Should we teach genomics and evolution to medical students?

Rama Singh,¹ a biology professor at McMaster Universtiy in Hamilton (Ontario, Canada) has just published an interesting article on The Conversation website. It's about Medical schools need to prepare doctors for revolutionary advances in genetics. You can read the full article yourself but let me highlight the last few paragraphs to start the discussion.

Future physicians will be part of health networks involving medical lab technicians, data analysts, disease specialists and the patients and their family members. The physician would need to be knowledgeable about the basic principles of genetics, genomics and evolution to be able to take part in the chain of communication, information sharing and decision-making process.

This would require a more in-depth knowledge of genomics than generally provided in basic genetics courses.

Much has changed in genetics since the discovery of DNA, but much less has changed how genetics and evolution are taught in medical schools.

In 2013-14 a survey of course curriculums in American and Canadian medical schools showed that while most medical schools taught genetics, most respondents felt the amount of time spent was insufficient preparation for clinical practice as it did not provide them with sufficient knowledge base. The survey showed that only 15 per cent of schools covered evolutionary genetics in their programs.

A simple viable solution may require that all medical applicants entering medical schools have completed rigorous courses in genetics and genomics.

Here's the problem. I've just finished research on a book about modern evolution and genomics so I think I know a little bit about the subject. I'm also on the editorial board of a journal that publishes research on biochemistry and molecular biology education. I've written a biochemistry textbook and I have far too many years of experience trying to teach this material to graduate students and undergraduates at the University of Toronto. I can safely say that we (university teachers) have done a horrible job of teaching evolution and genomics to our students. We have turned out an entire generation of students who don't understand modern molecular evolution and don't understand what's in your genome.

What this means is that there's an extremely small pool of students who have completed "rigorous courses in genetics and genomics." Nobody will be able to apply to medical school. I doubt that we could teach this material to medical students with or without the appropriate background.

But you don't have to take my word for it. Some people have tried to teach this material to health science workers so we can see how it's working at that level. Take a look at the The Genomics Education Programme supported by the NHS in the United Kingdom. They have a series of short videos and longer lessons that are designed to educate health care specialists. Here's the blurb that defines their objective.

Rapid advances in technology and understanding mean that genomics is now more relevant than ever before. As genomics increasingly becomes a part of mainstream NHS care, all healthcare professionals, and not just genomics specialists, need to have a good understanding of its relevance and potential to impact the diagnosis, treatment and management of people in our care.

In 2014, Health Education England (HEE) launched a four-year £20 million Genomics Education Programme (GEP) to ensure that our 1.2 million-strong NHS workforce has the knowledge, skills and experience to keep the UK at the heart of the genomics revolution in healthcare.

Funding for the programme has since been extended to enable us to continue our work in providing co-ordinated national direction of education and training in genomics and developing resources for a wide range of professionals.

They describe genes as 'coding' genes that build proteins. There's no mention of noncoding genes. The define a genome as "both genes (coding) and non-coding DNA." They also say that your genome is all of the DNA in our cells (46 chromosomes, 23 pairs). I don't see anything in their education packages that covers modern molecular evolution. In one of the packages they say,

The term ‘junk DNA’ has been used since the 1970s to describe non-coding regions of the genome, but today it is considered inaccurate and misleading. The term ‘junk’ suggests that 98% of the genome has no use, but in recent years, studies and projects have used advances in technology to shed light on these regions and have come to different conclusions about how much of the genome has a biological function.

Here's a link to a short video called What is a genome?. I recommend that you watch it to see the level that these experts think is suitable for health care professionals in the UK and to see the level of expertise of those who made the video. This is what seven years of work by experts and £20 million will get you.

All of this tells me that teaching genomics and evolution to medical students is going to be a lot more difficult than Rama Singh imagines. Not only would we have to counter several years of misinformation but we would have to rely on teachers who probably don't understand either topic.

Let's start by teaching these things correctly to biology and biochemistry majors. That's going to be hard enough for now.

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1. Full displosure: Rama and I shared an NSERC grant in 1981 on genetic variation in Drosophila.

