expression and not the sequence of DNA. The recruitment model states that regulation is primarily due to the binding of transcription factors to specific DNA sequences that control regulation and then lead to the epiphenomenon of DNA and histone modification.

The unauthorized expropriation of the histone code hypothesis should not be allowed to diminish the contribution of David Allis.

Wikipedia vs experts and a proposal for "arbitrators"

Wikipedia is a not-for-profit crowdsourced encyclopedia that's open to anybody who wants to contribute. This is both a strength and a weakness but the weaknesses are becoming important in an age of fake news and misinformation. The rules of Wikipedia mean that amateurs can insert any information into science articles as long as it is backed by a reliable source. But "reliable sources" include the popular press and books that may or may not report the scientific consensus accurately. When knowledgeable experts try to correct information, or put it into the proper context, they are often opposed by Wikipedia administrators who have a built-in bias against experts—a bias that's not entirely unjustified but much abused. Consequently, scientists often get frustrated trying to deal with the rules and traditions of Wikipedians because these rules are very different than the standards in the scientific community.

Here's an interesting article by Piotr Konieczny on From Adversaries to Allies? The Uneasy Relationship between Experts and the Wikipedia Community.

Sunday, February 12, 2023

Happy Darwin Day! 2023

Charles Darwin, the greatest scientist who ever lived, was born on this day in 1809 [Darwin still spurs tributes, debates] [Happy Darwin Day!] [Darwin Day 2017]. Darwin is mostly famous for two things: (1) he described and documented the evidence for evolution and common descent and (2) he provided a plausible scientific explanation of evolution—the theory of natural selection. He put all this in a book, The Origin of Species by Means of Natural Selection published in 1859—a book that spurred a revolution in our understanding of the natural world. (You can still buy a first edition copy of the book but it will cost you several hundred thousand dollars.)

Friday, February 10, 2023

I finished my book!

The last few weeks have been hectic. I got the first page proofs about a month ago and my job was to proof read those pages and prepare the index. Proof reading is tedious and the pressure is on because after that you can only make minor changes. I found several serious errors that I had made so that was a bit deflating. In one of them, I completely screwed up the calculations of the size of a typical protein-coding gene and the amount of the genome that was devoted to genes.

The index was hard because I wanted to have as comprehensive an index as possible. Publishers usually give you the option of hiring someone to do the index and taking the charges out of your royalty. If you look at some of the books on your shelf you can easily pick out the ones that were indexed by someone who doesn't understand the material.

The next step is "second pages" or the almost final version of the book. I had to proof read that version knowing that this was the last chance to fix anything. This includes the index, which I was seeing for the first time in a formatted version after the copy editor had dealt with it. I found 55 issues in this version that had to be fixed. This included several copy edit changes that I had missed on two previous passes (e.g. "cyIne" instead of "cytosine.") That's very scary—I wonder how many others we've missed?1

That's it for me! The book is now "locked" for me. The publisher will deal with the issues I found, and a few others, and then send it off to the printer at the end of next week. It's still scheduled for release on May 16th. You can't see much about my book on the US version of Amazon but there's more on the Canadian version [What's in Your Genome].

1. There have always been some errors in my textbooks but all the copy editors had degrees in biochemistry so there were lots of people who could catch mistakes. Publishing a trade book is an entirely different kettle of fish because none of the people who worked on the book knew anything about the subject and most had no science background whatsoever.

Thursday, February 02, 2023

Not in the room where it happens!

My 9th great grandfather is John Banks (1619-1685) who was born in Essex (England) and moved to the colony of Connecticut in 1634. He marrried Marie Tainter (1619-1667) and settled down in Greenwich, Fairfield, Connecticut. I descend from his son John Banks (1650-1699).

My 8th great grandfather had a sister named Hannah Banks (1654-1684) and she married Daniel Burr (1660-1727). This was exciting because I knew that Daniel Burr was the grandfather of Arron Burr who became the third vice president of the United States. But that wasn't Aaron's main claim to fame because he also murdered Alexander Hamilton and that caused a musical named after the victim to erupt in New York City.

Could it be that I was a distant cousin of the man who sang songs like "The room where it happens"?

