The CRISPR mutation of the baby significantly increases mortality

A genetic mutation that a Chinese scientist attempted to create in twins born last year, apparently to help them protect themselves from HIV infection, is also associated with an increase of 21 % of mortality at an older age, according to an analysis performed by the University of California at Berkeley. , scientists.

Researchers analyzed more than 400,000 genomes and associated health records contained in a UK database, UK Biobank, and found that people with two mutated copies of the gene had a significantly higher mortality rate between 41 and 78. years than those with only one copy or none. .

Previous studies have linked two mutated copies of the gene, CCR5, to a fourfold increase in the mortality rate after influenza infection, and the higher overall mortality rate may reflect this greater susceptibility to death from influenza. But the researchers say that there could be a number of explanations, since the protein for which CCR5 codes, and which no longer works in those with the mutation in both copies of the gene, is implicated in many bodily functions.

"Beyond the many ethical issues related to CRISPR babies, the fact is that now, with current knowledge, it is still very dangerous to try to introduce mutations without knowing the full effect of what these mutations are doing. Said Rasmus Nielsen, professor of integrative biology at the University of Berkeley. "In this case, it's probably not a mutation that most people would like to have. In fact, your situation is worse on average. "

"Because a gene can affect multiple characters and that, depending on the environment, the effects of a mutation can be very different, I think that there can be a lot of problems." 39, uncertainties and effects unknown in any germ line edition, "said Xinzhu, postdoctoral fellow," April "Wei.

Wei is the main author and Nielsen is the main author of an article describing the research that will appear online Monday, June 3 in the journal. Nature Medicine.

The mutation prevents HIV infection

The CCR5 gene encodes a protein that, among other things, is on the surface of immune cells and helps some HIV strains, including the most common, to enter and infect them. Jiankui He, the Chinese scientist who, last November, shocked the world by announcing that he had experimented with CCR5 on at least two babies, said he wanted to introduce a gene mutation that would prevent this. Natural mutations that deactivate protein are rare in Asians, but a mutation found in about 11% of northern Europeans protects them from HIV infection.

The genetic mutation, called Δ32 (Delta 32), refers to a segment lacking 32 base pairs in the CCR5 gene. This mutation interferes with the cell surface location of the protein for which CCR5 encodes, counteracting HIV binding and infection. He was unable to duplicate the natural mutation, but appears to have generated a similar deletion that would also inactivate the protein. One of the twin babies would have had a copy of CCR5 modified by the CRISPR-Cas9 gene modification, while the other baby would have had both copies published.

But inactivating a protein found in all humans and in most animals is likely to have negative effects, said Nielsen, particularly when it is performed on both copies of the gene, a so-called homozygous mutation. .

"Here is a functional protein that we know has an effect on the body and is well conserved among many species, so it is likely that a mutation that destroys the protein is, on average, not good. for you, "he said. I said. "Otherwise, the evolutionary mechanisms would have destroyed this protein a long time ago."

After the publication of his experiment, Nielsen and Wei, who study the current genetic variation to understand the origin of human, animal and plant traits, decided to examine the effect of the CCR5-Δ32 mutation from the data. from UK Biobank. The database contains genomic information on half a million British citizens related to their medical records. The genomic information is very similar to those acquired by Ancestry.com and 23andMe: detailed information on nearly one million individual variations of the genetic sequence, called single nucleotide polymorphisms (SNPs).

Two independent measures indicated a higher mortality rate for those with two mutated genes. Fewer people than expected with two mutations listed in the database, indicating that they had died at a higher rate than the general population. And less than expected have survived from 40 to 78 years.

"The proportions before registration and survival after registration tell the same story, namely that you have minimal survival or higher mortality if you have two copies of the mutation," Nielsen said. "There is simply a deficit of individuals with two copies."

As the Δ32 mutation is relatively widespread in northern Europe, it had to be favored by natural selection at some point, he added, without however protecting the HIV, because the virus n & # 39; 39 has circulated among humans only since the 1980s.

Wei said some evidence links the mutation to increased survival after stroke and protection against smallpox and flaviviruses, a group that includes dengue, Zika and West Nile viruses.

Despite these potential benefits, the potential unexpected effects of creating genetic mutations, both in adult somatic cells and in embryonic germ cells, argue for caution, the researchers said.

"I think there are a lot of things unknown at the current stage about gene functions," said Wei. "CRISPR technology is far too dangerous to use for germline editing."

This work was supported by the National Institutes of Health (R01GM116044).

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