Mutations that do not change a protein cause as much damage as those that change it. This is the surprising conclusion reached by a research group led by Jianzhi Zhang from the University of Michigan after a study of more than 8000 yeast mutants with targeted modifications in the genome. As the team reports in the journal "Nature", changes in the amino acid sequence of a protein often do not seem to be the main reason why mutations harm an organism. Only in five of the yeast genes examined in the study were changes in the protein significantly more harmful than mutations that had no influence on the structure of the protein. This contradicts long-standing assumptions about mutations and their role in evolution. It also questions the results of common analysis techniques based on it.
The fact that these two types of mutations are due to how the genetic code is translated into a protein. Three building blocks of the DNA each encode an amino acid from which the proteins are built up. Most of the time you can replace one of the three building blocks with another, so that the new sequence encodes the same amino acid - this is called a synonym or "silent" mutation that does not change the protein. About a quarter to a third of all mutations fall into this category. Other, non-synonyms mutations change the DNA code so that the new three-way combination also inserts a new amino acid into the protein. This changes the structure of the protein and thus also how well it fulfills its function.
It is now actually assumed that both types of mutations behave differently in evolution. Because of their impact on proteins, the non -synonymous mutations should change the "fitness" of an organism much more frequently, so that natural selection affects its frequency more. Synonyms mutations, on the other hand, assume that they are "neutral" much more often, so the fitness of the organism does not affect. Such mutations also have an impact, for example on how often genes are read out how stable the mRNA is and how quickly it is translated into proteins - but the effect is generally considered small. The working group now questions this central acceptance due to the knowledge.
Neutral or not neutral?
In the study by Zhang and his team, yeasts grew on average 1.5 percent slower due to non-synonymous mutations. Synonymous mutations slowed growth by an average of 1.2 percent – much more than expected. In addition, a detailed analysis of the 21 genes changed in the experiment showed that the effects of both types of mutations are quite similar on average for almost all genes. The proportions of significantly harmful and significantly useful mutations were also very similar in both, with around 76 percent and around 1.5 percent respectively. Mutations in a gene that do not interfere with the function of the protein therefore cause damage as often as those that do.
This raises a number of questions. Not least whether synonyms mutations perhaps play a significantly larger role, for example for diseases than expected. "To rethink our expectations of mutations should expand our view of the genetic foundations of human health," writes geneticist Nathaniel Sharp from the University of Wisconsin - Madison in a comment for "Nature".
But what is particularly puzzling is why synonymous mutations in the genome nevertheless behave as if they were predominantly neutral. This is because, viewed over evolutionary time periods, synonymous mutations accumulate in the genome to a greater extent than non-synonyms, which suggests that natural selection is virtually "leaving them alone". Based on preliminary experiments, Zhang's team suspects that altered proteins make an organism more susceptible to changes in the environment, while the effect of synonymous mutations is independent of the outside world. But this has not yet been finally clarified.
The experiments of the working group also present research with considerable problems. Because a whole series of analyzes are based on the assumption that synonyms are predominantly neutral. For example, the "molecular clock", in which you count synonyms mutations to find out when the last common ancestor lived two species. In fact, the importance of synonyms mutations ranges through various research fields to species protection.
"Patterns of synonymous genetic variation have been used as a "neutral" standard to elucidate how selection affects different genes, to estimate historical and current population sizes and much more," Sharp explains the problem. For some applications, it may still be sufficient to treat synonymous mutations as neutral, he continues, "but whether this is always the case now needs to be clarified".
