CCR5-Delta 32 Mutation Increases Mortality

An in-depth analysis of more than 400,000 genomes has shown that the genetic mutation that Jiankui He attempted to create in twin babies, ostensibly to help them fend off HIV infection, is also associated with a 21% increase in mortality in later life.

University of California, Berkeley researchers scanned more than 400,000 genomes and associated health records contained in the UK Biobank and found that people who had two mutated copies of CCR5 had a significantly higher death rate between ages 41 and 78 than those with one or no copies.

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

"Beyond the many ethical issues involved with the CRISPR babies, the fact is that, right now, with current knowledge, it is still very dangerous to try to introduce mutations without knowing the full effect of what those mutations do," said Rasmus Nielsen, senior author of a Nature Medicine paper published today. "In this case, it is probably not a mutation that most people would want to have. You are actually, on average, worse off having it."

"Because one gene could affect multiple traits, and because, depending on the environment, the effects of a mutation could be quite different, I think there can be many uncertainties and unknown effects in any germline editing," said first author Xinzhu "April" Wei.

CCR5 codes for a protein that, among other things, sits on the surface of immune cells and helps some strains of HIV, including the most common ones, to enter and infect them. Jiankui He said he wanted to introduce a mutation in the gene that would prevent this. The ∆32 mutation interferes with the localization on the cell surface of the protein for which CCR5 codes, thwarting 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 reportedly had one copy of CCR5 modified by CRISPR-Cas9 gene editing, while the other baby had both copies edited.