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Do coronavirus genes find their way into human chromosomes?

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Popular scientists have reaffirmed their controversial hypothesis that pandemic coronavirus genetic bits can integrate into our chromosomes and stay there long after the infection. The insertions could explain the rare occurrence of people recovering from COVID-19 but testing positive for SARS-CoV-2 months later.

The team lacks direct evidence of integrations in infected people or data indicating harm to a person’s health.

The research team led by MIT stem cell biologist Rudolf Jaenisch and gene regulation expert Richard Young sparked a Twitter frenzy in December 2020 when they published their findings on bioRxiv.

The researchers stressed that viral integration does not mean that people who recover from COVID-19 are no longer infectious. However, critics accused them of stoking unfounded fears that COVID-19 vaccines based on messenger RNA (mRNA) would alter human DNA in some way. (Jaenisch and Young emphasise that their findings, both old and new, do not imply that the vaccines’ sequences are integrated into our DNA.)

Researchers also presented a slew of scientific criticisms, some of which the team responds to in a paper published by the Proceedings of the National Academy of Sciences last week (PNAS).

“We now have unambiguous evidence that coronavirus sequences can integrate into the genome,” Jaenisch says.

SARS-CoV-2, the virus that causes COVID-19, has RNA-based genes, and Jaenisch, Young, and co-authors believe that an enzyme in human cells may copy viral sequences into DNA on rare occasions, allowing them to slip into our chromosomes. The enzyme reverse transcriptase is encoded by LINE-1 elements, which make up 17 percent of the human genome and are remnants of retrovirus infections from the past. When human cells spiked with extra LINE-1 elements were infected with the coronavirus, DNA versions of SARS-CoV-2 sequences nestled into the cells’ chromosomes, according to the researchers’ original preprint.

Many experts on LINE-1 elements and other “retrotransposons” thought the evidence was insufficient to back up the claim.

“If I would have had this data, I would have not submitted to any publication at that point,” says Cornell University’s Cedric Feschotte, who studies endogenous retrovirus chunks in the human genome.

He and others said they expected higher-quality work from scientists of Jaenisch’s and Young’s caliber.

Critics presented evidence in two subsequent studies, both published on bioRxiv, that the alleged chimaeras of human and viral sequences can be created using the same technique the group used to look for them in chromosomes. The human-virus sequences “are more likely to be a methodological product, rather than the result of genuine reverse transcription, integration, and expression,” according to one report.

Jaenisch, Young, and colleagues acknowledge in their new peer-reviewed paper that the technique they used creates human-viral chimaeras by accident.

“I think it’s a valid point,” Jaenisch says.

He goes on to say that when they first submitted the paper to a journal, they realised it needed more data, which they planned to add during the review process. However, the journal, like many others, requires authors to submit all COVID-19 results to a preprint server right away.

“I probably should have said screw you, I won’t put it on bioRxiv. It was a misjudgment,” Jaenisch says.

The team provides evidence in the PNAS paper that artifacts alone cannot explain the detected levels of virus-human chimeric DNA. The researchers also show that LINE-1 elements flank the integrated viral genetic sequence, confirming their hypothesis. They’ve also worked with Stephen Hughes of the National Cancer Institute, one of the original skeptics, who proposed an experiment to determine whether the integration was real or not, based on the orientation of the integrated viral sequences relative to the human ones. According to Hughes, a co-author of the new paper, the findings back up the original hypothesis.

“That analysis has turned out to be important,” he says.

Others agree. “The integration data in cell culture is much more convincing than what was presented in the preprint, but it’s still not totally clean,” says Feschotte, who now calls Jaenisch’s and Young’s hypothesis “plausible.” (SARS-CoV-2, he notes, can also persist in a person for months without integrating its genes.)

The real question is whether the cell culture data can be used to improve human health or diagnosis.

“In the absence of evidence of integration in patients, the most I can take away from these data is that it is possible to detect SARS-CoV-2 RNA retroposition events in infected cell lines where LINE-1 is overexpressed,” Feschotte says.

“The clinical or biological significance of these observations, if any, is a matter of pure speculation at this point.”

In tissue from living and autopsied COVID-19 patients, Jaenisch and Young’s team found hints of SARS-CoV-2 integration. The researchers discovered high levels of a type of RNA produced solely by integrated viral DNA as the cell reads its sequence to make proteins.

But, Young acknowledges, “We do not have direct evidence for that yet.”

Harmit Malik, a researcher at the Fred Hutchinson Cancer Research Center who specialises in ancient viruses in the human genome, says it’s a “legitimate question” to wonder why people who should have cleared the virus have positive polymerase chain reaction tests for its sequences. However, he isn’t convinced that the cause is an integrated virus.

“Under normal circumstances, there is so little reverse transcription machinery available” in human cells, Malik says.

Since December, the debate has become noticeably more civil. Young and Jaenisch both claim that their preprint drew more criticism than any other study in their careers, in part because some researchers were concerned that it would play into the hands of vaccine skeptics spreading false claims about the newly approved mRNA vaccines.

“If there ever was a preprint that should be deleted, it is this one! It was irresponsible to even put it up as a preprint, considering the complete lack of relevant evidence. This is now being used by some to spread doubts about the new vaccines,” Marie-Louise Hammarskjöld, a microbiologist at the University of Virginia, posted in a comment on bioRxiv at the time.

And what of the original journal submission? “They rejected it,” Jaenisch says.

Image Credit: Getty

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