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Friday, December 13, 2019

The "standard" view of junk DNA is completely wrong

I was browsing the table of contents of the latest issue of Cell and I came across this ....
For decades, the miniscule protein-coding portion of the genome was the primary focus of medical research. The sequencing of the human genome showed that only ∼2% of our genes ultimately code for proteins, and many in the scientific community believed that the remaining 98% was simply non-functional “junk” (Mattick and Makunin, 2006; Slack, 2006). However, the ENCODE project revealed that the non-protein coding portion of the genome is copied into thousands of RNA molecules (Djebali et al., 2012; Gerstein et al., 2012) that not only regulate fundamental biological processes such as growth, development, and organ function, but also appear to play a critical role in the whole spectrum of human disease, notably cancer (for recent reviews, see Adams et al., 2017; Deveson et al., 2017; Rupaimoole and Slack, 2017).

Slack, F.J. and Chinnaiyan, A.M. (2019) The Role of Non-coding RNAs in Oncology. Cell 179:1033-1055 [doi: 10.1016/j.cell.2019.10.017]
Cell is a high-impact, refereed journal so we can safely assume that this paper was reviewed by reputable scientists. This means that the view expressed in the paragraph above did not raise any alarm bells when the paper was reviewed. The authors clearly believe that what they are saying is true and so do many other reputable scientists. This seems to be the "standard" view of junk DNA among scientists who do not understand the facts or the debate surrounding junk DNA and pervasive transcription.

Here are some of the obvious errors in the statement.
  1. The sequencing of the human genome did NOT show that only ~2% of our genome consisted of coding region. That fact was known almost 50 years ago and the human genome sequence merely confirmed it.
  2. No knowledgeable scientist ever thought that the remaining 98% of the genome was junk—not in 1970 and not in any of the past fifty years.
  3. The ENCODE project revealed that much of our genome is transcribed at some time or another but it is almost certainly true that the vast majority of these low-abundance, non-conserved, transcripts are junk RNA produced by accidental transcription.
  4. The existence of noncoding RNAs such as ribosomal RNA and tRNA was known in the 1960s, long before ENCODE. The existence of snoRNAs, snRNAs, regulatory RNAs, and various catalytic RNAS were known in the 1980s, long before ENCODE. Other RNAs such as miRNAs, piRNAS, and siRNAs were well known in the 1990s, long before ENCODE.
How did this false view of our genome become so widespread? It's partially because of the now highly discredited ENCODE publicity campaign orchestrated by Nature and Science but that doesn't explain everything. The truth is out there in peer-reviewed scientific publications but scientists aren't reading those papers. They don't even realize that their standard view has been seriously challenged. Why?


Joe Felsenstein said...

When I first heard of the ENCODE announcement and saw the gullible response of the popular science press, I was depressed. It seemed clear that we were now set back 10 years, at least, in that it was going to take us that long to un-persuade the public. What I could not have guessed then was that genomicists, cell biologists, and molecular biologists would buy into the craziness so enthusiastically. It's been 7 years and not much progress has been made. This time the problem was not primarily caused by the popular science press, but by the ENCODE leadership and all the scientists who they fooled.

Larry Moran said...

I still don't understand why we haven't made any progress. Science is supposed to be a search for truth and scientists are supposed to be critical thinkers and skeptics. Surely in every big lab there are a few graduate students and post-docs who read the literature and raise questions at group meetings and seminars? Surely there are scientists who encounter contrary views at scientific meetings?

Once questions have been raised it becomes impossible to be as dogmatic about your beliefs as expressed in the paper quoted above. At the very least, good science demands that you qualify your statements by mentioning other points of view, right?

Gary S. Hurd said...

Of course my irritation is how the ENCODE twits facilitated the creationists;

"Junk DNA, and Junk Creationism"

Mitchell said...

For the nonspecialist, it is natural to think in terms of the dichotomy 'they used to think the 98% was useless and all junk DNA, but now we know better because we have discovered noncoding RNAs'.

Is there a history of noncoding RNA research which better reflects the reality?

Joe Felsenstein said...

As far as I know almost all (i.e. > 99.9%) of molecular evolutionists and population geneticists argue for there being lots and lots of "junk DNA" in the genome. Genomicists, molecular biologists and cell biologists seem not to listen to them. So there is a huge gulf between these groups.

Gary S. Hurd said...

That was the main point I made 7 years ago about so-called "junk DNA";

Gary S. Hurd said...

Larry's point is sadly true that there are still professionals publishing crap they repeat from the ENCODE nitwits.

Gary S. Hurd said...

AD Riggs (1990) “Marsupials and Mechanisms of X-Chromosome Inactivation”. Australian Journal of Zoology 37(3) 419 – 441 (Suggested that "junk DNA" would not be preserved without some function, identified control functions specifically as promoters of spreading).

J Brosius and S J Gould (1992) “On "genomenclature": a comprehensive (and respectful) taxonomy for pseudogenes and other "junk DNA"” PNAS November 15, vol. 89 no. 22 10706-10710 (They propose that “junk DNA” is evolutionarily significant by providing raw material for future functions, is implicitly the source for current gene functions, and preserves the evolutionary history of organisms. Received 1991).

Emile Zuckerkandl, 1992, “Revisiting junk DNA” Journal of Molecular Evolution Volume 34, Number 3 / March, 1992 (Received 1991) (Suggested that "junk DNA" would not be preserved without some function, speculated that there were control functions).

Larry Moran said...

I learned basic biochemistry and molecular biology in the 1960s. Back then I was well aware of noncoding genes and I knew about regulatory sequences, origins of replication, and centromeres. I never thought of those noncoding DNA elements as junk and neither did any of my colleagues.

Donald Forsdyke said...

Given recent events, I respectfully suggest that Larry and others should move from reiterating well known themes and turn to the manner in which common genes for gullibility and rarer genes for psychopathy have acquired their survival value over the ages.

Jonathan Badger said...

At least in the field I'm working on now (molecular cancer immunology) I think the issue is people think it is black or white -- that either you have to deny all new findings (with "new" being defined as 1990s or later like miRNAs, which are important in the field) or you have to accept any claim of possible function for non-coding transcripts.

Larry Moran said...

There's a third category. Slack and Chinnaiyan (and others) believe that noncoding genes were discovered in 2012.

Joe Felsenstein said...

The situation seems to me pretty grim -- genomicists and molecular biologists swallowing ENCODE's conclusions whole, believing in them implicitly. Meanwhile molecular evolutionists have been yelling their heads off, but to no avail.

Am I being too gloomy? Does anyone here see evidence that molecular biologists, cell biologists, and genomicists are actually coming to appreciate that most of the genome is "junk" DNA? I'd like to be told that I'm wrong to be so gloomy.