Mutations considered harmless have been found to cause problems

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

Mutations are the raw ingredient of evolution and provide variation that sometimes makes an organism more successful in its environment. But most mutations are expected to be neutral and not affect the fitness of an organism. These can be incredibly helpful, as these occasional changes help us track evolutionary relationships without worrying about selection for or against the mutation affecting frequency. For example, all genetic lineage tests rely heavily on tracking the presence of these neutral mutations.

But this week, a paper provided evidence that a significant category of mutations isn’t as neutral as we thought they were. The big caveat is that the research was done with yeast, which is a strange organism in some respects, so we’ll have to see if the results hold for others.

Really neutral?

One of the reasons most mutations are neutral is that most of our DNA doesn’t seem to be doing 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 nearby DNA is involved in controlling the activity of those genes. Outside of those regions, mutations don’t do much, either because the DNA there has no function or because the function isn’t very sensitive to having a precise sequence of bases in the DNA.

But even within the parts of genes that code for proteins, the exact sequence shouldn’t matter so much. The amino acid of each protein is encoded by a combination of three bases in the DNA. That means there are 64 possible codes for amino acids, but we only use 20 different amino acids. As a result, there is sufficient redundancy in the genetic code. For example, the base sequence ACG encodes the amino acid threonine. So is the ACA series. And ACC. All together, four different codes will deliver you threonine.

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

That’s the assumption that has put the new paper to the test.

Make all mutations

To test neutral mutations, the researchers started with 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 doesn’t kill the yeast, but makes it less healthy. This should make it easier to detect partial effects, whereby the mutation makes the yeast less healthy.

Within that stretch, the researchers picked a 150-base stretch in the DNA and made each possible mutation, using DNA editing to create a yeast strain that carried the mutation. That’s a total of more than 9,000 individual yeast strains, some of which carry mutations that will change the amino acid sequence and others that we would expect to be neutral. But this, of course, involved lab work, where things don’t work for random, unknown reasons, so the researchers had to settle for testing about 8,300 mutated yeast strains.

The test was quite simple. Put equal numbers of normal and mutated yeast in a flask and let them grow for a while. Then sample the population and check the relative levels of normal and mutant yeast. If the mutation lowered the condition, you would see more normal yeast when you sampled the bottle.

That applied to mutations that changed an amino acid. These saw their relative fitness drop a bit, though not much (their fitness was 0.988 that of the normal yeast). But the neutral mutations weren’t noticeably different — they also lowered the yeast’s condition by a small amount over a normal strain. In fact, the mutations that didn’t change amino acids were, on average, indistinguishable from those that did. Above this average you can see a small difference. There were more amino acid-altering mutations that had a stronger deleterious effect on the condition, and more neutral ones that had a minimal effect. But it is clear that the class that was expected to be neutral, as a whole was not.

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