Bold predictions for human genomics by 2030

After spending several years working on a book about the human genome I've come to the realization that the field of genomics is not delivering on its promise to help us understand what's in your genome. In fact, genomics researchers have by and large impeded progress by coming up with false claims that need to be debunked.

My view is not widely shared by today's researchers who honestly believe they have made tremendous progress and will make even more as long as they get several billion dollars to continue funding their research. This view is nicely summarized in a Scientific American article from last fall that's really just a precis of an article that first appeared in Nature. The Nature article was written by employees of the National Human Genome Research Institute (NHGRI) at the National Institutes of Health in Bethesda, MD, USA (Green et al., 2020). Its purpose is to promote the work that NHGRI has done in the past and to summarize its strategic vision for the future. At the risk of oversimplifying, the strategic vision is "more of the same."

Green, E.D., Gunter, C., Biesecker, L.G., Di Francesco, V., Easter, C.L., Feingold, E.A., Felsenfeld, A.L., Kaufman, D.J., Ostrander, E.A. and Pavan, W.J. and 20 others (2020) Strategic vision for improving human health at The Forefront of Genomics. Nature 586:683-692. [doi: 10.1038/s41586-020-2817-4]

Starting with the launch of the Human Genome Project three decades ago, and continuing after its completion in 2003, genomics has progressively come to have a central and catalytic role in basic and translational research. In addition, studies increasingly demonstrate how genomic information can be effectively used in clinical care. In the future, the anticipated advances in technology development, biological insights, and clinical applications (among others) will lead to more widespread integration of genomics into almost all areas of biomedical research, the adoption of genomics into mainstream medical and public-health practices, and an increasing relevance of genomics for everyday life. On behalf of the research community, the National Human Genome Research Institute recently completed a multi-year process of strategic engagement to identify future research priorities and opportunities in human genomics, with an emphasis on health applications. Here we describe the highest-priority elements envisioned for the cutting-edge of human genomics going forward—that is, at ‘The Forefront of Genomics’.

What's interesting are the predictions that the NHGRI makes for 2030—predictions that were highlighted in the Scientific American article. I'm going to post those predictions without comment other than saying that I think they are mostly bovine manure. I'm interested in hearing your comments.

Bold predictions for human genomics by 2030

Some of the most impressive genomics achievements, when viewed in retrospect, could hardly have been imagined ten years earlier. Here are ten bold predictions for human genomics that might come true by 2030. Although most are unlikely to be fully attained, achieving one or more of these would require individuals to strive for something that currently seems out of reach. These predictions were crafted to be both inspirational and aspirational in nature, provoking discussions about what might be possible at The Forefront of Genomics in the coming decade.

1. Generating and analysing a complete human genome sequence will be routine for any research laboratory, becoming as straightforward as carrying out a DNA purification.
2. The biological function(s) of every human gene will be known; for non-coding elements in the human genome, such knowledge will be the rule rather than the exception.
3. The general features of the epigenetic landscape and transcriptional output will be routinely incorporated into predictive models of the effect of genotype on phenotype.
4. Research in human genomics will have moved beyond population descriptors based on historic social constructs such as race.
5. Studies that involve analyses of genome sequences and associated phenotypic information for millions of human participants will be regularly featured at school science fairs.
6. The regular use of genomic information will have transitioned from boutique to mainstream in all clinical settings, making genomic testing as routine as complete blood counts.
7. The clinical relevance of all encountered genomic variants will be readily predictable, rendering the diagnostic designation ‘variant of uncertain significance (VUS)’ obsolete.
8. An individual’s complete genome sequence along with informative annotations will, if desired, be securely and readily accessible on their smartphone.
9. Individuals from ancestrally diverse backgrounds will benefit equitably from advances in human genomics.
10. Breakthrough discoveries will lead to curative therapies involving genomic modifications for dozens of genetic diseases.

I predict that nine years from now (2030) we will still be dealing with scientists who think that most of our genome is functional; that most human protein-coding genes produce many different proteins by alternative splicing; that epigenetics is useful; that there are more noncoding genes than protein-coding genes; that the leading scientists in the 1960 and 70s were incredibly stupid to suggest junk DNA; that almost every transcription factor binding site is biologically relevant; that most transposon-related sequences have a mysterious (still unknown) function; that it's still a mystery why humans are so much more complex than chimps; and that genomics will eventually solve all problems by 2040.

