Harm or benefit?

Carriers of the "protective" mutation from HIV risk living less than their peers

They live up to 76 years 20% less often

Polina Loseva, "The Attic"

In November 2018 , Chinese scientist Jiankui He said about the birth of two genetically modified girls. He and his team tried to reproduce in their genome the mutation ∆32 in the CCR5 gene, which makes the cells of its carriers resistant to HIV. Now, an analysis of the genomes of more than 400,000 Britons has shown that carriers of a mutation in both copies of the gene are more at risk of dying in old age than people with "healthy" gene variants. And this fact once again calls into question the ethics of genetic editing.

The CCR5 gene encodes a protein on the surface of lymphocytes, with which HIV particles penetrate into the cell. The mutation 32 helps to avoid this: in its carriers, the CCR5 gene is shortened, therefore, the protein is also shortened, so the viral particle cannot use it. Carriers of the mutation in both variants of the gene (homozygotes) are completely resistant to viral infection; if the mutation exists only in one of the copies (heterozygotes), then the disease develops slower and weaker.

He's research team used CRISPR/Cas9 "molecular scissors" to cut a section of the sequence from the CCR5 gene and thereby reproduce the ∆32 mutation. Despite the fact that He's work has not been published anywhere yet, the data he cited suggest that it was still possible to make some changes in the genes of girls. True, they do not fully reproduce the desired mutation, but they can cause defects in the CCR5 protein.

Over the past six months, He has received a lot of criticism: the ethics of experiments, the accuracy of the methodology, and the accuracy of editing have been questioned. Then the question of safety came to the fore: even if we assume that we will learn to introduce the mutation 32 into the genome, will it not harm the body? Some authors suggest that the mutation may be useful in an unexpected way, for example, by increasing mental abilities. Others remind that ∆32 is associated with the vulnerability of people to the flu virus and the risk of developing schizophrenia.

Now, the American scientist Xinzhu Wei (Xinzhu Wei) and the Dane Rasmus Nielsen (Rasmus Nielsen) decided to test the effects of the fatal mutation on a large sample of people. They turned to the genetic data of the large British project UK Biobank, during which scientists collected information on hundreds of thousands of people. They selected data on 409,693 Britons aged 41-78 and built a survival curve for them, that is, the probability of staying alive, and not dying from natural causes, depending on age. About 11.6% of Britons are carriers of ∆32, so the researchers were able to collect enough data to compare mortality in homo- and heterozygotes.

It turned out that the survival curve of heterozygotes does not differ from that of people who do not carry mutation 32. But in homozygotes after 60 years, the curve begins to lag behind the control, that is, their chances of survival decrease. In total, their chance of living to 76 years is about 20% lower than that of carriers of at least one healthy gene.

Figure from the article CCR5-∆32 is deleterious in the homozygous state in humans, published in the journal Nature Medicine – VM.

It is worth noting that this figure could be influenced by many factors. For example, the fact that UK Biobank studies involve, as a rule, quite healthy people. This is evidenced, for example, by the fact that the mortality rate among study participants aged 70-74 years is two times lower than the national average. In addition, there are relatively few older people in the database, so statistics on them may be distorted. Thus, the impact on survival in the entire British population may differ from 20%, however, this figure is large enough to ignore it. Finally, their origin may also play a role: since they all have British roots, it may simply be an uneven distribution of genotypes.

To test the latter assumption, the researchers calculated how common another 5,932 mutations are in the population. If the sample is large enough, and mutations do not affect survival, then they should occur with a frequency calculated according to the Hardy–Weinberg law. For most of the studied mutations, this was confirmed. But ∆32 was less common than the law predicted. And out of all 5,932 variants, only 20 were even rarer than her. This means that carriers of this mutation do not participate in the UK Biobank project, either simply because they do not want to, or – more likely – on average they are more likely to get sick and they simply have no time for it.

On the one hand, this is not surprising: homozygous people with important genes are usually less healthy than carriers of full-fledged copies of genes. On the other hand, the CCR5 gene was not considered vital until recently, which allowed He and his team to make changes to it. But if mutations in it affect human health so much, do we have the right to edit it at all? And can we edit any other genes if homozygous mutations affect survival so much?

In the same issue of Nature Medicine, where the article by Wei and Nielsen was published, a program text by American molecular biologists, including Shukhrat Mitalipov, on the prospects of genetic editing (Wolf et al., Principles of and Strategies for germline gene therapy). In it, scientists list modern achievements of technology and outline the nearest prospects. This means that the discussion about the acceptability of intervention in the human genome is far from over.

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