Nils Walter disputes junk DNA: (3) Defining 'gene' and 'function'

I'm discussing a recent paper published by Nils Walter (Walter, 2024). He is trying to explain the conflict between proponents of junk DNA and their opponents. His main focus is building a case for large numbers of non-coding genes.

This is the third 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.

-Nils Walter disputes junk DNA: (1) The surprise

-Nils Walter disputes junk DNA: (2) The paradigm shaft

Any serious debate requires some definitions and the debate over junk DNA is no exception. It's important that everyone is on the same page when using specific words and phrases. Nils Walter recognizes this so he begins his paper with a section called "Starting with the basics: Defining 'function' and 'gene'."

Nils Walter disputes junk DNA: (2) The paradigm shaft

I'm discussing a recent paper published by Nils Walter (Walter, 2024). He is trying to explain the conflict between proponents of junk DNA and their opponents. His main focus is building a case for large numbers of non-coding genes.

This is the second post in the series. The first one outlines the issues that led to the current paper.

Nils Walter disputes junk DNA: (1) The surprise

Walter begins his defense of function by outlining a "paradigm shift" that's illustrated in Figure 1.

FIGURE 1: Assessment of the information content of the human genome ∼20 years before (left)[110] and after (right)[111] the Human Genome Project was preliminarily completed, drawn roughly to scale.[9] This significant progress can be described per Thomas Kuhn as a “paradigm shift” flanked by extended periods of “normal science”, during which investigations are designed and results interpreted within the dominant conceptual frameworks of the sub-disciplines.[9] Others have characterized this leap in assigning newly discovered ncRNAs at least a rudimentary (elemental) biochemical activity and thus function as excessively optimistic, or Panglossian, since it partially extrapolates from the known to the unknown.[75] Adapted from Ref. [9].

Reference #9 is a paper by John Mattick promoting a "Kuhnian revolution" in molecular biology. I've already discussed that paper as an example of a paradigm shaft, which is defined as a strawman "paradigm" set up to make your work look like revolutionary [John Mattick's new paradigm shaft]. Here's the figure from the Mattick paper.

The Walter figure is another example of a paradigm shaft—not to be confused with a real paradigm shift.¹ Both pie charts misrepresent the amount of functional DNA since they don't show regulatory sequences, centromeres, telomeres, origins of replication, and SARS. Together, these account for more functional DNA than the functional regions of protein-coding genes and non-coding genes. We didn't know the exact amounts in 1980 but we sure knew they existed. I cover this in Chapter 5 of my book: "The Big Picture."

The 1980 view also implies, incorrectly, that we knew nothing about the non-functional component of the genome when, in fact, we knew by then that half of our genome was composed of transposon and viral sequences that were likely to be inactive, degenerate fragments of once active elements. (John Mattick's figure is better.)

The 2020 view implies that most intron sequences are functional since introns make up more than 40% of our genome but only about 3% of the pie chart. As far as I know, there's no evidence to support that claim. About 80% of the pie chart is devoted to transcripts identified as either small ncRNAs or lncRNAs. The implication is that the discovery of these RNAs represents a paradigm shift in our understanding of the genome.

The alternative explanation is that we've known since the late 1960s that most of the human genome is transcribed and that these transcripts—most of which turned out to be introns—are junk RNA that is confined to the nucleus and rapidly degraded. Advances in technology have enabled us to detect many examples of spurious transcripts that are present transiently at low levels in certain cells. I cover this in Chaper 8 of my book: "Noncoding Genes and Junk RNA.

The whole point of Nils Walter's paper is to defend the idea that most of these transcripts are functional and the alternative explanation is wrong. He's trying to present a balanced view of the controversy so he's well aware of the fact that some of us interpret the red part of the pie chart as spurious transcripts (junk RNA). If he's wrong, and I am right, then there's no paradigm shift.

You don't get to shift the paradigm all on our own, even if John Mattick is on your side. A true paradigm shift requires that the entire community of scientists changes their perspective and that hasn't happened.