Why in the world, you might ask, would we still be dealing with issues like that? Because of genomics.

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"Dark matter" as an argument against junk DNA

Opponents of junk DNA have been largely unsuccessful in demonstrating that most of our genome is functional. Many of them are vaguely aware of the fact that "no function" (i.e. junk) is the default hypothesis and the onus is on them to come up with evidence of function. In order to shift, or obfuscate, this burden of proof they have increasingly begun to talk about the "dark matter" of the genome. The idea is to pretend that most of the genome is a complete mystery so that you can't say for certain whether it is junk or functional.

One of the more recent attempts appears in the "Journal Club" section of Nature Reviews Genetics. It focuses on repetitive DNA.

Before looking at that article, let's begin by summarizing what we already know about repetitive DNA. It includes highly repetitive DNA consisting of mutliple tandem repeats of short sequences such as ATATATATAT... or CGACGACGACGA ... or even longer repeats. Much of this is located in centromeric regions of the chromosome and I estimate that functional highly repetitve regions make up about 1% of the genome.[see Centromere DNA and Telomeres]

The other part of repetitive DNA is middle repetitive DNA, which is largely composed of transposons and endogenous viruses, although it includes ribosomal RNA genes and origins of replication. Most of these sequences are dispersed as single copies throughout the genome. It's difficult to determine exactly how much of the genome consists of these middle repetitive sequences but it's certainly more than 50%.

Almost all of the transposon- and virus-related sequences are defective copies of once active transposons and viruses. Most of them are just fragments of the originals. They are evolving at the neutral rate so they look like junk and they behave like junk.¹ That's not selfish DNA because is doesn't transpose and it's not "dark matter." These fragments have all the characterstics of nonfunctional junk in our genome.

We know that the C-value paradox is mostly explained by differing amounts of repetitive DNA in different genomes and this is consistent with the idea that they are junk. We know that less that 10% of our genome is conserved and this fits in with that conclusion. Finally, we know that genetic load arguments indicate that most our genome must be impervious to mutation. Combined, these are all powerful bits of evidence and logic in favor of repetitive sequences being mostly junk DNA.

Now let's look at what Neil Gemmell says in this article.

Gemmell, N.J. (2021) Repetitive DNA: genomic dark matter matters. Nature Reviews Genetics:1-1. [doi: 10.1038/s41576-021-00354-8]

"Repetitive DNA sequences were found in hundreds of thousands, and sometimes millions, of copies in the genomes of most eukaryotes. while widespread and evolutionarily conserved, the function of these repeats was unknown. Provocatively, Britten and Kohne concluded 'a concept that is repugnant to us is that about half of the DNA of higher organisms is trivial or permanently inert.'”"

That's from Britten and Kohne (1968) and it's true that more than 50 years ago those workers didn't like the idea of junk DNA. Britten argued that most of this repetitive DNA was likely to be involved in regulation. Gemmell goes on to describe centromeres and telomeres and mentions that most repetitive DNA was thought to be junk.

"... the idea that much of the genome is junk, maintained and perpetuated by random chance, seemed as broadly unsatisfactory to me as it had to the original authors. Enthralled by the mystery of why half our genome is repetitive DNA, I have followed this field ever since."

Gemmell is not alone. In spite of all the evidence for junk DNA, the majority of scientists don't like the fact that most of our genome is junk. Here's how he justifies his continued skepticism.

"But it was not until the 2000s, as full eukaryotic genome sequences emerged, that we discovered that the repetitive non-coding regions of our genome harbour large numbers of promoters, enhancers, transcription factor binding sites and regulatory RNAs that control gene expression. More recently, the importance of repetitive DNA in both structural and regulatory processes has emerged, but much remains to be discovered and understood. It is time to shine further light on this genomic dark matter."

This appears to be the ENCODE publicity campaign legacy rearing its ugly head once more. Most Sandwalk readers know that the presence of transcription factor binding sites, RNA polymerase binding sites, and junk RNA is exactly what one would predict from a genome full of defective transposons. Most of us know that a big fat sloppy genome is bound to contain millions of spurious binding sites for transcription factors so this says nothing about function.

