Mutations thought to be harmless turn out to be problematic

Enlarge / The genetic code. Note that many amino acids (the outer layer, in gray) are encoded by multiple sets of three-base codes that share the first two letters.

Mutations are the raw ingredient of evolution, providing variations that sometimes make an organism more efficient in its environment. But most mutations are expected to be neutral and have no impact on an organism’s fitness. These can be incredibly useful because these accidental changes help us track evolutionary relationships without worrying about selection for or against the mutation affecting its frequency. All genetic ancestry tests, for example, rely heavily on tracking the presence of these neutral mutations.

But this week, a paper provided evidence that an important category of mutations isn’t as neutral as we thought. The big caveat is that the study was done on yeast, which is a strange organism in many ways, so we’ll have to see if the results hold for others.

True Neutral?

One of the reasons most mutations are neutral is that most of our DNA doesn’t seem to do anything useful. Only a few percent of the human genome is made up of the portion of genes that code for proteins, and only a portion of neighboring DNA is involved in controlling the activity of these genes. Outside of these regions, mutations don’t do much, either because the DNA doesn’t have a function there, or because the function isn’t very sensitive to the presence of a precise sequence of bases. in DNA.

But even in the parts of genes that code for proteins, the precise sequence shouldn’t matter much. The amino acid of each protein is encoded by a combination of three bases in DNA. This means that there are 64 possible codes for amino acids, but we only use 20 different amino acids. As a result, there is a lot of redundancy in the genetic code. For example, the ACG base series codes for the amino acid threonine. Just like the ACA series. And VAC. A total of four different codes will give you Threonine.

The key thing to note is that all four codes begin with AC. If you have a mutation in either of these two bases, you no longer get threonine. But if you get a mutation in third position, it doesn’t matter – whatever you change base, you still get threonine. It should be a completely neutral mutation. And researchers have used the assumption that it is neutral to help them track protein evolution.

This is the hypothesis that the new document has put to the test.

Make all mutations

To test for neutral mutations, the researchers started from a panel of 21 yeast genes, chosen in part because they are involved in a wide variety of cellular activities. The other part behind their choice is that eliminating these genes does not kill the yeast but makes it less healthy. This should make it easier to detect partial effects, where the mutation makes the yeast less healthy.

In this stretch, the researchers chose a 150-base stretch in the DNA and created all possible mutations, using DNA editing to create a strain of yeast carrying the mutation. This represents a total of over 9,000 individual yeast strains, some carrying mutations that will alter the amino acid sequence and others carrying mutations that one would expect to be neutral. But of course, this involved lab work, where things didn’t work for random and unknown reasons, so the researchers had to settle for testing around 8,300 mutant yeast strains.

The test was quite simple. Throw an equal number of normal and mutant yeast into a bottle and let them grow for a bit. Next, sample the population and check the relative levels of normal and mutant yeast. If the mutation reduced the aptitude, you would see more normal yeast when you picked up the vial.

This was true for mutations that changed an amino acid. These saw their relative fitness drop a bit, but not much (their fitness was 0.988 that of normal yeast). But the neutral mutations weren’t particularly different — they also reduced the yeast’s fitness by a tiny amount compared to a normal strain. Indeed, mutations that did not modify any amino acid were, on average, indistinguishable from those that did. Beyond this average, you might see a slight difference. There were more amino acid-modifying mutations that had a stronger deleterious effect on fitness, and more neutral ones that had minimal effect. But it is clear that, on the whole, the class supposed to be neutral was not.

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