That’s interesting. I guess my next question is, how confident are we that this sequence has been undergoing close-to-neutral selection?
I ask because if it has been undergoing close-to-neutral selection, that implies that almost all possible mutations in that region are fitness-neutral. (Which is why my thoughts turned to “something is necessary, but it doesn’t matter what”. When you call that unlikely, is that because there’s no known mechanism for it, or you just don’t think there was sufficient evidence for the hypothesis, or something else?) But… according to this study they’re not, which leaves me very confused. This doesn’t even feel like I just don’t know enough, it feels like something I think I know is wrong.
if it has been undergoing close-to-neutral selection, that implies that almost all possible mutations in that region are fitness-neutral.
There is no “neutral” evolution, as all DNA sequences are subject to several constraints, such as maintaining GC content and preventing promoters) from popping out needlessly. There is also large variability of mutation rates along different DNA regions. Together, this results in high variance of “neutral” mutation rate, and because of huge genome, making it (probably) impossible to detect even regions having quarter of neutral mutation rate. I think this is the case here.
This extends what zslastsman written regarding structure.
We can’t be totally confident. I’d guess that if you did a sensitive test of fitness (you’d need a big fish tank and a lot of time) you’d find the human sequence didn’t rescue the deletion perfectly. They’ve done this recently in c elegans—looking at long term survival in the population level, and they find a huge number of apparantly harmless mutations are very detrimental at the population level.
The reason I’d say it was unlikely is just that spacers of that kind aren’t common (I don’t know of any that aren’t inside genes). If there were to sequences on either side that needed to bend around to eachother to make contact, it could be plausible, but since they selected by epigenetic marks, rather than sequence conservation, it would be odd and novel if they’d managed to perfectly delete such a spacer (actually it would be very interesting of itself.)
I think you are being confused by two things
1) The mutation I said they made was deliberately targeted to a splice site, which are constrained (though you can’t use them to identify sequences because they are very small, and so occur randomly outside functional sequence all the time)
2) You are thinking too simplistically about sequence constraint. RNA folds by wrapping up and forming helices with itself, so the effect of a mutation is dependent on the rest of the sequence. Each mutation releases constraint on other base pairs, and introduces it to others. So as this sequence wanders through sequence space it does so in a way that preserves relationships, not absolute sequence. From it’s current position in sequence space, many mutations would be detrimental. But those residues may get the chance to mutate later on, when other residues have relieved them. This applies to proteins as well by the way. Proteins are far more conserved in 3d shape than in 2d sequence.
That’s interesting. I guess my next question is, how confident are we that this sequence has been undergoing close-to-neutral selection?
I ask because if it has been undergoing close-to-neutral selection, that implies that almost all possible mutations in that region are fitness-neutral. (Which is why my thoughts turned to “something is necessary, but it doesn’t matter what”. When you call that unlikely, is that because there’s no known mechanism for it, or you just don’t think there was sufficient evidence for the hypothesis, or something else?) But… according to this study they’re not, which leaves me very confused. This doesn’t even feel like I just don’t know enough, it feels like something I think I know is wrong.
There is no “neutral” evolution, as all DNA sequences are subject to several constraints, such as maintaining GC content and preventing promoters) from popping out needlessly. There is also large variability of mutation rates along different DNA regions. Together, this results in high variance of “neutral” mutation rate, and because of huge genome, making it (probably) impossible to detect even regions having quarter of neutral mutation rate. I think this is the case here.
This extends what zslastsman written regarding structure.
We can’t be totally confident. I’d guess that if you did a sensitive test of fitness (you’d need a big fish tank and a lot of time) you’d find the human sequence didn’t rescue the deletion perfectly. They’ve done this recently in c elegans—looking at long term survival in the population level, and they find a huge number of apparantly harmless mutations are very detrimental at the population level.
The reason I’d say it was unlikely is just that spacers of that kind aren’t common (I don’t know of any that aren’t inside genes). If there were to sequences on either side that needed to bend around to eachother to make contact, it could be plausible, but since they selected by epigenetic marks, rather than sequence conservation, it would be odd and novel if they’d managed to perfectly delete such a spacer (actually it would be very interesting of itself.)
I think you are being confused by two things 1) The mutation I said they made was deliberately targeted to a splice site, which are constrained (though you can’t use them to identify sequences because they are very small, and so occur randomly outside functional sequence all the time) 2) You are thinking too simplistically about sequence constraint. RNA folds by wrapping up and forming helices with itself, so the effect of a mutation is dependent on the rest of the sequence. Each mutation releases constraint on other base pairs, and introduces it to others. So as this sequence wanders through sequence space it does so in a way that preserves relationships, not absolute sequence. From it’s current position in sequence space, many mutations would be detrimental. But those residues may get the chance to mutate later on, when other residues have relieved them. This applies to proteins as well by the way. Proteins are far more conserved in 3d shape than in 2d sequence.