Apparently Gemmell's skepticism doesn't apply to the ENCODE results so he still thinks that all those bits and pieces of transposons are mysterious bits of dark matter that could be several billion base pairs of functional DNA. I don't know what he imagines they could be doing.

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Photo Credit: The photo shows human chromosomes labelled with a telomere probe (yellow), from Christoher Counter at Duke University.

1. In my book, I cover this in a section called "If it walks like a duck ..." It's a form of abductive reasoning.

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

The bad news from Ghent

A group of scientists, mostly from the University of Ghent¹ (Belgium), have posted a paper on bioRxiv.

Lorenzi, L., Chiu, H.-S., Cobos, F.A., Gross, S., Volders, P.-J., Cannoodt, R., Nuytens, J., Vanderheyden, K., Anckaert, J. and Lefever, S. et al. (2019) The RNA Atlas, a single nucleotide resolution map of the human transcriptome. bioRxiv:807529. [doi: 10.1101/807529]

The human transcriptome consists of various RNA biotypes including multiple types of non-coding RNAs (ncRNAs). Current ncRNA compendia remain incomplete partially because they are almost exclusively derived from the interrogation of small- and polyadenylated RNAs. Here, we present a more comprehensive atlas of the human transcriptome that is derived from matching polyA-, total-, and small-RNA profiles of a heterogeneous collection of nearly 300 human tissues and cell lines. We report on thousands of novel RNA species across all major RNA biotypes, including a hitherto poorly-cataloged class of non-polyadenylated single-exon long non-coding RNAs. In addition, we exploit intron abundance estimates from total RNA-sequencing to test and verify functional regulation by novel non-coding RNAs. Our study represents a substantial expansion of the current catalogue of human ncRNAs and their regulatory interactions. All data, analyses, and results are available in the R2 web portal and serve as a basis to further explore RNA biology and function.

They spent a great deal of effort identifying RNAs from 300 human samples in order to construct an extensive catalogue of five kinds of transcripts: mRNAs, lncRNAs, antisenseRNAs, miRNAs, and circularRNAs. The paper goes off the rails in the first paragraph of the Results section where they immediately equate transcripts wiith genes. They report the following:

• 19,107 mRNA genes (188 novel)
• 18,387 lncRNA genes (13,175 novel)
• 7,309 asRNA genes (2,519 novel)
• 5,427 miRNAs
• 5,427 circRNAs

The 20th anniversary of the human genome sequence: 6. Nature doubles down on ENCODE results

Nature has now published a series of articles celebrating the 20th anniversary of the publication of the draft sequences of the human genome [Genome revolution]. Two of the articles are about free access to information and, unlike a similar article in Science, the Nature editors aren't shy about mentioning an important event from 2001; namely, the fact that Science wasn't committed to open access.

By publishing the Human Genome Project’s first paper, we worked with a publicly funded initiative that was committed to data sharing. But the journal acknowledged there would be challenges to maintaining the free, open flow of information, and that the research community might need to make compromises to these principles, for example when the data came from private companies. Indeed, in 2001, colleagues at Science negotiated publishing the draft genome generated by Celera Corporation in Rockville, Maryland. The research paper was immediately free to access, but there were some restrictions on access to the full data.

The 20th anniversary of the human genome sequence: 5. 90% of our genome is junk

This is the fifth (and last) post in celebration of the 20th anniversary of publishing the draft sequence. The first four posts dealt with: (1) the way Science chose to commemorate the occasion [Access to the data]; (2) finishing the sequence; (3) the number of genes; and (4) the amount of functional DNA in the genome.

Back in 2001, knowledgeable scientists knew that most of the human genome is junk and the sequence confirmed that knowledge. Subsequent work on the human genome over the past 20 years has provided additional evidence of junk DNA so that we can now be confident that something like 90% of our genome is junk DNA. Here's a list of data and arguments that support that claim.

On the importance of controls

When doing an exeriment, it's important to keep the number of variables to a minimum and it's important to have scientific controls. There are two types of controls. A negative control covers the possibility that you will get a signal by chance; for example, if you are testing an enzyme to see whether it degrades sugar then the negative control will be a tube with no enzyme. Some of the sugar may degrade spontaneoulsy and you need to know this. A positive control is when you deliberately add something that you know will give a positive result; for example, if you are doing a test to see if your sample contains protein then you want to add an extra sample that contains a known amount of protein to make sure all your reagents are working.

