Why do the same mutations work differently in different organisms

Kirill Stasevich, "Science and Life"Genes and proteins in different species of living beings are often very similar in structure and function, and one would expect that an unfavorable mutation, once in such a protein, would be equally bad for any "owner" of this protein, be it a human or a mouse.

But when researchers from Duke University together with colleagues from Harvard compared the presence or absence of such mutations in hundreds of genomes, including human, it turned out that the same errors in DNA can cause serious diseases in humans and at the same time not harm animals in any way (Understanding Why Animals Are Healthy Offers Path to Precision Medicine). 

In fact, similar work has been done before, though not on such extensive material. The theory of evolution has a completely satisfactory explanation of why the same mutation in different species leads to different consequences: unfavorable modifications can be balanced, "buffered" by other mutations that some species have and others do not. On the one hand, the buffer mechanism can be triggered within the same gene that the bad mutation got into. 

As is known, the features of the functioning of protein molecules depend on what volume configuration the polypeptide chain has acquired. The configuration depends on the amino acid sequence encoded in the gene, and if a replacement has occurred in the gene, then instead of one amino acid in the protein there may be another, because of which the correct spatial arrangement will no longer work. But other substitutions may occur in the amino acid sequence of the protein, which will become something like "props" for the functional structure of the molecule. On the other hand, compensation can occur due to many mutations in other parts of the genome: let some protein start to work poorly, but we will balance its poor performance by optimizing other proteins. 

In an article in Nature (Jordan et al., Identification of cis-suppression of human disease mutations by comparative genomics) Nicholas Katsanis and his colleagues describe how they were able to confirm the existence of a buffer mechanism. They were able to trace the fate of the same unfavorable mutations in different species: if such a mutation had support, it persisted, if not, the species quickly lost such a variant of the protein. In a stricter formulation, it looks like this: in each subsequent generation, those individuals remained alive whose bad mutation was either balanced, or simply disappeared. If she remained alone, without a buffer mechanism, then she greatly worsened the life of her owner, and the individual with the mutation died due to being unsuitable to the environment, being unable to leave enough descendants. 

The authors of the work even managed to create a model that made it possible to predict where the gene should have compensating modifications for one or another unfavorable mutation. We emphasize that we are talking here only about changes in the same gene; the situation when compensation can occur due to changes in many other parts of the genome, the researchers did not consider in detail. 

The results obtained once again suggest that it is not worth evaluating mutations (or their absence) in black and white, even if we are talking about unambiguously unfavorable DNA defects. Their effect can greatly depend on the context, and this should be especially remembered when we study human mutations, transferring them to model organisms – once in a new environment, the mutation is able to behave differently from the host organism. 

Moreover, even in two different people, the same mutation can manifest itself in different ways. Firstly, there are individual differences in our DNA, errors in the genetic code that only a specific individual and no one else has. By themselves, they are often completely neutral, but they can create the notorious context. Another recent article published in The American Journal of Human Genetics (Johnston et al., Individualized Iterative Phenotyping for Genome-wide Analysis of Loss-of-Function Mutations) states that about 40% of about a hundred people with pathogenic mutations will be quite healthy, both according to subjective feelings and and according to the clinical picture. 

For geneticists, all this is not news: in ordinary school textbooks, you can find a description of what the manifestation of the gene in the phenotype depends on, that is, in the "external sign" (for example, in the form of disease, eye color, height, etc.). Firstly, genes are usually present in two copies, the maternal both the paternal and the fatal mutation in one of them can be balanced by a completely healthy second copy. In addition, many genes are present in the genome in more than two copies, and the manifestation of the trait that such a gene controls depends on how many of them are in working condition. Secondly, what we call a trait can be determined by the work of several genes at once, and in order for the trait to "get bad", it is necessary to spoil several of its genetic components. Thirdly, different genes related to different traits affect each other – this phenomenon is called epistasis, and it can work when there is a "buffering" of a bad mutation by other genes. The list of mechanisms that determine the effect of a mutation and of a gene in general can be continued, and the more we know about them, the clearer it will be to us how to deal with diseases that begin with DNA damage. 

Portal "Eternal youth" http://vechnayamolodost.ru

06.07.2015