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Tuesday, December 31, 2019

Are introns mostly junk?

There are many reasons for thinking that introns are mostly junk DNA.
  1. The size and sequence of introns in related species are not conserved and almost all of the sequences are evolving at the rate expected for neutral substitutions and fixation by drift.
  2. Many species have lost introns or reduced their lengths drastically suggesting that the presence of large introns can be detrimental in some cases (probably large populations).
  3. After decades of searching, there are very few cases where introns and/or parts of introns have been shown to be essential.
  4. Researchers routinely construct intronless versions of eukaryotic genes and they function normally when re-inserted into the genome.
  5. Intron sequences are often littered with transposon and viral sequences that have inserted into the intron and this is not consistent with the idea that intron sequences are important.
  6. About 98% of the introns in modern yeast (Saccharomyces cerevisiae) have been eliminated during evolution form a common ancestor that probably had about 18,000 introns [Yeast loses its introns]. This suggests that there was no selective pressure to retain those introns over the past 100 million years.
  7. About 245/295 of the remaining introns in yeast have been artificially removed by researchers who are constructing an artificial yeast genome suggesting that over 80% of the introns that survived evolutionary loss are also junk [Yeast loses its introns].

Sunday, December 15, 2019

The evolution of citrate synthase

Citrate synthase [EC] is one of the key enzymes of the citric acid cycle. It catalyzes the joining of acetyl-CoA and oxaloacetate to produce citrate.
acetyl-CoA + H2O + oxaloacetate → citrate + HS-CoA + H+
We usually think of this reaction in terms of energy production since acetyl-CoA is the end product of glycolysis and the citric acid cycle produces substrates that enter the electron transport system leading to production of ATP. However, it's important to keep in mind that the enzyme also catalyzes the reverse reaction.

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?