Speculation on MTHFR evolution

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Speculation on MTHFR evolution

Postby zetreque on March 7th, 2018, 12:32 am 

MTHFR is known for the enzyme involved in metabolizing folate.
There are variants (C677T, 03 P39P and A1298C) to the gene making the gene less active.

It is also known that humans and more recent primates do not have the ability to synthesize vitamin C.

Theorizing with the theory of evolution. As primates evolved into humans there must have been enough vitamin C sources in their diets to lose the pathway synthesizing vitamin C. Why put out energy into creating the enzymes or pathway when it's not needed? Conservation of energy.

I have been wondering about something similar going on with B vitamins and the MTHFR gene enzyme. It's pretty well known that folate is vital to health (neural tube defects, and the reason we fortify most foods with folic acid) just like if we don't get enough vitamin C it can be disastrous to our health (scurvy, gum disease...).

There is controversy of course. To try to get the controversy out of the way, we CAN live with very little vitamin C (long sea voyages) and high doses are controversial in their health benefits. The same can be said for folate and there are conflicting studies on the MTHFR variants and disease correlations.

The question here is using the same theorizing about why we don't synthesize vitamin c even though it's important to our health, would it make sense to theorize using the same concept for the change in MTHFR?

If humans were eating a diet high in folate or whatever it's synthesized into using the enzyme, that might lead to gene variants to eliminate the need to put energy into that synthesis pathway? Again, why would our bodies put out energy into making enzymes and metabolizing pathways for something we can get straight from the diet?

Thoughts?
Am I missing anything? I haven't yet looked into the specifics of the pathway for MTHFR enzyme metabolizing folate so if anyone can learn me on that one while pointing out flaws or support for my theory it would be great.
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Re: Speculation on MTHFR evolution

Postby Serpent on March 7th, 2018, 10:10 am 

I have no science to offer, but I'd like to pick one small bone of theory.
If humans were eating a diet high in folate or whatever it's synthesized into using the enzyme, that might lead to gene variants to eliminate the need to put energy into that synthesis pathway? Again, why would our bodies put out energy into making enzymes and metabolizing pathways for something we can get straight from the diet?

The loss of that ability may not be matter of efficiency or energy saving. Generally, evolution doesn't work that way: shutting functions down when they're obsolete is too deliberate an action for a blind process.
It may be that, since the vitamin or nutrient is readily available from the diet (over a long period!) the inactive gene variant was able to survive, alongside the active one. Which raises the more interesting question: why did the inactive variant became prevalent, dominant, and eventually exclusive? Perhaps it's associated with some other gene variation that was significantly advantageous.
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Re: Speculation on MTHFR evolution

Postby Braininvat on March 7th, 2018, 12:58 pm 

Or if there were small populations, genetic drift could eliminate the active variant.
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Re: Speculation on MTHFR evolution

Postby zetreque on March 7th, 2018, 1:19 pm 

Serpent » Wed Mar 07, 2018 6:10 am wrote:I have no science to offer, but I'd like to pick one small bone of theory.
If humans were eating a diet high in folate or whatever it's synthesized into using the enzyme, that might lead to gene variants to eliminate the need to put energy into that synthesis pathway? Again, why would our bodies put out energy into making enzymes and metabolizing pathways for something we can get straight from the diet?

The loss of that ability may not be matter of efficiency or energy saving. Generally, evolution doesn't work that way: shutting functions down when they're obsolete is too deliberate an action for a blind process.
It may be that, since the vitamin or nutrient is readily available from the diet (over a long period!) the inactive gene variant was able to survive, alongside the active one. Which raises the more interesting question: why did the inactive variant became prevalent, dominant, and eventually exclusive? Perhaps it's associated with some other gene variation that was significantly advantageous.


I think I agree with you. I think you are kind of saying the same thing I did (or meant to say) but in different words.

It's not that any deliberate action is being taken but if humans evolved through times of scarcity/famine/bottle neck, needless processes would disappear to make the body more energy efficient for survival.

If we are talking epigenetics, correct me if I am wrong but almost "deliberately" shutting things down and gene expression are ways to attempt to adapt to the environment to save energy and be more efficient for more vital biological functions.

