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When Jiankui He shocked the world last year by changing the genomes of twins, he explained that the CCR5-32 mutation would protect babies from HIV infection. Not only has this reason been widely denounced by the scientific community, but new research from the University of California at Berkeley suggests that the mutation could actually shorten the lives of the twins.
The researchers used the genotyping and death registry information of 409,693 people from the British Biobank to study the effects on the physical condition of the CCR5-32 mutation. They found that people with two mutated copies of the gene had a significantly higher mortality rate between ages 41 and 78 than those with one copy or none. The authors "estimate a 21% increase in all-cause mortality in individuals homozygous for the Δ32 allele".
The work is published in an article in Nature Medicine entitled "CCR5-Δ32 is deleterious in the homozygous state in humans."
"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, PhD, professor of integrative biology at UC 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. "
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.
"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 many uncertainties and unknown effects in any germ line edition, "said the first author, Xinzhu," April ". Wei, PhD, postdoctoral researcher at the Neilsen laboratory.
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. 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, 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 present in all humans and in most animals is likely to have negative effects, said Nielsen, especially when he is homozygous. "It's a functional protein that, we know, has an effect on the body and is well conserved among many species. So it's likely that a mutation that destroying the protein is, on average, not good for you, "said Nielsen. 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.
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."
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