Sorry, another evolution thread...

[w1z4rd]

Hi ladies and gents,

This post got posted in a local forum, and I was wondering if someone could help me work through it. I do not have the knowledge to be able to answer this myself as I am not an authority on the subject.

This is the post:

Deleterious mutation rate:

In 2000, the genomic deleterious mutation rate (U) was calculated (using conservative calculations of the proportion of the genome subject to purifying selection) to be at least 3 [1]. This was done by comparing only pseudogenes in humans and chimpanzees. U value estimates in Escherichia coli, Drosophila melanogaster and Caenorhabditis elegans were estimated (using observable living organisms, not a hypothetical common ancestor model) to be 0.0002, 0.2-1 and 0.005 respectively[3,4,5]. For U =3, the average fitness is reduced to 0.05, meaning each female would need to produce 40 offspring for 2 to survive and maintain the population at constant size due to deleterious mutations with multiplicative effects given by 1-e^U [6]. Can this be reconciled with current observation? Synergistic epistasis and truncation selection are added as ad hoc explanations for this high U-value, and it seems unlikely that it is the case as well.

The way indels are calculated in the deleterious mutation rate is also a topic of discussion. Indels give a 90MB difference (by far the biggest) but only 5 million length mutation (indels) events are incorporated into the deleterious mutation calculation.
Larger insertions (> 15 kb) were identified in 163 human regions containing 8.3 Mb of the human-specific sequence and a whopping 73% (approx. 70,000) of the indels are larger than 80 bp. That alone should be cause for concern because supposedly junk DNA also gets transcribed. Cells also make RNA copies of many other sections of DNA and none of the extra RNA fragments gets translated into proteins [7]. And it does not seem that they are produced by darwinian accident. They might be functioning like microRNA’s or RNAi’s (RNA interference)[7]. The notion that some DNA might be “junk” or leftovers of evolution is an evolutionary ignorant idea. Thing is, we don’t know the function, but it does not mean it is useless. This is the “vestigial organ” myth all over again.
Also, length mutations (indels) have the lowest mutation rate at 2.3 x 10^-9. They are 10 times less common than single substitutions.
If each of the 90MB indel difference was calculated as a single mutation, the U-value would be disastrous for the hypothesis. The already extremely high U-value would be unexplainable.

The problem is simple enough, since our common ancestor there would have had to be 35 million single base substitutions. That comes to 140 per diploid generation (7 per year) for 5 million years. That is in addition to 1 indel 14 base pairs long per year for the same amount of time and the vast majority of these would have to be fixed. FIXED being the operative word. Reconcile this with observation.

1. Nachman MW, Crowell SL. Estimate of the mutation rate per nucleotide in humans. Genetics. 2000 Sep;156(1):297-304.
2. Thread
3. Kibota, T. T., and M. Lynch, 1996 Estimate of the genomic mutation rate deleterious to overall fitness in E. coli. Nature 381: 694-696.
4. Fry, J. D., P. D. Keightley, S. L. Heinsohn and S. V. Nuzhdin, 1999 New estimates of the rates and effects of mildly deleterious
mutation in Drosophila melanogaster. Proc. Natl. Acad. Sci. USA. 96: 574–579
5. Keightley, P. D., and A. Caballero, 1997 Genomic mutation rates for lifetime reproductive output and lifespan in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 94: 3823–3827.
6. Kimura, M., 1968 Evolutionary rate at the molecular level. Nature. 217: 624–626
7. Andy Coghlan. 'Junk' DNA makes compulsive reading. New Scientist 194.2608 (June 16, 2007): p20(1).




Does any of this make sense to anyone?

 

[cosmictraveler]

Easier just to say that variations happen!

 

[S.A.M.]

Does this help?

Deleterious mutations are considered a major impediment to adaptation, and there are straightforward expectations for the rate at which they accumulate as a function of population size and mutation rate. In a simulation model of an evolving population of asexually replicating RNA molecules, initially deleterious mutations accumulated at rates nearly equal to that of initially beneficial mutations, without impeding evolutionary progress. As the mutation rate was increased within a moderate range, deleterious mutation accumulation and mean fitness improvement both increased. The fixation rates were higher than predicted by many population-genetic models. This seemingly paradoxical result was resolved in part by the observation that, during the time to fixation, the selection coefficient (s) of initially deleterious mutations reversed to confer a selective advantage. Significantly, more than half of the fixations of initially deleterious mutations involved fitness reversals. These fitness reversals had a substantial effect on the total fitness of the genome and thus contributed to its success in the population. Despite the relative importance of fitness reversals, however, the probabilities of fixation for both initially beneficial and initially deleterious mutations were exceedingly small (on the order of 10(-5) of all mutations).