In any case, I think my original theory is still valid because "Why did the inactive variant become prevalent, dominant, and eventually elusive?" My theory is due to a change in the abundance of a nutrient intake.
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Re: Speculation on MTHFR evolution

Postby Serpent on March 7th, 2018, 1:37 pm 

Usually, though, in the presence of plentiful food-supply, primates would have fairly large, interactive populations - unless one group was cut off and isolated by some geographical obstacle. Then that same isolation would protect that group from a catastrophic event that killed the larger populations outside the protected zone. Eventually, the descendants of the small group move into and populate the vacated territory. That happens, too.

zetreque - If we are talking epigenetics, correct me if I am wrong but almost "deliberately" shutting things down and gene expression are ways to attempt to adapt to the environment to save energy and be more efficient for more vital biological functions.

I'm no expert! The way I picture the mechanism is a sort of groping forward, rather than tinkering. So I imagine the shutting-down, not as a single stroke but as a gradual - over generations - ascension of individuals whose metabolism is just that little bit more adaptable, efficient, streamlined than the average.

In any case, I think my original theory is still valid because "Why did the inactive variant become prevalent, dominant, and eventually elusive?" My theory is due to a change in the abundance of a nutrient intake.

Yes, but given the number of enzymes and hormones and antibodies in a complex organism, I'm not convinced that the synthesis of one enzyme takes up an appreciable amount of energy. Turning that one gene off wouldn't provide its bearer(s) with a decisive advantage - especially in an environment of food surplus. They would probably have more than one preferred genetic modification. I'm just speculating that those preferred modifications came in a related cluster.
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Re: Speculation on MTHFR evolution

Postby zetreque on March 7th, 2018, 1:44 pm 

Ok, look at a time when instead of food surplus you have food scarcity.

If for example all you had to eat were two food items over many generations with a lot of certain nutrients like vitamin C. Over all those generations the genes to synthesize vitamin C will slowly go away since you are eating it already synthesized. Is that not a plausible explanation?
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Re: Speculation on MTHFR evolution

Postby Serpent on March 7th, 2018, 2:29 pm 

zetreque » March 7th, 2018, 12:44 pm wrote:Ok, look at a time when instead of food surplus you have food scarcity.

If for example all you had to eat were two food items over many generations with a lot of certain nutrients like vitamin C. Over all those generations the genes to synthesize vitamin C will slowly go away since you are eating it already synthesized. Is that not a plausible explanation?

I suppose so. But I'm having trouble imagining such a situation. Where there is plenty of vitamin c-rich vegetation, there is unlikely to be scarcity: that vegetation would support a diverse population...
...unless there was a corresponding scarcity of one or two specific nutrients - say, iron or calcium - and the enzyme-producing cells were diverted to a different function.* That could work.

* More accurately, the genetic modification that allowed a more effective processing of the scarce minerals was present in individuals that did not produce the Vitamin C, and absent in individuals that did. This is what I mean by gene clusters: not a single trait, but related (A+B; Q or M; if F then not A) configurations.
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Re: Speculation on MTHFR evolution

Postby doogles on March 7th, 2018, 5:12 pm 

I liked your original thinking about vitamin C, Zetrique.

Serpent and Braininvat have raised questions about the possibility of devolution.

Wouldn't the anatomical presence of vestigial organs such as the appendix and coccyx in humans be evidence of devolution as a natural effect of disuse? -- Just a thought.

...................................................................

The mention of folic acid and the MTHFR gene earlier prompts me to mention my own experience over the last three years. I've previously related my experience with vitamin K in this forum and how, after three months, it became obvious that the osteoarthritis in my right ankle was reversing. It occurred to me that I would need healthy stem cells to produce chondrocytes and osteocytes for cartilage replacement and calcium deposition in my ankle bones (Xrays showed osteopenia, a stage worse than osteoporosis).

Folic acid and vitamin B12 are both required for DNA health. But one of my co-morbidities for the six years before that had been chronic anaemia (3.8 to 4 million RCC) that had resisted all official medical diagnoses and treatments. Folic acid for months had not helped. I'd read about the MTHFR deficiency about that time and asked myself the question -- "If a gene absence could cause a failure in an enzyme, is it possible that old age per se could have a similar minor effect?"

