When did ApoE3 first arise?

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petri.d
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Re: When did ApoE3 first arise?

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mike wrote: Tue Jun 21, 2022 2:56 pm
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.
Mike - thanks for starting this very interesting topic. One thing to note is that in addition to diet, various infectious diseases also likely put strong selective pressure on ApoE.

The major receptor for ApoE, LDL-R, is highly conserved among animals and insects. Thus, many viruses have used it and other cholesterol receptors) to cross the species barrier and infect human cells. For example: Vesicular stomatitis virus (LDL-R), Rift Valley (LRP-1), alphaviruses like Yellow fever (ApoER), Ebola (NPC1), rhinoviruses (LDL-R), trypanosomes (LDL-R), Hepatitis C (incorporates ApoE into viral particle)... the list goes on and on. Probably many other viruses that we don't know about use ApoE receptors.

ApoE and its receptors were likely under strong selective pressure to prevent pathogens from using them. ApoE binds with higher affinity to the LDL receptor than ApoE2 or ApoE3. ApoE4 may compete with pathogens for the receptor and this in turn block infection. If E4 is bound to LDL-R then virus wouldn't be able to enter the cell. There could be a strong evolutionary advantage to E4 with pathogen burden is high.

Countries around the equator have a high pathogen burden. Infection is common. As humans moved out of Africa and into higher latitudes the pathogen burden lessened (and as you note diets changed). Winters kill many biting insects thus reducing exposure to viruses. In this lower pathogen environment other ApoE alleles, such as ApoE3 may have been favored.
mike
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Re: When did ApoE3 first arise?

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petri.d wrote: Thu Jun 23, 2022 9:08 am The major receptor for ApoE, LDL-R, is highly conserved among animals and insects. Thus, many viruses have used it and other cholesterol receptors) to cross the species barrier and infect human cells. For example: Vesicular stomatitis virus (LDL-R), Rift Valley (LRP-1), alphaviruses like Yellow fever (ApoER), Ebola (NPC1), rhinoviruses (LDL-R), trypanosomes (LDL-R), Hepatitis C (incorporates ApoE into viral particle)... the list goes on and on. Probably many other viruses that we don't know about use ApoE receptors.

ApoE and its receptors were likely under strong selective pressure to prevent pathogens from using them. ApoE binds with higher affinity to the LDL receptor than ApoE2 or ApoE3. ApoE4 may compete with pathogens for the receptor and this in turn block infection. If E4 is bound to LDL-R then virus wouldn't be able to enter the cell. There could be a strong evolutionary advantage to E4 with pathogen burden is high.

Countries around the equator have a high pathogen burden. Infection is common. As humans moved out of Africa and into higher latitudes the pathogen burden lessened (and as you note diets changed). Winters kill many biting insects thus reducing exposure to viruses. In this lower pathogen environment other ApoE alleles, such as ApoE3 may have been favored.
Yes, there have been many theories on why E4 should persist, when it seems to mostly affect older individuals. I personally like the Grandmother theory. But in your example, the fact that E4 binds lipids in the blood differently than E3, and this results in higher cholesterol in E4s - I should know! Seems like the risk of CVD would be more likely.

But let's change your thinking a bit... Let's say that E3 is VERY advantageous in farming communities. That would mean that where farming has existed for 5-10 kya, the population becomes all E3. Then you have a new wave of E4s come in to these farming areas around 5 kya. They have horses and the wheel and easily take over, killing the men and mating with the women. You now have many mixed E3/E4s. If you compare where the Yamnaya went in Europe, it is where E4% is highest. The % Yamnaya DNA is similar to % E4.

https://www.science.org/content/article ... population
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AnnaM
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Re: When did ApoE3 first arise?

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Hi Sonoma Mike,
I am an intern here and no new posts yet today, so I thought I would search info on ApoE4 from a search of this site back in 2018:
Is ApoE4 Neanderthal?
Interesting conversation.
Thanks,
AnnaM
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mike
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Re: When did ApoE3 first arise?

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AnnaM wrote: Sat Jun 25, 2022 6:30 am Hi Sonoma Mike,
I am an intern here and no new posts yet today, so I thought I would search info on ApoE4 from a search of this site back in 2018:
Is ApoE4 Neanderthal?
Interesting conversation.
Thanks,
AnnaM
Hi Anna. Yes, that was an interesting discussion - one of my earliest Posts started it... Looking back at it though, it appears that I was wrong, and the 220,000 ya for E3 was the same back then as well. Faulty memory on my part...who whould'a thunk!? From what I've looked at since though, I think that number is off by quite a bit and not supported by fossil evidence. That number comes from a calculation that assumed E3 had no competitive advantage. I'm thinking it will end up being less than 100,000 ya, and maybe even less. I'm also thinking the Neanderthal was ApoE4, but unlikely to have been the E4 of modern man. Too long ago.
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AnnaM
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Re: When did ApoE3 first arise?

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Wow Sonoma Mike! Thanks for the reply and info. So interesting that ApoE4 could have two ancient types. Must fill an important role in an ancient past. I have read that Neanderthal was apoE4, so that one is different and older than the ApoE4 that circulates today? There is a lot to learn about this gene.
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Re: When did ApoE3 first arise?

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AnnaM wrote: Wed Jun 29, 2022 11:43 am Wow Sonoma Mike! Thanks for the reply and info. So interesting that ApoE4 could have two ancient types. Must fill an important role in an ancient past. I have read that Neanderthal was apoE4, so that one is different and older than the ApoE4 that circulates today? There is a lot to learn about this gene.
Best,
AnnaM
I'm not sure that "different and older" is exactly how I would describe it. Same genetic code came out of Africa multiple times. Neanderthal was one such period. Other groups went east. My theory is that more recently E3 came about, possibly in the Fertile Crescent, and in my theory E3 is competitively advantageous in carb rich environments and overran any remaining ApoE4 in Europe over 50,000 years. Then around 5,000 years ago, Horse tribes from the east that still had E4 came west end re-introduced E4 into Europe, particularly in the North. The study of fossil DNA over the more recent past is illuminating the migrations of early man. Should see more evidence one way or the other soon.
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