Lots of controls are more complicated than the examples I gave but the principle is important. It's true that some experiments don't appear to need the appropriate controls but that may be an illusion. The controls might still be necessary in order to properly interpret the results but they're not done because they are very difficult. This is often true of genomics experiments.

What do believers in epigenetics think about junk DNA?

I've been writing some stuff about epigenetics so I've been reading papers on how to define the term [What the heck is epigenetics? ]. Turns out there's no universal definition but I discovered that scientists who write about epigenetics are passionate believers in epigenetics no matter how you define it. Surprisingly (not!), there seems to be a correlation between belief in epigenetics and other misconceptions such as the classic misunderstanding of the Central Dogma of Molecular Biology and rejection of junk DNA [The Extraordinary Human Epigenome]

Here's an illustraton of this correlation from the introduction to a special issue on epigenetics in Philosophical Transactions B.

Ganesan, A. (2018) Epigenetics: the first 25 centuries, Philosophical Transactions B. 373: 20170067. [doi: 10.1098/rstb.2017.0067]

Epigenetics is a natural progression of genetics as it aims to understand how genes and other heritable elements are regulated in eukaryotic organisms. The history of epigenetics is briefly reviewed, together with the key issues in the field today. This themed issue brings together a diverse collection of interdisciplinary reviews and research articles that showcase the tremendous recent advances in epigenetic chemical biology and translational research into epigenetic drug discovery.

In addition to the misconceptions, the text (see below) emphasizes the heritable nature of epigenetic phenomena. This idea of heritablity seems to be a dominant theme among epigenetic believers.

A central dogma became popular in biology that equates life with the sequence DNA → RNA → protein. While the central dogma is fundamentally correct, it is a reductionist statement and clearly there are additional layers of subtlety in ‘how’ it is accomplished. Not surprisingly, the answers have turned out to be far more complex than originally imagined, and we are discovering that the phenotypic diversity of life on Earth is mirrored by an equal diversity of hereditary processes at the molecular level. This lies at the heart of modern day epigenetics, which is classically defined as the study of heritable changes in phenotype that occur without an underlying change in genome sequence. The central dogma's focus on genes obscures the fact that much of the genome does not code for genes and indeed such regions were derogatively lumped together as ‘junk DNA’. In fact, these non-coding regions increase in proportion as we climb up the evolutionary tree and clearly play a critical role in defining what makes us human compared with other species.

At the risk of bearting a dead horse, I'd like to point out that the author is wrong about the Central Dogma and wrong about junk DNA. He's right about the heritablitly of some epigenetic phenomena such as methylation of DNA but that fact has been known for almost five decades and so far it hasn't caused a noticable paradigm shift, unless I missed it [Restriction, Modification, and Epigenetics].

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On the misrepresentation of facts about lncRNAs

I've been complaining for years about how opponents of junk DNA misrepresent and distort the scientific literature. The same complaints apply to the misrepresentation of data on alternative splicing and on the prevalence of noncoding genes. Sometimes the misrepresentation is subtle so you hardly notice it.

I'm going to illustrate subtle misrepresentation by quoting a recent commentary on lncRNAs that's just been published in BioEssays. The main part of the essay deals with ways of determining the function of lncRNAs with an emphasis on the sructures of RNA and RNA-protein complexes. The authors don't make any specific claims about the number of functional RNAs in humans but it's clear from the context that they think this number is very large.

On the importance of random genetic drift in modern evolutionary theory

The latest issue of New Scientist has a number of articles on evolution. All of them are focused on extending and improving the current theory of evolution, which is described as Darwin's version of natural selection [New Scientist doesn't understand modern evolutionary theory].

Most of the criticisms come from a group who want to extend the evolutionary synthesis (EES proponents). Their main goal is to advertise mechanisms that are presumed to enhance adaptation but that weren't explicitly included in the Modern Synthesis that was put together in the late 1940s.

