Human CRISPR twins are predicted to have “shortened life spans”

hese GEITP pages have followed the story, the ethical dilemma, of biophysicist Jiankui He (in late 2018, from the Southern Univ of Sci & Technol in Shenzhen, China), who reported births of twin girls whose genomes had been edited using the new CRISPR/Cas9 technology — without having gone through normal ethics committee procedures first (to obtain approval to do such a human experiment). Although no write-up or publication of this experiment appeared in the scientific literature, online information describes insertion of mutations in the embryo’s CCR5 gene (C-C motif chemokine receptor-5, which the AIDS virus uses to enter cells), early in the pregnancy. The goal was to mimic the effect of the CCR5-Δ32 mutation, which provides protection against HIV. The consequences of these mutations on the lives and well-being of those who carry this mutant allele are unknown (but Dr. He’s stated purpose was nevertheless ‘prevention of HIV any time during the lives of these humans’).

Because a mutation can be advantageous, or disadvantageous — depending on environmental conditions and developmental stages — authors [see attached article and editorial] chose to study whether the Δ32 mutation is beneficial. Direct effects on fitness and longevity of individual segregating mutations are expected to be small; therefore, they would be very hard to measure directly. However, owing to the recent availability of large databases of genomic data, direct studies of fitness effects of individual mutations have now become feasible. Thus, authors used the genotyping and death register information of 409,693 individuals of British ancestry from the UK Biobank.

The Δ32 mutation has a frequency of 0.1159 in the British population, meaning that the UK Biobank contains data from thousands of individuals who are homozygous for the Δ32 allele (i.e. having two copies of the allele for the CCR5 gene) — providing an opportunity to compare the mortality of these Δ32/Δ32 individuals to that of Δ32/+ and +/+ individuals. Authors found that there is a 21% increase in the “all-cause mortality rate” in individuals who are homozygous for the Δ32 allele. A deleterious effect of the Δ32/Δ32 mutation was also independently supported by a significant deviation from the Hardy–Weinberg equilibrium (HWE), i.e. a deficiency of Δ32/Δ32 individuals at the time of recruitment.

The Hardy–Weinberg equilibrium (also known as the HW principle, model, theorem, or law) is fundamental to genetics: “allele and genotype frequencies in a population will remain constant, from generation to generation, in the absence of other evolutionary (gene-environment interactions) influences” In other words, offspring from A/A and a/a parents — would be expected to be distributed in an A/A:A/a:a/a pattern with a frequency of 1:2:1 (an example commonly used is “two A/a parents having brown eyes would have a 25% chance of having an a/a blue-eyed child”).

Therefore, if you look at 100 offspring, you would expect the pattern to be 25:50:25; if you found a pattern of 32/64/4, this is strong evidence that the a/a offspring are “not there” at their expected frequency. Note the experiment that these authors did — was entirely a “dry-lab” bioinformatics study that any knowledgeable person could have carried out. Their analysis discovered that Δ32/Δ32 individuals are 21% more likely to die before the age of 76 than Δ32/+ or +/+ individuals. Pretty straightforward, eh? 😊


Nature 6 June 2o19; 570: 16-17

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