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'CRISPR Babies' Protective HIV Mutation Linked to Increased Mortality

NEW YORK (GenomeWeb) – The mutation that researcher He Jiankui reportedly attempted to introduce into human embryos may be linked to increased mortality, according to a new analysis.

Last November, He announced the birth of twin girls whose genomes he had edited as embryos using CRISPR. The announcement drew condemnation and raised numerous ethical questions among the research community.

Researchers also criticized the gene editing He sought to perform. Although He's work has yet to be published, it has been reported that he aimed to edit the CCR5 gene to make the girls immune to HIV infection. It is unclear whether He was able to make the edits he sought to induce, but it has been suggested that He induced different mutations in CCR5 and that one twin might be heterozygous.

CCR5-Δ32 gene mutations — in which a 32-basepair stretch of the gene is missing — occur naturally among about 11 percent of Northern Europeans. But while a CCR5-Δ32 gene mutation confers protection against HIV infection, and possibly also smallpox and flaviviruses, researchers have suggested it might also increase susceptibility to infectious diseases like influenza.

The University of California, Berkeley's Xinzhu Wei and Rasmus Nielsen examined data from the UK Biobank on individuals with CCR5-Δ32 gene mutations and all-cause mortality and calculated whether there was a deviation from the Hardy–Weinberg equilibrium. As they reported today in Nature Medicine, their analyses indicated that individuals homozygous for the CCR5-Δ32 gene mutation have a 21 percent increase in their rate of all-cause mortality.

"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," Nielsen said in a statement. "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."

Within the UK Biobank, there are thousands of individuals naturally homozygous for the CCR5-∆32 allele. Wei and Nielsen calculated the survival rate for individuals who were homozygous for the ∆32 allele, heterozygous for the ∆32 allele and the wild-type allele, and homozygous for the wild-type allele. After correcting for delays in death registration and possible ascertainment biases, they found individuals with the ∆32/∆32 genotype are 20 percent less likely to reach age 76 than other individuals.

Further analyses using log-rank testing and Cox modeling similarly found that individuals homozygous for the ∆32 allele have higher death rates than ∆32/+ and +/+ individuals. Those ∆32/+ and +/+ individuals, the researchers noted, had similar death rates.

Wei and Nielsen also examined whether there was a deviation from the Hardy–Weinberg equilibrium, which would indicate selection against homozygous individuals. They calculated the allele-specific inbreeding coefficient for ∆32/∆32 and compared it to the coefficients of other alleles with similar minor allele frequencies. Only 20 of the nearly 6,000 other alleles tested had an inbreeding coefficient lower than that of ∆32/∆32, they reported.

These two lines of evidence, Wei and Nielsen wrote, are broadly consistent with each other and suggest that being homozygous for CCR5-Δ32 gene mutation is linked to decreased life expectancy. "In this case, the cost of resistance to HIV may be increased susceptibility to other, and perhaps more common, diseases," they added.