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17054393

Apparently there is an assumption that deleterious mutations that start bad, stay bad. Which is not necessarily true.

Here is another article that explains how deleterious mutations are a price for adaptation through variation.

The basic idea of adaptive mutation is that under normal conditions, low mutation rate is favored by selection because most mutations are deleterious. However, in a very poor environment, death is certain in the absence of a beneficial mutation that confers high fitness in that environment. Individuals with high mutation rates are more likely to “find” that beneficial mutation. Thus, natural selection will favor inducible mutation rates, which are low under normal conditions but greatly increased under stressful (i.e., low-fitness) conditions.

 

[w1z4rd]

Thanks S.A.M, you are a star

 

[sillywabbit]

Hi S.A.M.

Thanks for the articles.

A few initial questions.
1) The Cowperthwaite et al. paper used genomic deleterious mutation rates (U) values of 0.01, 0.08, 0.32 and 0.95 in their simulations. What do you think will the effect of U = 3 be on mean final fitness of a finite population?
2) The second article was interesting in discussing on the possibility condition-dependent (context-dependent) mutation rates and how they relate to human fitness and future "genetic load". What kind of conditions to you think would be needed to explain the high human genomic deleterious mutation rates (U =3 or even higher)?

Thanks

 

[S.A.M.]

Hi S.A.M.

Thanks for the articles.

A few initial questions.
1) The Cowperthwaite et al. paper used genomic deleterious mutation rates (U) values of 0.01, 0.08, 0.32 and 0.95 in their simulations. What do you think will the effect of U = 3 be on mean final fitness of a finite population?
2) The second article was interesting in discussing on the possibility condition-dependent (context-dependent) mutation rates and how they relate to human fitness and future "genetic load". What kind of conditions to you think would be needed to explain the high human genomic deleterious mutation rates (U =3 or even higher)?

Thanks

Sorry thats way out of my scope as a molecular nutritionist. I distinctly smell statistical models in there /shudder

The second aspect, I can hazard a guess, that adaptive mutation rates would (as described in the second article) be more relevant with asexual reproduction. So higher DM rates in humans would be a function of conditions other than for generating beneficial mutations. Offhand I could think of many "stresses" that engender mutation, from changes in food habits, lack of physical activity, exposure to formulated and transformed food components, carcinogens, inflammation, allergens, radiation and toxins.

 

[sillywabbit]

Thanks.

Molecular nutritionist? You must dislike reactive oxygen species and like the antioxidant approach (flavonoids, isoflavonoids etc) in fighting cancer and old age.
Any interesting research you are following atm?

 

[S.A.M.]

Thanks.

Molecular nutritionist? You must dislike reactive oxygen species and like the antioxidant approach (flavonoids, isoflavonoids etc) in fighting cancer and old age.
Any interesting research you are following atm?

I'm investigating mechanisms of obesity. One could say (to keep on topic), as a rapidly developing global epidemic, its an excellent example of environmental stress.

Current models in inflammation, for example, hypothesise on the role of protein kinases in mediating receptor resistance and modulating signalling cascades that define shifts in substrate utilisation in ways which favor energy storage and chronic disease development. Which can be traced back to possible micronutrient deficiencies or imbalance or even lack of exercise.

 

[Enmos]

I'm investigating mechanisms of obesity. One could say (to keep on topic), as a rapidly developing global epidemic, its an excellent example of environmental stress.

Current models in inflammation, for example, hypothesise on the role of protein kinases in mediating receptor resistance and modulating signalling cascades that define shifts in substrate utilisation in ways which favor energy storage and chronic disease development. Which can be traced back to possible micronutrient deficiencies or imbalance or even lack of exercise.

What does the stress usually consist of ?

 

[S.A.M.]

What does the stress usually consist of ?

There are several, but most involve a mismatch between what is required and what is provided. Thats a discussion for a separate thread.

 

[sillywabbit]

@ S.A.M.
So basically, obesity has a genetic and an epigenetic (micronutrient deficiencies/imbalance, exersize, other environmental stress) make-up. The trick is to determine how big a role each plays in the development of the disease and how each genome reacts to epigenetic factors.