Alas, no. Daniel Burr and my distant cousin, Hannah Banks, were only married for a few years before she died. Burr then married Mary Sherwood1 but she had only two children (Eleanor and Hannah) before she died. Daniel Burr's third wife, Jane "Elizabeth" Pinkley, is the mother of Rev. Aaron Burr who is the father of the vice president and successful duelist.

1. I'm also related to Mary Sherwood.

How big is the human genome (2023)?

There are several different ways to describe the human genome but the most common one focuses on the DNA content of the nucleus in eukaryotes; it does not include mitochondrial and chloroplast DNA . The standard reference genome sequence consists of one copy of each of the 22 autosomes plus one copy of the X chromosome and one copy of the Y chromosome. That's the definition of genome that I will use here.

The earliest direct estimates of the size of human genome relied on Feulgen staining. The stain is quantitative so a properly conducted procedure gives you the weight of DNA in the nucleus. According to these measurements, the standard diploid content of the human nucleus is 7.00 pg and the haploid content is 3.50 pg [See Ryan Gregory's Animal Genome Size Database].

Since the structure of DNA is known, we can estimate the average mass of a base pair. It is 650 daltons, or 1086 x 10-24 g/bp. The size of the human genome in base pairs can be calculated by dividing the total mass of the haploid genome by the average mass of a base pair.

                        3.5 pg/1086 x 10-12 pg/bp = 3.2 x 109 bp

The textbooks settled on this value of 3.2 Gb by the late 1960s since it was confirmed by reassociation kinetics. According to C0t analysis results from that time, roughly 10% of the genome consists of highly repetitive DNA, 25-30% is moderately repetitive and the rest is unique sequence DNA (Britten and Kohne, 1968).

A study by Morton (1991) looked at all of the estimates of genome size that had been published to date and concluded that the average size of the haploid genome in females is 3,227 Mb. This includes a complete set of autosomes and one X chromosome. The sum of autosomes plus a Y chromosome comes to 3,122 Mb. The average is about 3,200 which was similar to most estimates.

These estimates mean that the standard reference genome should be more than 3,227 Mb since it has to include all of the autosomes plus an X and a Y chromosome. The Y chromosome is about 60 Mb giving a total estimate of 3,287 Mb or 3.29 Gb.

The standard reference genome

The common assumption about the size of the human genome in the past two decades has dropped to about 3,000 Mb because the draft sequence of the human genome came in at 2,800 Mb and the so-called "finished" sequence was still considerably less than 3,200 Mb. Most people didn't realize that there were significant gaps in the draft sequence and in the "finished" sequence so the actual size is larger than the amount of sequence. The latest estimate of the size of the human genome from the Genome Reference Consortium is 3,099,441038 bp (3,099 Mb) (Build 38, patch 14 = GRCh38.p14 (February, 2022)). This includes an actual sequence of 2,948,318,359 bp and an estimate of the size of the remaining gaps. The total size estimates have been steadily dropping from >3.2 Gb to just under 3.1 Gb.

The telomere-to-telomere assembly

The first complete sequence of a human genome was published in April, 2022 [The complete human genome sequence (2022)]. This telomere-telomere (T2T) assembly of every autosome and one X chromosome came in at 3,055 Mb (3.06 Gb). If you add in the Y chromosome, it comes to 3.12 Gb, which is very similar to the estimate for GRCh38.p14 (3.10 Gb). Based on all the available data, I think it's safe to say that the size of the human genome is about 3.1 Gb and not the 3.2 Gb that we've been using up until now.

Variations in genome size

Everything comes with a caveat and human genome size is no exception. The actual size of your human genome may be different than mine and different from everyone else's, including your close relatives. This is because of the presence or absence of segmental duplications that can change the size a human genome by as much as 200 Mb. It's possible to have a genome that's smaller than 3.0 Gb or one that's larger than 3.3 Gb without affecting fitness.

Nobody has figured out a good way to incorporate this genetic variation data into the standard reference genome by creating a sort of pan genome such as those we see in bacteria. The problem is that more and more examples of segmental duplications (and deletions) are being discovered every year so annotating those changes is a nightmare. In fact, it's a major challenge just to reconcile the latest telomere-to-telomere sequence (T2T-CHM13) and the current standard reference genome [What do we do with two different human genome reference sequences?].