One of the articles addresses random genetic drift [see Survival of the ... luckiest]. The emphasis in this short article is on the effects of drift in small populations and it gives examples of reduced genetic diversity in small populations.

The Function Wars Part VIII: Selected effect function and de novo genes

Discussions about the meaning of the word "function" have been going on for many decades, especially among philosphers who love that sort of thing. The debate intensified following the ENCODE publicity hype disaster in 2012 where ENCODE researchers used the word function an entirely inappropriate manner in order to prove that there was no junk in our genome. Since then, a cottege indiustry based on discussing the meaning of function has grown up in the scientific literature and dozens of papers have been published. This may have enhanced a lot of CV's but none of these papers has proposed a rigorous definition of function that we can rely on to distinguish functional DNA from junk DNA.

The world is not inhabited exclusively by fools and when a subject arouses intense interest and debate, as this one has, something other than semantics is usually at stake.
Stephen Jay Gould (1982)

That doesn't mean that all of the papers have been completely useless. The net result has been to focus attention on the one reliable definition of function that most biologists can accept; the selected effect function. The selected effect function is defined as ...

Alan McHughen defends his views on junk DNA

Alan McHughen is the author of a recently published book titled DNA Demystified. I took issue with his stance on junk DNA [More misconceptions about junk DNA - what are we doing wrong?] and he has kindly replied to my email message. Here's what he said ...

More misconceptions about junk DNA - what are we doing wrong?

I'm actively following the views of most science writers on junk DNA to see if they are keeping up on the latest results. The latest book is DNA Demystified by Alan McHughen, a molecular geneticist at the University California, Riverside. It's published by Oxford University Press, the same publisher that published John Parrington's book the deeper genome. Parrington's book was full of misleading and incorrect statements about the human genome so I was anxious to see if Oxford had upped it's game.¹, ²

You would think that any book with a title like DNA Demystified would contain the latest interpretations of DNA and genomes, especially with a subtitle like "Unraveling the double Helix." Unfortunately, the book falls far short of its objectives. I don't have time to discuss all of its shortcomings so let's just skip right to the few paragraphs that discuss junk DNA (p.46). I want to emphasize that this is not the main focus of the book. I'm selecting it because it's what I'm interested in and because I want to get a feel for how correct and accurate scientific information is, or is not, being accepted by practicing scientists. Are we falling for fake news?

ENCODE 3: A lesson in obfuscation and opaqueness

The Encyclopedia of DNA Elements (ENCODE) is a large-scale, and very expensive, attempt to map all of the functional elements in the human genome.

The preliminary study (ENCODE 1) was published in 2007 and the main publicity campaign surrounding that study focused on the fact that much of the human genome was transcribed. The implication was that most of the genome is functional. [see: The ENCODE publicity campaign of 2007].

The ENCODE 2 results were published in 2012 and the publicity campaign emphasized that up to 80% of our genome is functional. Many stories in the popular press touted the death of junk DNA. [see: What did the ENCODE Consortium say in 2012]

Both of these publicity campaigns, and the published conclusions, were heavily criticized for not understanding the distinction between fortuitous transcription and real genes and for not understanding the difference between fortuitous binding sites and functional binding sites. Hundreds of knowledgeable scientists pointed out that it was ridiculous for ENCODE researchers to claim that most of the human genome is functional based on their data. They also pointed out that ENCODE researchers ignored most of the evidence supporting junk DNA.

ENCODE 3 has just been published and the hype has been toned down considerably. Take a look at the main publicity article just published by Nature (ENCODE 3). The Nature article mentions ENCODE 1 and ENCODE 2 but it conveniently ignores the fact that Nature heavily promoted the demise of junk DNA back in 2007 and 2012. The emphasis now is not on how much of the genome is functional—the main goal of ENCODE—but on how much data has been generated and how many papers have been published. You can read the entire article and not see any mention of previous ENCODE/Nature claims. In fact, they don't even tell you how many genes ENCODE found or how many functional regulatory sites were detected.

The News and Views article isn't any better (Expanded ENCODE delivers invaluable genomic encyclopedia). Here's the opening paragraph of that article ...