Environmental factors might induce mutations in mitochondrial DNA, resulting in a sub-functional electron-transport chain (ETC) or ATPase and ultimately mimic hypoxia. Hypoxia causes downstream up-regulation of glycolysis (up-regulation of hexokinase), causing a shift in energy usage and storage and possibly obesity and/or cancer (somatic evolution of obesity or cancer).
Also, increase in energy uptake increases reactive oxygen species (ROS) and ultimately causes DNA damage and mutations (adding to mitochondrial DNA damage). This, in part, explains recent findings why underfed mice and rats tend to live longer.

Have you looked at the propagation of mutations of specifically the ETC and their correlation between obesity? Has it been determined that mutation rates vary according to energy intake, exercise and ROS generation? Perhaps mutations and gene expression changes induced through epigenetic factors contribute to the activity of various kinases (E.g. Akt, AMPK. PI3-kinase I, PIP2, PTEN etc) and nuclear receptor (E.g. PPAR) activity that is particularly relevant to obesity.

 

[S.A.M.]

@ S.A.M.
So basically, obesity has a genetic and an epigenetic (micronutrient deficiencies/imbalance, exersize, other environmental stress) make-up. The trick is to determine how big a role each plays in the development of the disease and how each genome reacts to epigenetic factors.

Yes, this is a major aspect of current research, with many off beat findings adding to the picture. e.g. the epidemiological observation that Insig-2 is mutated in 10% of obese subjects is significant in light of the fact that it regulates SCAP and hence SREBP activity, leading to changes in sterol metabolism and fatty acid synthesis. Combined with the knowledge that micronutrients can modulate Insig-2 expression and hence membrane polarity through cholesterol synthesis, affecting for example insulin resistance or GLUT4 translocation and tethering, which in turn affects glucose uptake, is an engaging possibility.

Environmental factors might induce mutations in mitochondrial DNA, resulting in a sub-functional electron-transport chain (ETC) or ATPase and ultimately mimic hypoxia. Hypoxia causes downstream up-regulation of glycolysis (up-regulation of hexokinase), causing a shift in energy usage and storage and possibly obesity and/or cancer (somatic evolution of obesity or cancer).

The role of hypoxia in cancer progression is also interesting in light of the fact that there are parallel pathways that are involved in responses to hypoxia (see sticky on Journal club for paper on PGC-1alpha pathway that is HIF independent). The observation that angiogenesis may arise independently of the HIF pathway through a transcription factor that is also involved in mitochondrial biogenesis, oxidative phosphorylation, respiration and fat metabolism is a link between energy metabolism and cancer.

Recent papers which emphasises the issue of cross talk example the role of bone in regulation of energy metabolism and vice versa, warn against a reductionist approach in nutrition research for fear of missing the picture entirely.

Also, increase in energy uptake increases reactive oxygen species (ROS) and ultimately causes DNA damage and mutations (adding to mitochondrial DNA damage). This, in part, explains recent findings why underfed mice and rats tend to live longer.

Thats actually a pretty old story, chronic energy deficit in the presence of adequate protein intake also increases longevity through a reduced basal metabolic rate.

Have you looked at the propagation of mutations of specifically the ETC and their correlation between obesity? Has it been determined that mutation rates vary according to energy intake, exercise and ROS generation? Perhaps mutations and gene expression changes induced through epigenetic factors contribute to the activity of various kinases (E.g. Akt, AMPK. PI3-kinase I, PIP2, PTEN etc) and nuclear receptor (E.g. PPAR) activity that is particularly relevant to obesity.

I'm studying more clinical aspects rather than genetic ones. But those are interesting ones to look out for.

For instance, the role of macrophage accumulation and monocyte invasion in adipocyte inflammation, the role of TNF-alpha and JNK in insulin resistance, tissue specific effects of cytokines and micronutrients in adipose and muscle, etc.

 

[CharonZ]

Actually two major points that are frequently put forth to explain the seemingly high rate of deleterious mutations in humans (I actually read values as high as ten) have not discussed here.
First, epistatic effects deleterious alleles might result in a cumulative higher loss of deleterious mutations in one go (possibly even pre-natal by means of unsuccessful pregnancies) and the second being the genome size.
So if we use the values of the Nachman paper, in which 175 mutations per diploid genome per generation were estimated and further assume that 3 percent are deleterious , one would have to expect around 2.9% of the genome to be under purification (or 5.8% if we assume a rate of 10). If one puts that into perspective of the amount that is actual under functional constraint (estimated to be about 5-10%) this is really not that much.

But in general epistatic effects are put forth as primary explanation (in fact the cited paper did this, too). Indubitably further effects will play a role, though.