[Image Credit: Wikipedia: Creative Commons Attribution 2.0 Generic license]

Britten, R. and Kohne, D. (1968) Repeated Sequences in DNA. Science 161:529-540. [doi: 10.1126/science.161.3841.529]

Morton, N.E. (1991) Parameters of the Human Genome. Proc. Natl. Acad. Sci. (USA) 88:7474-7476 [free article on PubMed Central]

International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature 431:931-945 [doi:10.1038/nature03001]

Saturday, January 28, 2023

ChatGPT won't pass my exams!

Here are a few questions for ChatGPT and its answers. The AI program takes the most common information on the web and spews it back at you. It cannot tell which information is correct or which information is more accurate.

It's easy to recognize that these answers were written by something that's not very good at critical thinking. I agree with other professors that they mimic typical undergraduate answers but I disagree that these answers would get them a passing grade.

ChatGPT shares one very important feature that's common in undergraduate answers to essay questions: it gives you lots of unecessary information that's not directly relevant to the question.

It's important to note that (lol) these ChatGPT answers share another important feature with many of the answers on my exams: they look very much like BS!

Monday, January 23, 2023

Read a short preview of What's in Your Genome

Check out this website, What's in Your Genome if you want to see a preview of my book (Preface, Prologue, part of Chapter 1).

The book will be released on May 16, 2023. We are currently working on the proofs prior to typesetting. You can preorder the hardcover version on (Canada) for $39.95 (Cdn). I don't know when the electronic version will be available. You can also preorder on for £26.99.

You can't yet preorder on and there's no information on that site about availability. I don't know about other Amazon sites.

Monday, January 02, 2023

Jupiter weighs two quettagrams

New names for very large and very small weights and sizes have been adopted.

Last November's meeting of the General Conference on Weights and Measures wasn't covered by the major media outlets so you probably don't know that the mass of an electron is now one rontogram and the diameter of the universe is about one ronnameter [SI units get new prefixes for huge and tiny numbers].1

The official SI prefixes for very large things are now ronna (1027) and quetta (1030) and the prefixes for very small things are ronto (10-27) and quecto (10-30).

This is annoying because we've just gotten used to zetta, yotta, zepto, and yocto (adopted in 1991). I suspect that the change was prompted by the huge storage capacity of your latest smartphone (several yottabytes) and the wealth of the world's richest people (several zeptocents). Or maybe it was the price of houses in Toronto. Or something like that. In any case, we needed to prepare for kilo or mega increases.

The bad news is that the latest additions used up the last two available letters of the alphabet so if things get any bigger or smaller we may have to add a few more letters to the alphabet.

1. A friendly reader has pointed out that my title should have been "The mass of Jupiter is two quettagrams." My bad.

Sunday, January 01, 2023

The function wars are over

In order to have a productive discussion about junk DNA we needed to agree on how to define "function" and "junk." Disagreements over the definitions spawned the Function Wars that became intense over the past decade. That war is over and now it's time to move beyond nitpicking about terminology.

The idea that most of the human genome is composed of junk DNA arose gradually in the late 1960s and early 1970s. The concept was based on a lot of evidence dating back to the 1940s and it gained support with the discovery of massive amounts of repetitive DNA.

Various classes of functional DNA were known back then including: regulatory sequences, protein-coding genes, noncoding genes, centromeres, and origins of replication. Other categories have been added since then but the total amount of functional DNA was not thought to be more than 10% of the genome. This was confirmed with the publication of the human genome sequence.

From the very beginning, the distinction between functional DNA and junk DNA was based on evolutionary principles. Functional DNA was the product of natural selection and junk DNA was not constrained by selection. The genetic load argument was a key feature of Susumu Ohno's conclusion that 90% of our genome is junk (Ohno, 1972a; Ohno, 1972b).

A multivalent mRNA flu vaccine

Scientists have recently developed an mRNA-lipid nanoparticle flu vaccine that protects against all known flu variants.

There are four types of influenza viruses but only the A and B viruses cause significant problems [Types of Influenza Viruses]. Influenza A viruses are the ones can have caused pandemics in the past and the current flu vaccinations are unlikely to offer a lot of protection since they are only directed toward the specific subtypes that are predicted to cause problems in the next flu season. The next global flu pandemic will probably come from a new influenza A virus that nobody predicted.