Less than 2% of the human genome encodes proteins. A grand challenge for genomic sciences has been mapping the functional elements — the regions that determine the extent to which genes are expressed — in the remaining 98% of our DNA. The Encyclopedia of DNA Elements (ENCODE) project, among other large collaborative efforts, was established in 2003 to create a catalogue of these functional elements and to outline their roles in regulating gene expression. In nine papers in Nature, the ENCODE consortium delivers the third phase of its valuable project.¹

You'd think with such an introduction that you would be about to learn how much of the genome is functional according to ENCODE 3 but you will be disappointed. There's nothing in that article about the number of genes, the number of regulatory sites, or the number of other functional elements in the human genome. It almost as if Nature wants to tell you about all of the work involved in "mapping the functional elements" without ever describing the results and conclusions. This is in marked contrast to the Nature publicity campaigns of 2007 and 2012 where they were more than willing to promote the (incorrect) conclusions.

In 2020 Nature seems to be more interested in obfuscation and opaqueness. One other thing is certain, the Nature editors and writers aren't the least bit interested in discussing their previous claims about 80% of the genome being functional!

I guess we'll have to rely on the ENCODE Consortium itself to give us a summary of their most recent findings. The summary paper has an intriguing title (Perspectives on ENCODE) that almost makes you think they will revisit the exaggerated claims of 2007 and 2012. No such luck. However, we do learn a little bit about the human genome.

• 20,225 protein-coding genes [almost 1000 more than the best published estimates - LAM]
• 37,595 noncoding genes [I strongly doubt they have evidence for that many functional genes]
• 2,157,387 open chromatin regions [what does this mean?]
• 1,224,154 transcription factor binding sites [how many are functional?]

That's it. The ENCODE Consortium seems to have learned only two things in 2012. They learned that it's better to avoid mentioning how much of the genome is functional in order to avoid controversy and criticism and they learned that it's best to ignore any of their previous claims for the same reason. This is not how science is supposed to work but the ENCODE Consortium has never been good at showing us how science is supposed to work.

Note: I've looked at some of the papers to try and find out if ENCODE stands by it's previous claim that most the genome is functional but they all seem to be written in a way that avoids committing to such a percentage or addressing the criticisms from 2007 and 2012. The only exception is a paper stating that cis-regulatory elements occupy 7.9% of the human genome (Expanded encyclopaedias of DNA elements in the human and mouse genomes). Please let me know if you come across anything interesting in those papers.

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1. Isn't it about time to stop dwelling on the fact that 2% (actually less than 1%) of our genome encodes protein? We've known for decades that there are all kinds of other functional regions of the genome. No knowledgeable scientist thinks that the remaining 98% (99%) has no function.

What's in Your Genome? Chapter 3: Repetitive DNA and Mobile Genetic Elements

By the end of chapter 3, readers will be familiar with two main lines of evidence for junk DNA: the C-Value Paradox, and the fact that most of our genome is full of bits and pieces of dead transposons and viruses. They will also understand that this is perfectly consistent with modern evolutionary theory.

Chapter 3: Repetitive DNA and Mobile Genetic Elements

• Centromeres
• Telomeres
• Mobile genetic elements
• Hidden viruses in your genome
• What the heck is a transposon?
• LINES and SINES
• How much of our genome is composed of transposon-related sequences?
• BOX 3-1: What does the humped bladderwort tell us about junk DNA?
• Selfish genes and selfish DNA
• Mitochondria are invading your genome!
• Selection hypotheses
• Exaptation and the post hoc fallacy
• Box 3-2: Natural genetic engineering?
• If it walks like a duck ...

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What's in Your Genome? Chapter 1: Introducing Genomes

My book is progressing slowly. The main task is to reduce it to about 120,000 words and that's proving to be a lot more difficult that I imagined.

Here's what's now in Chapter 1: Introducing Genomes

• The genome war
• Finishing the human genome sequence
• What is DNA?
• The double helix
• The sequence of all the base pairs was the goal of the human genome project
• How big is your genome?
• Packaging DNA: chromatin
• Transcription
• Translation
• The genetic code
• Introns and exons
• The history of junk DNA

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Dan Graur proposes a new definition of "gene"

I've thought a lot about how to define the word "gene." It's clear that no definition will capture all the possibilities but that doesn't mean we should abandon the term. Traditionally, the biochemical definition attempts to describe the part of the genome that produces a functional product. Most scientists seem to think that the only possible product is a protein so it's common to see the word "gene" defined as a DNA sequence that produces a protein.

