1

I am a bit confused about a publication (few month old) which seems to say that RNA can modify our DNA. The publication is the following one.

Unfortunately, I am not a medical expert (and even more in english :D) so I'd like opinions for more expert persons ;). From my understanding, in some cases, the SARS-COV-2 RNA can modify our DNA :

We show here that SARS-CoV-2 RNA can be reverse-transcribed and integrated into the genome of the infected cell and be expressed as chimeric transcripts fusing viral with cellular sequences.

All three methods provided evidence that SARS-CoV-2 sequences can be integrated into the genome of the host cell.

If my understanding is true, why is there a consensus saying that mRNA cannot go into the DNA ?

Thanks in advance,

Nicolas

7

The short answer is maybe, but rarely, and the whole Covid virus has never been seen to integrate into the cell's DNA intact. Any integration requires "helper" molecules not found in the Covid virus, and only very rarely found in a normal cell.

It's been known for many decades that RNA in a cell can be converted into DNA and integrated into the cell's genomic DNA. This is extremely rare except under certain conditions. For example, a class of viruses (including HIV) called "retroviruses" carries an enzyme called reverse transcriptase or RT that the viruses use to convert their RNA genome into DNA and "hide" by splicing that into the cell's own DNA. Covid does NOT have such an enzyme.

However, during evolution, our cells have picked up many small DNA elements ("jumping genes" or transposons), many of which "hop" by reverse-transcribing their transcript and inserting that new DNA somewhere in the cell's DNA. They continue to "hop" to this day, rarely. Occasionally, they make an error and convert some of the other mRNA in the cell into DNA and insert it into the genome. LINE1 elements in particular make up almost 20% of our cellular DNA, so the paper's authors tried to see if any LINE1 elements were able to (rarely) incorporate Covid fragments into a cell's DNA.

Greatly simplified, the authors tried to answer the following questions:

  1. Can laboratory cells which have been engineered to make lots of the LINE1 transposase, then infected with Covid, end up with fragments of Covid virus in their DNA?

  2. Can "normal", non-engineered laboratory cells infected with Covid, end up with fragments of Covid virus in their DNA?

  3. Do any patient samples from Covid-infected patients show any fragments of Covid virus in their cellular DNA?

The method the authors used to check this was to massively sequence mRNAs from cells, and look for any that had normal cellular gene sequences spliced onto Covid sequences. It turned out there was a big technical problem with this (hence the wishy washy conclusions of the paper) - the sequencing sample preparation process will also rarely splice two mRNA sequences together even if they were not spliced in the cell. However, that artificial process tends to almost always only splice two "antisense" strands, while the LINE1 process should have no preference between sense and antisense. Thus, the authors reasoned that if they were finding only antisense/antisense that could be an artifact, while significant amounts of antisense/sense splices would indicate real splices from the genomic DNA.

The answers they inferred were roughly:

  1. Yes, artifcially expressing lots of LINE1 tranposase resulted in detectable integration of partial Covid virus sequences in the cellular DNA.
  2. With more normal laboratory cells, they found many fewer integrated Covid virus fragments, but still found some.
  3. With patient samples, there were many additional technical problems; they think they found some Covid fragments integrated in cells from 1 patient, but are not nearly as confident with that result as for (1) and (2).

In any case, the integrated Covid sequences they found seem to be only fragments of the virus (although their techniques could not be fully sure on this); they never found a whole virus integrated into any cell.

As a practical matter, the "consensus" is correct, but given billions of people and quadrillions of Covid viruses, there might be a few outliers.

Paper ref: Reverse-transcribed SARS-CoV-2 RNA can integrate into the genome of cultured human cells and can be expressed in patient-derived tissues PNAS May 25, 2021 118 (21) e2105968118; https://doi.org/10.1073/pnas.2105968118

LINE1 review: "LINE-1 Elements in Structural Variation and Disease" Annu Rev Genomics Hum Genet. 2011; 12: 187–215. doi: 10.1146/annurev-genom-082509-141802 Author's manuscript freely downloadable from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4124830/pdf/nihms606127.pdf

4
  • Sounds like a great answer. Supporting references?
    – Carey Gregory
    Jul 15 at 4:08
  • Just the paper itself.
    – Armand
    Jul 15 at 4:09
  • 1
    Thanks for the edit. The link is all that was needed.
    – Carey Gregory
    Jul 15 at 4:12
  • Thanks a lot for the detailled explanation. Makes things a lot clearer.
    – Nicolas M.
    Jul 15 at 6:47

Your Answer

By clicking “Post Your Answer”, you agree to our terms of service, privacy policy and cookie policy

Not the answer you're looking for? Browse other questions tagged or ask your own question.