This enzyme apparently has one simple task - it promotes the conversion of folic acid into folinic acid. Now folinic acid is freely available and quite cheap as an 800 microgram tablet. I've been taking one a day ever since and a methylcyanocobalamine (methyl B12) every few days or so.

My blood count went up to 4.3 within months, but the interesting thing is that almost from the first week of taking them, my gym performances increased dramatically. I do a 3-hour session once a week. If I multiplied the weights I put on the machines by the number of reps I do at that weight, I was shifting maybe 20 tonnes every session. I began to do PBs almost every week to the point where I am shifting approx. 40 tonnes each session. Last Saturday I did another five PBs.

Biceps curls on the biceps bench may be my best example of improvement. Four years ago I was doing maybe 50 reps with 2.5 kg on each end of a 10 kg bar. Four weeks ago I did 140 reps wit 5.0 kg on each end. I added another 1.25 kg 3 weeks ago and did 50 reps. Last visit I did 70 reps The arthritis has disappeared from my left wrist. And I'm sure I'll be doing 100 reps within a month or so. I'm sure the reversal of wrist arthritis has much to do with that but I'm also sure that the folinic acid and B12 are involved.

Forget the MTHFR gene. Just get some folinic acid and bypass that step in metabolism.
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Re: Speculation on MTHFR evolution

Postby zetreque on March 7th, 2018, 6:09 pm 

Thank you all.

I appreciate your personal experience doogles.

I was hoping to put this off further in the conversation but I have had fun doing my own self experimentation. I have slowly been thinking about and getting into stuff like this MTHFR gene. It was cheap a while back to have my and both my parents DNA sequenced. This has opened up a lot of opportunities to dig into all the new science coming out with a personal perspective.

I know there is a lot of skepticism and hype behind genetics and health. I think the smart people are taking it with a grain of salt while keeping an open mind. It's both important and not that important. It's also very hard to find good studies when it comes to correlating disease to genes because of all of the confounding factors. People's individual gene expression, DNA variants, and history complicate things and I accept personal experiences that conflict research studies. It seems like more and more the doctors looking deeper into personalized treatment are finding value in using genetics while still recognizing that it's just part of the story.

This has been on my todo list for a while but I am starting to look at some specifics of my DNA along with my own experience and diet. I am a strong believer in evolution and when it comes to health I love exploring diet along side evolution. As I said though, it's very hard to tease out small things such as gene variants when it comes to optimizing health. Most people would just assume think it a waste of time.

I am able to run my raw DNA data through various free tools available now and explore these concepts if for nothing else than fun to geek out on it.

For example. Here is my own DNA for well known methylation related genes. I also find it really really cool that I can look at both of my parents DNA as well and clearly see how I inherited any variants. I can then experiment on myself with specific supplements and use personal experience of my parents, their unique ancestry and compare it to mine and my own variants. I like thinking about the whole story of evolution too and how these genes and variants came to be. Clearly there is a lot to it

meth.jpg


You can see A66G is something that is out of normal for me. It's cool that I can look at both my parents and see that they were both heterozygous for A66G leading me to be homozygous for the mutation.
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Re: Speculation on MTHFR evolution

Postby zetreque on March 7th, 2018, 6:52 pm 

I just now looked up MTRR A66G.

The first match is this website.
http://www.mtrra66g.com/

Thinking about it critically I find it a little strange that there is a whole website dedicated to this one gene and advertises 23andme kits. So I then did a search to see what I can find about the ownership of the domain name. It appears to be owned by an employee of Indiana University so there is no connection thus far for a conflict of interest. Also not finding any conflicts of interest in the amazon and Thorn supplements he posts. I could dig deeper.

This looks like an opportunity for me to do an experiment on myself if I ever want to and have the time. There is also a bit of fun speculation and research I could do on this. I could look up what B12 is best known for. There are aspects of my parents health that are better than my own and I could see if having the full mutation is related to them. Form a hypothesis and then run a supplementation experiment. So much to do and learn!
If your results show you have the mutation, you should consider supplementing with methylcobalamin and methylfolate.
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