Wright et al. on the Process of Mutation

We've already had a long thread (Adding information to the genome.) a big chunk of which was you failing to understand Kimura's work in relation to natural selection despite having it explained to you repeatedly. I'm not sure that we really need another one, in fact that thread is still open so maybe you should take discussion of your 'understanding' of Kimura there rather than derailing this thread.But just to address the specific point in your post, all you have shown is that Kimura believed chance was important in the generation of the genetic variation that we see in populations. You haven't shown that he thought it had anything to do with selection. The whole point of neutral theory is that selection and drift are two distinct forces which act to produce the patterns of genetic variation that we see, one random (drift) and the other non-random (selection). *ABE just for Percy* Of course in the context of Wright's work the question is whether the mutations themselves are random or non-random and in precisely what sense.*/ABE*Kimura put forward that the large majority of molecular evolution was neutral, reflecting no selection for fitness. So if you changed your opening sentence to say, "To my suggestion that luck might be the deciding factor in [evolution], in line with kimura's beliefs" then you would have actually been making sense. You would still have been wrong but at least you would have been simply grossly exaggerating and simplifying what Kimura actually put forward rather than your bizarre creationist bastardisation of it.And there we go, despite my best intentions you trolled me into explaining this to you yet again, well done.TTFN,WKEdited by Wounded King, : Added a smidgen of relevancy.Edited by Wounded King, : No reason given.

I don't think this argument really hangs together to counter the 'directed mutation' idea. I agree that substantially the same mechanism, the non transcribed strand in the single stranded DNA state during transcription's increased susceptibility to mutation, does make constitutively transcribed housekeeping genes more susceptible to mutation in general. But in the particular case from the Wright paper there is another important factor, the specific upregulation of Leu operon transcription in response to leucine starvation. Therefore the mutation rate has increased specifically for the leu operon locus, it hasn't increased for any the constitutively expressed house keeping genes. So the housekeeping genes wont see any increase in their normal mutation rate, which we already agree is likely to be above the basal rate for the genome.Do you have any reason to think that gyrase is substantially upregulated above its constitutive levels by leucine starvation? But Wright's whole argument rests on it being a targeted increase. The leu operon specifically is being upregulated and therefore undergoing an increased level of mutation. Wright acknowledges that this will include beneficial, neutral and deleterious mutations but suggests that such a targeted increase will nevertheless improve the chances of the population producing beneficial mutations in that region above the constitutive rate of beneficial mutations in that region, while not affecting the mutation rate at other loci.TTFN,WKEdited by Wounded King, : No reason given.

Ok, so what genes are upregulated in response to leucine starvation? Are you claiming that all housekeeping genes are? I'm just trying to get hold of a dataset from a microarray study on isoleucine starvation, not ideal since it is the wrong amino acid but at least we can see most of the genes that are part of the stringent and general starvation responses. There is another one where serine hydroxymate is used to trigger the stringent response, a quick scan of that paper suggests there are about 300 genes significantly upregulated, which is certainly a pretty big chunk of the 4000 or so genes in the E. coli K12 genome.You seem to be redefining 'upregulated' to mean simply expressed. Upregulation denotes a change in the expression level. A highly expressed housekeeping gene is not upregulated if it simply continues to be highly expressed at the same level.I don't see a problem with other genes involved in the response being upregulated, after all Wright's argument is that genes upregulated in a response are likely to be the best targets for producing novel beneficial mutations since they should be the most relevant to the given stress. It just so happens that in the specific experimental setup in the paper there is a very limited repertoire of potential mutations that will rescue the leuB^- mutant. Whether Wright would actually see it this way I don't know, I've said before that I think she exaggerates a number of things, and one of them is the specificity of the response.As far as I can see the specificity resides in the specific amino acid biosynthesis operon that is turned on, along with all the other stringent response effects. So a mutation in the leu Operon becomes more likely than one in trp.There is certainly some redistribution of the mutational spectrum across the genome, whether it favours beneficial mutations arising in the population is another question, certainly in the paper a large number of beneficial mutations do occur in the population above the mutation/reversion rate if we accept the mutation/reversion rates will be comparable between unstarved and starved relA populations in line with the expression levels.TTFN,WK

I don't think it is quite as restrictive as you make out. Looking at the paper Wrights gives as a reference for that 80% figure (Wright and Minnick, 1997) we find a more detailed analysis ... The paper defines true revertants as those which produce an amino acid substitution at aa286 for one of 3 different amino acids. Only those which produced serine would be the exact reverse mutation to the original C-T transition. In fact that was slightly edged out by a T-G transition at a different nucleotide which substituted a valine at aa286. Because LeuB is not the only gene upregulated by the stringent response during leucine starvation. So while a specific small spectrum of mutations may be capable of producing revertants, and an even smaller set of producing what Wright calls 'true' revertants, there is no control to see what other mutations are being produced in other genes being upregulated.By focussing on such a specific target and ignoring the possibility of any other elevated mutation rates in the rest of the responsive genome Wright effectively exaggerates the specificity of the response. The reverting mutation may be highly specific, but without a better characterisation of the change in mutation rates at a wider sample of upregulated loci we can't really say how specific the response was.If all of the ~300 genes upregulated as part of the stringent response have increased mutation rates (about 8% of the E. coli genome) then does that constitute a sound basis for a claim of directed mutation? And more to the point does if form as good a basis for a claim of mutation being directed towards the LeuB gene?In her discussion in the original paper from the OP Wright says ... But how exclusive is this increase? In reality it appears only to be 'exclusive' to the exclusion of the other amino acid biosynthesis operons.Wright is essentially claiming that everything else is equal in the stringent response whichever amino acid the population is being starved for so the only difference in those responses is in the resulting upregulated operon. At least that is how I interpret it.TTFN,WKEdited by Wounded King, : No reason given.

Well this isn't quite in line with the findings in the paper. I would agree that all the genes with the same expression level might be expected to experience the same mutation rate, all other things being equal, but the fact that a gene is upregulated in a response does not mean it will have the same level of expression as every other gene upregulated in the response.So if for example LeuB expression was to see a much more substantial expression level in response than the majority of other responsive genes we might expect it to similarly have a more substantially elevated mutation rate. It gets a bit tricky here in that so often upregulation is described in terms of the fold change in expresssion while for the mechanisms in Wright's paper the actual absolute expression level seems to be the key thing, so a gene seeing a 100 or 1000 fold increase may still have an absolute expression level well below one that had a much more moderate 2-5 fold increase. I agree, and I don't think HereBeDragons or even Wright would disagree. I think we have reached here what is essentially a semantic issue whether we agree with Wright's position that ... and further that ... Wright claims the response is specific because the the amino acid synthesis operon induced is specific to the particular starvation the bacterium is experiencing.In the introduction she makes the distinction between different meanings of random in respect to evolution ... I think she has made a reasonable case that specific environmental conditions can produce specific changes in expression which will affect the frequency distribution of mutations at the regulated genes. the mutation rate in the housekeeping genes should continue as it was previously, unaffected by the whole process.TTFN,WK