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Tuesday, February 27, 2024

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.


Before discussing this article you need a little background. On December 1, 2022 some changes were made to a Wikipedia article on Repeated sequence (DNA). Among other things, the editor removed all references to junk DNA. A few hours later Paul Gardner corrected the Wikipedia article by adding back the references to junk DNA. Paul Gardner is a professor of biochemistry at the University of Otago in Dunedin, New Zealand. He works on the functional characterization of non-coding RNAs.

I noticed that the original edits were made by a student as part of a course taught at the University of Michigan. I contacted the student and the instructors in an attempt to find out what was being taught and why the student was opposed to junk DNA. I sent them a link to a post on Sandwalk about some issues with the course description [University of Michigan biochemistry students edit Wikipedia].

Nils Walter was the course instructor and he responded by email. This led to an email exchange lasting several weeks where we debated our views of junk DNA. My colleague, Alex Palazzo, joined the email discussion after the initial contact. Alex Palazzo is a professor in the department of biochemistry at the University of Toronto (Toronto, Ontario, Canada). He works on nuclear export and localization of mRNA and has published several articles on junk DNA. He also published a highly relevant article on whether most lncRNAs are functional or junk (Pallazo and Lee, 2015).

We were surprised to learn that Nils Walter was unfamiliar with much of the evidence for junk DNA and the debate about how to define function. He aligned himself with the views of John Mattick who promotes the idea that most of our genome contains newly discovered non-coding RNA genes. He is knowledgeable about molecular evolution since he did his PhD under Manfred Eigen, "one of the founders of the molecular evolution field."

Here's how Walter describes this in his recent publication.

As many stories, this essay starts with a personal experience. One fall term, teaching a special topics course on “Nucleic Acid Biochemistry” for senior undergraduates and beginning graduate students, I had asked teams of students to each develop or expand a Wikipedia entry related to our course material. One group identified “Repeated sequence (DNA)” as a rudimentary entry that needed some work. The students added—based on an exhaustive literature search—much flesh to the existing “bones” in the form of the history, types, and functions in physiology and disease of these pervasive repeat sequences. At the end of the term, the students moved the entry from their “Sandbox” to Wikipedia proper.[1] Remarkably, within 24 h an international team of retired and active geneticists and evolutionary biologists had prominently added a sentence to the entry, suggesting that these repeat sequences are likely non-functional and belong to the “junk” or “selfish” DNA of the cell. Additionally, they published an accompanying blog about their grievance that the term “junk DNA” had been removed by the students.[2]

Reference #2 is my original blog post so I assume that I'm the "retired" member of the international team.1 None of the three of us would self-identify as geneticists or evolutionary biologists although we are certainly familiar with those subjects. We are all biochemists and molecular biologists. This distinction will become important later on.

Walter continues ...

Personally, this strong reaction surprised me as I had assumed that modern transcriptome analyses, funded in part since 2004 by the National Human Genome Research Institute (NHGRI) through the ENCODE project,[3-8] had long dispelled the early misperception that our genome harbors 90% useless “junk DNA”, since most of it is transcribed into non-protein coding, or non-coding, RNAs (ncRNAs, both small and long, that is, lncRNAs; Figure 1).[9] Through a long exchange of thoughtful emails with several members of the community favoring the terms “junk DNA” and “junk RNA”, as well as through conversations with local colleagues, I realized that much of the difference of opinion is predicated on distinctions between scientific fields. It all starts with a definition of fundamental terms such as “biological function” and “gene”, as well as the perceived relevance of observing “conservation” among genomes.

To help bridge this divide, I will first define some of these fundamental terms, then aim to discuss the rationales of the two opposing points of view, and finally offer ideas for how to reconcile the geneticist's and evolutionary biologist's ways of thinking with that of the molecular biologist and biochemist.

That makes a lot of people who were "surprised." I was surprised to discover that there were still prominent biochemists who believed that ENCODE had "dispelled the early misperception that our genome harbors 90% useless 'junk DNA' ...." Nils Walter was surprised to discover that there were biochemists who still think that most of our genome is junk.

I will discuss the rest of the paper in subsequent posts.

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

1. I was a little disappointed that he didn't mention me by name and very disappointed that he didn't make any reference to my book even though it came out five months before he submitted his paper.

Palazzo, A.F. and Lee, E.S. (2015) Non-coding RNA: what is functional and what is junk? Frontiers in genetics 6:2(1-11). [doi: 10.3389/fgene.2015.00002]


apalazzo said...

This article was almost incomprehensible. Nils was just jumping from subject to subject and not really making any point.

SPARC said...
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SPARC said...

Walter stated in his article.
“While there are ever more paths toward identifying ncRNA function in service of completing the human gene catalogue, few of these tools are high in throughput, in large part because most ncRNAs participate in specific functional pathways in unique ways. This tediousness leads to the fact that the definition of a broader biological function through hypothesis-driven mechanistic studies by necessity will almost always lag behind the discovery of an RNA sequence element via modern high-throughput sequencing approaches. The absence of evidence, therefore, can be argued not to be the same as evidence of absence of a function.”

This is like arguing that it is just not obvious that everybody is very likely a criminal because the resources of the justice system are limited and its processes are slow.