In the next few posts we'll see whether Nils Walter can make a strong case that all those lncRNAs are functional. They cover about two-thirds of the genome in the pie chart. If we assume that the average length of these long transcripts is 2000 bp then this represents one million transcripts and potentially one million non-coding genes.

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1. The term "paradigm shaft" was coined by reader Diogenes in a comment on this blog from many years ago.

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: (1) The surprise

Nils Walter attempts to present the case for a functional genome by reconciling opposing viewpoints. I address his criticisms of the junk DNA position and discuss his arguments in favor of large numbers of functional non-coding RNAs.

Nils Walter is Francis S. Collins Collegiate Professor of Chemistry, Biophysics, and Biological Chemistry at the University of Michigan in Ann Arbor (Michigan, USA). He works on human RNAs and claims that, "Over 75% of our genome encodes non-protein coding RNA molecules, compared with only <2% that encodes proteins." He recently published an article explaining why he opposes junk DNA.

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]

The human genome project's lasting legacies are the emerging insights into human physiology and disease, and the ascendance of biology as the dominant science of the 21st century. Sequencing revealed that >90% of the human genome is not coding for proteins, as originally thought, but rather is overwhelmingly transcribed into non-protein coding, or non-coding, RNAs (ncRNAs). This discovery initially led to the hypothesis that most genomic DNA is “junk”, a term still championed by some geneticists and evolutionary biologists. In contrast, molecular biologists and biochemists studying the vast number of transcripts produced from most of this genome “junk” often surmise that these ncRNAs have biological significance. What gives? This essay contrasts the two opposing, extant viewpoints, aiming to explain their basis, which arise from distinct reference frames of the underlying scientific disciplines. Finally, it aims to reconcile these divergent mindsets in hopes of stimulating synergy between scientific fields.

How to end the war in Ukraine according to a Canadian Conservative "diplomat"

In my opinion, the war in Ukraine is much more complicated than most people realize. We are constantly bombarded with propaganda from all sides and it inhibits rational thinking. One of the few reliable facts is that Vladimir Putin is a very smart bad person.

Lots of people think they have the answer to ending the war in Ukraine. One of the latest pundits is Chris Alexander who has published his thoughts in the Feb. 16, 2024 edition of Canada's Globe and Mail: Ukraine is paying the price for our nonchalance toward Russia’s leadership. Alexander spent years in Canada's Foreign Service, including many years in Moscow and a stint as Canada's ambassador to Afghanistan. In 2011 he was elected to Parliament as a Conservative MP and served as Minister of Citizenship and Immigration in Stephen Harper's cabinet. His reputation as a politician was very different than his previous, mostly admirable, reputation as a diplomat. Here's a excerpt from his Wikipedia article.

Copilot answers the question, "What is junk DNA?"

The Microsoft browser (Edge) has a built in function called Copilot. It's an AI assistant based on ChatGPT-4.

I decided to test it byt asking "What is junk DNA?" and here's the answer it gave me.

Older but wiser?

With age comes wisdom, but sometimes age comes alone.

Oscar Wilde

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

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

Open and closed chromatin domains (and epigenetics)

Gene expression in eukaryotes is influenced by the state of chromatin. Tightly packed nucleosomes inhibit the binding of transcription factors and RNA polymerase so that genes in these regions are "repressed." From time to time these regions loosen up a bit allowing access to transcription complexes and subsequent transcription.

The tightly packed regions are known as closed domains and the accessible regions are open domains. Some authors add an intermediate domain called a permissive domain. This model of eukaryotic gene expression has been around for 50 years and the important mechanisms controlling the switch were worked out in the 1980s. I found a recent review that covers this issue in the context of epigenetics and the image below comes from that paper (Klemm et al., 2019).

Philip Ball's new book: "How Life Works"

Philip Ball has just published a new book "How Life Works." The subtitle is "A User’s Guide to the New Biology" and that should tell you all you need to know. This is going to be a book about how human genomics has changed everything.