When did ApoE3 first arise?

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mike
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When did ApoE3 first arise?

Post by mike »

I have been away from this site for much of the pandemic. Prior, the literature seemed to suggest that E3 came about around 40,000 years ago. Now, everywhere (including Wikipedia and Bredesen's latest book) it says E3 came about more like 220,000 (correction) years ago. This difference is critical - was E3 a response to more meat in the diet, or more carbs? None of the references in either Wikipedia or Bredesen point to anything that explains these dates, but one does point to another reference which does seem to explain this number - https://www.cell.com/ajhg/fulltext/S000 ... 07)63282-0 where it says
As noted above, the net sequence divergence between human and chimp APOE genes was estimated as 64.7; the average pairwise sequence difference among human haplotypes in the same genomic region was 2.93. If a constant molecular clock is assumed and the humans-chimpanzee time of divergence is taken as 5 million years BP, the time required to generate the observed variation would be ∼226,000 years.
So this seems to justify the new time, but the paper also warns that this is only true if the variation is "selectively neutral," which I flat out don't believe. So instead of using a mathematical model with a suspect assumption, lets look at Fossil evidence. I found this paper quite interesting - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471373/
It has lots of good stuff, but what I found most interesting looking at modern man DNA from fossils in Europe ranging in age between 1,500 and 43,000 years ago (post Neanderthal) to see if there was a temporal pattern to ApoE varients. They came up with the following:
ApoE.jpg
Which had two big surprises
1. The oldest E4 was 8,000 years ago, and most were less than 5,000 years ago. This while E3s went as far back as 24,000 years ago.
2. All except the oldest one were homozygotes - 4/4, 3/3 or 2/2.

Since we know E4 is the oldest variant, it suggests to me a couple of things. First off, there seems to be little mixture of ancient DNA among separate groups, Each group was either all 4 or all 3. E3 likely arose around 40,000 years ago and gave advantage to farming/high carb groups and spread throughout Europe during the next 35,000 years until it was the only one. Around 5,000 years ago, the Yamnaya people from near the Black Sea developed the wheel and used horses. They swept west into Europe, particularly in the North. If you compare the Yamnaya percentage of DNA in different areas of Europe, you will find it very similar to the percentage of E4. https://en.wikipedia.org/wiki/Yamnaya_c ... migrations
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Last edited by mike on Thu Jun 23, 2022 10:35 am, edited 1 time in total.
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Re: When did ApoE3 first arise?

Post by BigInJapanDan »

Hi Mike,

it is still unclear, but the estimations of Fullerton seem to be the most plausible, with e3 likely arising over 100,000 years ago, before major expansion out of Africa. As for the Abondio paper, their genotypes for APOE are incorrect and rely on pseudohaploid calls, you may as well disregard them.
I am working on this topic myself in more detail, and will keep you posted if I manage to publish my work.

Best wishes
mike
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Re: When did ApoE3 first arise?

Post by mike »

BigInJapanDan wrote: Mon Jun 20, 2022 6:58 am Hi Mike,

it is still unclear, but the estimations of Fullerton seem to be the most plausible, with e3 likely arising over 100,000 years ago, before major expansion out of Africa. As for the Abondio paper, their genotypes for APOE are incorrect and rely on pseudohaploid calls, you may as well disregard them.
I am working on this topic myself in more detail, and will keep you posted if I manage to publish my work.

Best wishes
Dan, can you point me to where you are getting the 100 kya figure? Even that figure likely makes it the carb variant, since man has been eating meat for a lot longer. What avenue are you working on? Has anyone yet been able to determine what variant Neanderthals had? I'm assuming E4, based on when they left Africa, but have yet to see any research...
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mike
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Re: When did ApoE3 first arise?

Post by mike »

BigInJapanDan wrote: Mon Jun 20, 2022 6:58 am Hi Mike,

it is still unclear, but the estimations of Fullerton seem to be the most plausible, with e3 likely arising over 100,000 years ago, before major expansion out of Africa. As for the Abondio paper, their genotypes for APOE are incorrect and rely on pseudohaploid calls, you may as well disregard them.
I am working on this topic myself in more detail, and will keep you posted if I manage to publish my work.

Best wishes
Dan, can you point me to where you are getting the 100 kya figure? Even that figure likely makes it the carb variant, since man has been eating meat for a lot longer. What avenue are you working on? Has anyone yet been able to determine what variant Neanderthals had? I'm assuming E4, based on when they left Africa, but have yet to see any research...
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Re: When did ApoE3 first arise?

Post by BrianR »

mike wrote: Mon Jun 20, 2022 10:22 am
Hi Mike, you might take some of the timetable inferences from genetic drift (as opposed to specific ancient dna evidence) a little skeptically. See, e.g., a couple of recent review/commentaries from Razib regarding new papers suggesting reinterpretations of population splits. It seems like the science is still in flux.

[note, no direct APOE4 relevance for these papers]

The last glacial maximum bottlenecks and human phylogeny

The modern human family tree might be shallower that I’ve been saying
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Re: When did ApoE3 first arise?

Post by Nicnac0526 »

BigInJapanDan wrote: Mon Jun 20, 2022 6:58 am Hi Mike,

it is still unclear, but the estimations of Fullerton seem to be the most plausible, with e3 likely arising over 100,000 years ago, before major expansion out of Africa. As for the Abondio paper, their genotypes for APOE are incorrect and rely on pseudohaploid calls, you may as well disregard them.
I am working on this topic myself in more detail, and will keep you posted if I manage to publish my work.

Best wishes
Hi BigInJapanDan, Welcome! Thank-you for posting on our wonderful forum. It's great to have you and well done for your first post. Whilst you may have been using the forum for a while, as a welcome intern it is my job to highlight the areas that people tend to find most useful.

