3 ms·

> Why are we significantly less likely to have mutations on our mitochondria than in our fingers? I’m afraid this is simply not a biologically meaningful state

by klmr 7y ago

> Why are we significantly less likely to have mutations on our mitochondria than in our fingers? I’m afraid this is simply not a biologically meaningful statement to begin with. Mitochondria are subcellular organelles. Fingers are complex organs that are formed from spatial arrangements of multiple cell types. Furthermore, mutations happen on the level of DNA, not on the level of either organelles or organs. Apart from that, mutation rate is (not quite, but more or less) uniform across the whole genome (the exceptions, due to e.g. GC bias, are not relevant here). Viable mutations are not uniformly distributed because of selection; that’s precisely the striking insight that Darwin had (though he was unaware of DNA and genes). Importantly, this does not require a guided error correction mechanism. Simply put, even slight variations in the oxidative phosphorylation pathway of the mitochondrion are likely to kill you during gestation; whereas similarly extreme variations in finger morphogenesis, at worst, make you unable to hold a tool. > some subsystems are more stringently error corrected than others This is virtually certainly not the case, because of what I’ve just described. Selection is sufficient to describe the outcome, and there is no evidence whatsoever to point to the mechanism you postulate. > I would be incredibly surprised if a crocodile, who has been in a state of relative homeostasis for millions of years, has the same rate of mutation as a human. Evolutionary mutation rate is governed by effective population size and generation time. That’s why fruit flies evolve fast and crocodiles evolve slowly. This, too, doesn’t require variable mutability of different traits, and no biologist has yet seriously suggested such a mechanism.

blotter_paper 7y ago
> [...] Furthermore, mutations happen on the level of DNA, not on the level of either organelles or organs. This is all besides the point. Mitochondria are just an easy example because of the marked difference in mutation rate, and my loosely worded bit about fingers evolving should obviously be taken as "some parts of the genome associated with the development of fingers." > Apart from that, mutation rate is (not quite, but more or less) uniform across the whole genome (the exceptions, due to e.g. GC bias, are not relevant here). Not my field, but I'm pretty sure you're incorrect. Here's a citation: https://www.ncbi.nlm.nih.gov/pubmed/11057667?dopt=Abstract https://www.ncbi.nlm.nih.gov/pubmed/11057667?dopt=Abstract >> A few patterns have been found: proteins involved in antagonistic co-evolution (for example, immune genes, parasite antigens and reproductive conflict genes) tend to be rapidly evolving, and there is a correlation between the rate of protein evolution and the mutation rate of the gene. Here we report a new highly statistically significant predictor of a protein's rate of evolution, and show that linked genes have similar rates of protein evolution. >This is virtually certainly not the case, because of what I’ve just described. Selection is sufficient to describe the outcome, and there is no evidence whatsoever to point to the mechanism you postulate. This is virtually certainly not the case, because of what I've just cited. > Evolutionary mutation rate is governed by effective population size and generation time. I'm not arguing that these aren't factors, but we do have good reason to believe that the rate of change for some subsets of the genome can itself change. Here's another source: https://www.ncbi.nlm.nih.gov/pubmed/10469563?dopt=Abstract https://www.ncbi.nlm.nih.gov/pubmed/10469563?dopt=Abstract >> Our results provide the first substantial statistical evidence for the existence of a regional variation in the synonymous substitution rate within the mammalian genome, indicating that different chromosomal regions evolve at different rates. This regional phenomenon which shapes gene evolution could reflect the existence of 'evolutionary rate units' along the chromosome.
- klmr 7y ago
  You fundamentally misunderstand the article you cite. It describes population-level events, and it’s entirely compatible with what I’ve said: variable mutation rates, in modern evolutionary biology, are entirely explained by variable selective pressure (see “purifying selection”, which is what I’ve described in my previous comment using your example). As for the second article, I’ve made reference to that in my previous comment, too (that’s GC bias). And, as mentioned, this isn’t relevant here.
  - blotter_paper 7y ago
    > You fundamentally misunderstand the article you cite. That seems entirely possible. > As for the second article, I’ve made reference to that in my previous comment, too (that’s GC bias). And, as mentioned, this isn’t relevant here. Can you unpack why you think this isn't relevant? The rate of change varying across regions of the genome seems highly relevant to me, even if our current knowledge of it were hypothetically confined to a specific type of change.
    - klmr 7y ago
      GC content (the local ratio of G and C nucleotides, i.e. (#C + #G) / (#A + #C + #G + #T)) varies in patches across certain mammalian genomes. GC content correlates with stability because stacked C–G base pairs are chemically more stable than A–T base pairs. However, while gene density correlates with GC content, gene function is uncorrelated. This means that genes (which tend to be in high-GC regions) in general tend to be (very, very slightly) less susceptible to mutations than non-genic DNA (by contrast, they are vastly less susceptible to mutation than non-genic DNA due to negative selection^1). But the difference in GC content between different genes is purely stochastic, and there’s no mechanism for changing the GC content of a given gene, except by random (!) mutation. This can happen, and it indeed improves the stability of a gene, but the same is true for all genes to the same extent, and it isn’t directed. ^1 I’ve never seen anybody explicitly quantify this but the relative impact of GC content and negative selection on mutation rate must be several orders of magnitude different … at a guess at least thousandfold, more likely millionfold.