But from the very beginning of molecular biology the textbooks also talked about genes for ribosomal RNAs and tRNAs so there was never a time when knowledgeable scientists restricted their definition of a gene to protein-coding regions. My best molecular definition is described in What Is a Gene?.

A gene is a DNA sequence that is transcribed to produce a functional product.
Dan Graur has also thought about the issue and he comes up with a different definition in a recent blog post: What Is a Gene? A Very Short Answer with a Very Long Footnote

A gene is a sequence of genomic material (DNA or RNA) that has a selected effect function.

This is obviously an attempt to equate "function" with "gene" so that all functional parts of the genome are genes, by definition. You might think this is rather silly because it excludes some obvious functional regions but Dan really does want to count them as genes.

Performance of the function may or may not require the gene to be translated or even transcribed.

Genes can, therefore, be classified into three categories:

(1) protein-coding genes, which are transcribed into RNA and subsequently translated into proteins.

(2) RNA-specifying genes, which are transcribed but not translated

(3) nontranscribed genes.

Really? Is it useful to think of centromeres and telomeres as genes? Is it useful to define an origin of replication as a gene? And what about regulatory sequences? Should each functional binding site for a transcription factor be called a gene?

The definition also leads to some other problems. Genes (my definition) occupy about 30% of the human genome but most of this is introns, which are mostly junk (i.e. no selected effect function). How does that make sense using Dan's definition?

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Three scientists discuss junk DNA

I just found this video that was posted to YouTube on May 2019. It's produced by the University of California and it features three researchers discussing the question, "Is Most of Your DNA Junk!" The three scientists are:

• Rusty Gage, a neuroscientist at the Salk Institute
• Alysson Muotri, who studies brain development at the University of California, San Diego
• Miles Wilkinson, who studies neuronal and germ cell development at the University of San Diego

None of them appear to be experts on genomes or junk DNA although one of them (Wilkinson) appears to have some knowledge of the evidence for junk DNA, although many of his explanations are garbled. What's interesting is that they emphasize the fact that some transposon-related sequences are expressed in some cells and they rely on this fact to remain skeptical of junk DNA. They also propose that excess DNA might be present in order to ensure diversity and prepare for future evolution. All three seem to be comfortable with the idea that excess DNA may be protecting the rest of the functional genome.

This is a good example of what we are up against when we try to convince scientists that most of our genome is junk.

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Alternative splicing: function vs noise

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

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

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

The Function Wars Part VII: Function monism vs function pluralism

This post is mostly about a recent paper published in Studies in History and Philosophy of Biol & Biomed Sci where two philosophers present their view of the function wars. They argue that the best definition of function is a weak etiological account (monism) and pluralistic accounts that include causal role (CR) definitions are mostly invalid. Weak etiological monism is the idea that sequence conservation is the best indication of function but that doesn't necessarily imply that the trait arose by natural selection (adaptation); it could have arisen by neutral processes such as constructive neutral evolution.

The paper makes several dubious claims about ENCODE that I want to discuss but first we need a little background.

Background

The ENCODE publicity campaign created a lot of controversy in 2012 because ENCODE researchers claimed that 80% of the human genome is functional. That claim conflicted with all the evidence that had accumulated up to that point in time. Based on their definition of function, the leading ENCODE researchers announced the death of junk DNA and this position was adopted by leading science writers and leading journals such as Nature and Science.

Let's be very clear about one thing. This was a SCIENTIFIC conflict over how to interpret data and evidence. The ENCODE researchers simply ignored a ton of evidence demonstrating that most of our genome is junk. Instead, they focused on the well-known facts that much of the genome is transcribed and that the genome is full of transcription factor binding sites. Neither of these facts were new and both of them had simple explanations: (1) most of the transcripts are spurious transcripts that have nothing to do with function, and (2) random non-functional transcription factor binding sites are expected from our knowledge of DNA binding proteins. The ENCODE researchers ignored these explanations and attributed function to all transcripts and all transcription factor binding sites. That's why they announced that 80% of the genome is functional.