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Re: When did ApoE3 first arise?

Post by BigInJapanDan »

mike wrote: Mon Jun 20, 2022 10:17 am
BigInJapanDan wrote: Mon Jun 20, 2022 6:58 am Hi Mike,

it is still unclear, but the estimations of Fullerton seem to be the most plausible, with e3 likely arising over 100,000 years ago, before major expansion out of Africa. As for the Abondio paper, their genotypes for APOE are incorrect and rely on pseudohaploid calls, you may as well disregard them.
I am working on this topic myself in more detail, and will keep you posted if I manage to publish my work.

Best wishes
Dan, can you point me to where you are getting the 100 kya figure? Even that figure likely makes it the carb variant, since man has been eating meat for a lot longer. What avenue are you working on? Has anyone yet been able to determine what variant Neanderthals had? I'm assuming E4, based on when they left Africa, but have yet to see any research...
The Fullerton paper, although they say it is between 150 - 220 kya.
Why do you think it is the carb variant? Farming (theoretically) started less than 10 kya.
And neanderthals and denisovan do have e4. I am working on aDNA.
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Re: When did ApoE3 first arise?

Post by mike »

BigInJapanDan wrote: Tue Jun 21, 2022 3:58 am The Fullerton paper, although they say it is between 150 - 220 kya.
Why do you think it is the carb variant? Farming (theoretically) started less than 10 kya.
And neanderthals and denisovan do have e4. I am working on aDNA.
Man has been eating wild grains and the like much longer than official farming. Man has been eating meat for a million years at least.

I have a personal theory that much of our evolution revolved around the tuber. Did you know that all native tubers in the old world are poisonous? I think they evolved that way because man discovered them and over-ate them. New World tubers are not poisonous. No early man. Early Man discovers tubers, and they leave the jungle to where they grow. They get better at walking as they need to travel further distances. At some point, there are only the poison ones left. They are forced to do more hunting and transition to being more carnivorous. Brain gets larger and digestive tract gets smaller. At some point in the not so distant past (100 kya ?) they discovered that if you first soaked the tuber, the poison would leach out, and they could then eat/cook them. They wouldn't need to farm to start getting more carbs in the diet. Maybe a lot more.

Further more, the current theory is that a low-carb keto diet is best to avoid AD. Why if E3 were not the Carb Variant?
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Re: When did ApoE3 first arise?

Post by BigInJapanDan »

mike wrote: Tue Jun 21, 2022 12:38 pm
BigInJapanDan wrote: Tue Jun 21, 2022 3:58 am The Fullerton paper, although they say it is between 150 - 220 kya.
Why do you think it is the carb variant? Farming (theoretically) started less than 10 kya.
And neanderthals and denisovan do have e4. I am working on aDNA.
Man has been eating wild grains and the like much longer than official farming. Man has been eating meat for a million years at least.

I have a personal theory that much of our evolution revolved around the tuber. Did you know that all native tubers in the old world are poisonous? I think they evolved that way because man discovered them and over-ate them. New World tubers are not poisonous. No early man. Early Man discovers tubers, and they leave the jungle to where they grow. They get better at walking as they need to travel further distances. At some point, there are only the poison ones left. They are forced to do more hunting and transition to being more carnivorous. Brain gets larger and digestive tract gets smaller. At some point in the not so distant past (100 kya ?) they discovered that if you first soaked the tuber, the poison would leach out, and they could then eat/cook them. They wouldn't need to farm to start getting more carbs in the diet. Maybe a lot more.

Further more, the current theory is that a low-carb keto diet is best to avoid AD. Why if E3 were not the Carb Variant?
Very interesting theory regarding tubers :D unfortunately, my research is focused more on recent developments (last 10kya), so I cannot contribute much to your theory. Although it would be great if you could provide any sources for your theory :)

Regarding the carb variant, AD is not (at least directly) affecting fitness/survival in the reproductive stages of humans, so AD alone wouldn't have been able to lead to selection of E3 over E4 – even if nowadays we see that it is typically a western diet that leads to the increased risk associated with E4.
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Re: When did ApoE3 first arise?

Post by mike »

BigInJapanDan wrote: Tue Jun 21, 2022 1:00 pm Very interesting theory regarding tubers :D unfortunately, my research is focused more on recent developments (last 10kya), so I cannot contribute much to your theory. Although it would be great if you could provide any sources for your theory :)

Regarding the carb variant, AD is not (at least directly) affecting fitness/survival in the reproductive stages of humans, so AD alone wouldn't have been able to lead to selection of E3 over E4 – even if nowadays we see that it is typically a western diet that leads to the increased risk associated with E4.
No references beyond the timeframe of various evolutionary steps of early man and logic. Why would early man leave the jungle? Had to be some kind of new food source. Man could easily use the tools needed to did up tubers. Why are tubers in Africa poisonous, but not in the New World? What's the difference? Early Man. At some point they learned how to soak them before cooking. You don't think that happened before farming by quite a bit? Start doing enamel sampling of fossils to determine how much tubers played a part of the diet at various times. Make someone a nice PhD project.

I'm not saying that AD is causing a difference in survival, I'm saying E3 in a Carb rich world does. Glucose requires more oxygen to get a given amount of ATP compared to ketones. More oxidation, more ROS. The E3 variant is shaped differently and can take care of some of the damage that E4 can't. ROS causes bending of proteins, and then clumping in the case of AB. E4 isn't able to grab these folded proteins, while E3s can and get it removed. So one path to AD, but ROS causes damage elsewhere as well, so not just AD.

You say you are working in the last 10 kya - so you should see more of the many "recent" western migrations into Europe. It is amazing what you can do with Big Data and DNA analysis these days. Makes me want to go back to school. I look forward to seeing your work.
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