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How dangerous are harmful mutations
Kirill Stasevich, Science and Life (nkj.ru )
Many diseases arise due to genetic defects, and we often hear that we have discovered another mutation that increases the likelihood of Alzheimer's disease, atherosclerosis, diabetes, a particular type of cancer, etc. But what does "increases probability" mean? What are the percentages here — 10%, 50%, 80%?
This is a task for medical research combining genetic and statistical methods. It cannot be said that there are no such studies — on the contrary, there are quite a lot of them and they are becoming more and more due to the fact that DNA reading methods are becoming more accessible, faster and cheaper. After all, what is the point here: it is necessary to compare individual medical histories with the presence or absence of specific mutations in certain genes. However, according to researchers from Mount Sinai Medical Center, in such studies, the danger of mutations is often overestimated. This happens because either a small number of people are analyzed, or they are generally limited to medical histories of families in which predisposition to certain diseases is inherited, or they take material for statistical processing from specialized clinics where most patients suffer from a specific disease.
That is, for an objective assessment of the danger of mutations, you need to take more material, and you need to take it from general databases that do not specialize in what kind of genetic or medical information they contain. The staff of the Mount Sinai Center used two such databases; in total, they compared the genomes and medical histories of more than 72 thousand people who had almost 38 thousand different variants of various genes. (Of course, one person could have twenty genes with deviations, and not necessarily with bad deviations, another had five, the third had the same five, but the mutations in these five were different than the second, etc.)
In total, 5360 pathogenic mutations associated with 157 diseases were found. As expected, mutations had different penetrance — the so-called probability that the mutation will manifest itself in physiology, biochemistry, anatomy, etc., that is, in general, in the life of the organism. On average, the probability that the mutation will lead to a diagnosis turned out to be 6.9%. And the risk that a person with a mutation would have this or that disease was very slightly higher than the risk of getting the same disease for a person without a mutation. At the same time, some mutations do have a fairly high penetrance. For example, there are very well—known mutations in the BRCA1 and BRCA2 genes that are fraught with breast cancer - their frequency of manifestation is on average 38%.
A curious result was obtained with respect to mutations that are believed to increase the likelihood of type 2 diabetes with age, as well as malignant tumors of the breast and prostate. In people over 70 years of age, such mutations manifested themselves in the diagnosis with a probability of about 10% — but at the same time, if we take the mass of people over 20, then the penetration of mutations will be 8%. In other words, those who are younger can also feel the effects of such "age-related" mutations, although with a slightly lower probability.
Finally, analyzing the harmfulness of some mutations, one should make a reservation about ethnicity: an article on the JAMA portal (Forrest et al., Population-Based Penetration of Deleterious Clinical Variants) describes more than a hundred mutations that occur mainly in people of non-European origin.
We also wrote about other studies in which mutations, let's say, reduced the harmfulness. A few years ago, an article was published in Science stating that the absence of many genes considered important does not affect health, and another one followed, the authors of which tried to understand why this happens.
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