by klmr 7y ago

blotter_paper 7y ago

> [...] Furthermore, mutations happen on the level of DNA, not on the level of either organelles or organs. This is all besides the point. Mitochondria are just an easy example because of the marked difference in mutation rate, and my loosely worded bit about fingers evolving should obviously be taken as "some parts of the genome associated with the development of fingers." > Apart from that, mutation rate is (not quite, but more or less) uniform across the whole genome (the exceptions, due to e.g. GC bias, are not relevant here). Not my field, but I'm pretty sure you're incorrect. Here's a citation: https://www.ncbi.nlm.nih.gov/pubmed/11057667?dopt=Abstract https://www.ncbi.nlm.nih.gov/pubmed/11057667?dopt=Abstract >> A few patterns have been found: proteins involved in antagonistic co-evolution (for example, immune genes, parasite antigens and reproductive conflict genes) tend to be rapidly evolving, and there is a correlation between the rate of protein evolution and the mutation rate of the gene. Here we report a new highly statistically significant predictor of a protein's rate of evolution, and show that linked genes have similar rates of protein evolution. >This is virtually certainly not the case, because of what I’ve just described. Selection is sufficient to describe the outcome, and there is no evidence whatsoever to point to the mechanism you postulate. This is virtually certainly not the case, because of what I've just cited. > Evolutionary mutation rate is governed by effective population size and generation time. I'm not arguing that these aren't factors, but we do have good reason to believe that the rate of change for some subsets of the genome can itself change. Here's another source: https://www.ncbi.nlm.nih.gov/pubmed/10469563?dopt=Abstract https://www.ncbi.nlm.nih.gov/pubmed/10469563?dopt=Abstract >> Our results provide the first substantial statistical evidence for the existence of a regional variation in the synonymous substitution rate within the mammalian genome, indicating that different chromosomal regions evolve at different rates. This regional phenomenon which shapes gene evolution could reflect the existence of 'evolutionary rate units' along the chromosome.

klmr 7y ago
You fundamentally misunderstand the article you cite. It describes population-level events, and it’s entirely compatible with what I’ve said: variable mutation rates, in modern evolutionary biology, are entirely explained by variable selective pressure (see “purifying selection”, which is what I’ve described in my previous comment using your example). As for the second article, I’ve made reference to that in my previous comment, too (that’s GC bias). And, as mentioned, this isn’t relevant here.
- blotter_paper 7y ago
  > You fundamentally misunderstand the article you cite. That seems entirely possible. > As for the second article, I’ve made reference to that in my previous comment, too (that’s GC bias). And, as mentioned, this isn’t relevant here. Can you unpack why you think this isn't relevant? The rate of change varying across regions of the genome seems highly relevant to me, even if our current knowledge of it were hypothetically confined to a specific type of change.
  - klmr 7y ago
    GC content (the local ratio of G and C nucleotides, i.e. (#C + #G) / (#A + #C + #G + #T)) varies in patches across certain mammalian genomes. GC content correlates with stability because stacked C–G base pairs are chemically more stable than A–T base pairs. However, while gene density correlates with GC content, gene function is uncorrelated. This means that genes (which tend to be in high-GC regions) in general tend to be (very, very slightly) less susceptible to mutations than non-genic DNA (by contrast, they are vastly less susceptible to mutation than non-genic DNA due to negative selection^1). But the difference in GC content between different genes is purely stochastic, and there’s no mechanism for changing the GC content of a given gene, except by random (!) mutation. This can happen, and it indeed improves the stability of a gene, but the same is true for all genes to the same extent, and it isn’t directed. ^1 I’ve never seen anybody explicitly quantify this but the relative impact of GC content and negative selection on mutation rate must be several orders of magnitude different … at a guess at least thousandfold, more likely millionfold.