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Thursday, December 22, 2022

Junk DNA, TED talks, and the function of lncRNAs

Most of our genome is transcribed but so far only a small number of these transcripts have a well-established biological function.

The fact that most of our genome is transcribed has been known for 50 years but that fact only became widely known with the publication of ENCODE's preliminary results in 2007 (ENCODE, 2007). The ENOCDE scientists referred to this as "pervasive transription" and this label has stuck.

By the end of the 1970s we knew that much of this transcription was due to introns. The latest data shows that protein coding genes and known noncoding genes occupy about 45% of the genome and most of that is intron sequences that are mostly junk. That leaves 30-40% of the genome that is transcribed at some point producing something like one million transcripts of unknown function.

Most of these transcripts are long noncoding RNAs (lncRNAs) and there has been a lot of speculation over whether they are junk RNA due to spurious transcription or whether they are functional RNAs whose role has yet to be discovered. Many serious scientists believe that most of them are junk (Palazzo and Lee, 2015; Ponting and Haerty, 2022).

Most lncRNAs are junk
Nature journalist is confused about noncoding RNAs and junk
On the misrepresentation of facts about lncRNAs
John Mattick's latest attack on junk DNA

The FANTOM ((Functional ANnoTation Of the Mammalian genome) project was established to do find all the functional elements in the mammalian genome; something that ENCODE no longer considers a priority since they were so badly burned in 2012 when they made the unsubstantiated claim that 80% of our genome was functional. The latest version of FANTOM is FANTOM6 whose goal is to find out how many lncRNAs are functional [FANTOM6].

So far, they've tested 2021 lncRNAs by knocking down the levels of RNA in fibroblast cells with antisense oligonucleotides. Most of the attempts were unsuccessful but 879 succeeded in reducing the level of the lncRNAS by more than 40%. Of these, 246 were selected because they showed phenotypic effects on cell growth and 194 of these were analyzed further. 15 of them showed a cell growth phenotype meaning that 7.7% (15/194) of lncRNAs might be functional by this criterion (Rmilowski et al. 2020).

This is typical of the results from similar experiments that look at the very best candidate transcripts. They usually find evidence that 2-4% show some phenotypic effects then the DNA sequence (putative gene) responsible for the transcript is knocked out.

The work continues, but now I want to draw your attention to a 2018 TED talk by Jay W. Shin, one of the three coordinators of FANTOM6. It's interesting because it gives us some perspective on the worldview of a leading RNA researcher.

Here is Shin's view of the history of junk DNA and junk RNA.

  • Genes can only be found in 2% of our DNA
  • For the longest time, ever since the 1970s, scientists thought that the other 98% was junk.
  • When he learned this in high school (~1997) he felt that something didn't feel right so he decided on a career in research to find out what is hidden in this part of our DNA. (Starting with a B.A. in computer science.)
  • Over the past several years, Shin's lab, and many others have found that there's lots of information in this noncoding DNA.
  • Noncoding DNA can be involved in regulating gene expression.
  • Mutations in noncoding DNA can cause disease.
  • Scientists then realized that they had to study this noncoding DNA.
  • They realized that noncoding DNA could be transcribed to make noncoding RNA.
  • They discovered that there are 25,000 or more noncoding RNAs but only 3% have a known function.
  • Shin and his collaborators set up FANTOM6 to find out whether any of the rest have a function.
  • We've come a long way from the time when we labeled noncoding DNA as junk and we are entering a whole new world where no one has gone before.

This is a mostly false narrative. No reasonable scientist ever defended the view that all noncoding DNA was junk and, furthermore, a host of noncoding genes have been known for 30-40 years. This is not a new discovery. Shin has invented a false paradigm and then claims to have overthrown that paradigm. This is called a paradigm shaft.1

It also highlights the problems with TED talks; there's no quality control. Anyone who looks good and gives a good presentation will seem like an authority even if what they are saying is misleading or incorrect.

If you want to see an excellent example of a really, really good TED talk then watch "The best TED talk ever."

1. Thanks to reader Diogenes who invented the term paradigm shaft.

ENCODE Project Consortium (2007) (Birney, E., Stamatoyannopoulos, J. A., Dutta, A., Guigó, R., Gingeras, T. R., Margulies, E. H., . . . Thurman, R. E.) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature, 447:799-816. [doi: 10.1038/nature05874]

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

Ponting, C. P., and Haerty, W. (2022) Genome-Wide Analysis of Human Long Noncoding RNAs: A Provocative Review. Annual review of genomics and human genetics, 23:153-172. [doi:10.1146/annurev-genom-112921-123710]

Ramilowski, J. A., Yip, C. W., Agrawal, S., Chang, J.-C., Ciani, Y., Kulakovskiy, I. V., . . . Parkinson, N. (2020) Functional annotation of human long noncoding RNAs via molecular phenotyping. Genome Research, 30:1060-1072. [doi: 10.1101/gr.254219.119]

1 comment :

Lamarck said...


within the framework of lnc, func, junk:

In this context, the term "neutral" instead of "junk" is somewhat unfortunate in terms of scientific theory... ;-)