Synonymous mutations in representative yeast genes are mostly strongly non-neutral

[John_Harshman]

@Rumraket

He’s talking about all mutations in all organisms, including viruses.

Then he’s much closer to right than wrong, though more so for eukaryotes (including yeast).

[dsterncardinale]

@John_Harshman

Then he’s much closer to right than wrong, though more so for eukaryotes (including yeast).

Until he (Sanford) get’s the to “and these non-selectable mutations accumulate to the point where they drive everything to extinction without ever being selected against” part.

But we’ve talked about this before. If you still don’t take my word for it, I beg you, read his book. It really is that bad.

[Rumraket (Mikkel R.)]

Oh I agree, but that’s because neutral theory is true and you can’t - contrary to what @thoughtful appears to believe - generalize the result of this study to the genome as a whole, nor to other organisms.

[John_Harshman]

@dsterncardinale

If you still don’t take my word for it, I beg you, read his book. It really is that bad.

If I don’t take your word for what?

@Rumraket

Oh I agree, but that’s because neutral theory is true and you can’t - contrary to what @thoughtful appears to believe - generalize the result of this study to the genome as a whole, nor to other organisms.

Well, now, who knows what @thoughtful believes?

[Nesslig20]

@evograd

First, some people are highly skeptical that the wild-type controls in the study are sufficient, as they weren’t edited in the same way as the mutants so don’t control for any off-target effects etc. As a result, the fitness of all mutants may reduced relative to the WT regardless of their identity, potentially exaggerating fitness effects of synonymous mutations. Indeed, if you set a stricter threshold of fitness reduction to be counted as truly deleterious, more non-synonymous mutations pass it than synonymous ones. In other words, non-synonymous mutations tend to cause larger fitness declines than synonymous mutations.

Just wanted to add this:

I think it is also notable that, aside from distinguishing between between missense and nonsense mutations within the non-synonymous category, they don’t seem to distinguish between conservative and non-conservative mutations within the missense catagory.

Conservative mutations (leading to amino acid substitutions with similar properties) often have different effects than those that are non-conservatives. Also, Not every amino acid substitution that could occur along of the primary protein structure is equal, and proteins are often robust against such changes. Even a single (non-conservative) amino-acid substitution may not compromise the function of the protein.

Here is a sensitivity map of HIV-1 Protease, showing that most residues are not very sensitive to most aa substitutions:

In other words, a good portion of non-synonymous mutations may be nearly neutral. This could explain why many non-synonymous mutations have had little impact on fitness similar to most synonymous mutations.

Another idea to throw out there, some synonymous codons may be more accurately translated and thus their preferential use may lead to fewer translational errors. (Atlhough the authors did mention this in the paper).

In any case, I also don’t see how this refutes (nearly-)neutral theory, since it doesn’t claim that all synonymous mutations have to be neutral.