When did ApoE3 first arise?

[petri.d]

Very interesting theory regarding tubers 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]

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

[AnnaM]

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

[mike]

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.

[AnnaM]

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

[mike]

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.

[AnnaM]

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.

Morning Sonoma Mike! My mother's family is from Iceland, settled around 890 AD from Norwegian Vikings. She had 4/4 and so do I (my Dad was of Swedish decent, 2nd generation). The Icelandic Sagas say something about being related to the 7th son of Agamemnon, King of Mycenae, from Greek mythology! Iceland was isolated and a homogenous group, so makes sense that at least some would retain the 4/4 alleles. Also in my genealogy are the Yakut Natives, similar to the Laplanders in Finland. So missed all of the invading E3s.
Happy 4th!
AnnaM

[Greyhound]

"The appearance of apoE3 and apoE2 appears to be a late event in evolution since other primates, such as chimpanzees and bonobos, have a single major protein characteristic of apoE4"
https://onlinelibrary.wiley.com/doi/ful ... 2/pro.2597

If you are trying to link with diet.. then there is something of interest in the Timmy Wood interview @ 53:39min
but they also refer to 220,000 years E3 appearance. which might be incorrect as you say. A preserved wooly mamooth early born remains was found in the permafrost in Canada recently and dated to 30,000 years so maybe it could be related to humans at the time eating them which brings to an sooner dating??
https://heartandsoil.co/tommy-wood-md-p ... s-disease/

you will find a imho a mixed up discussion of keto high fat which is claimed to be bad and the the carnivore diet is the other which you may be associating with E4 oldest gene as the solution.. there is a observational study which I now cannot find with very impressive results that lines up with the podcast cited.

edit addition.

"The lifespans of intermediate species during human evolution cannot be known, because the spotty skeletal evidence at hand allows only general estimates of age classes. According to tooth wear, early modern H. sapiens and H. neanderthalensis had a larger proportion of older adults than prior Homo species and Australopithecus (5)."
https://www.pnas.org/doi/10.1073/pnas.0909606106

edit addition.#2
If one is looking for improved health conditions just go to the self reported changes in health status. consider than the APOE4 population is around 25% in any group and you will able to conclude that the carnivore diet is likely the normal and healthiest diet for that group.
69% improved chronic disease
95% improved overall health
91% improved hunger/food cravings
85% improved mental clarity
66% improved memory
83% improved focus
69% improved sleep
78% improved strength
76% improved endurance
89% improved energy.
https://www.allthingscarnivore.com/the- ... vard-study

[mike]

If you are trying to link with diet.. then there is something of interest in the Timmy Wood interview @ 53:39min
but they also refer to 220,000 years E3 appearance. which might be incorrect as you say. A preserved wooly mamooth early born remains was found in the permafrost in Canada recently and dated to 30,000 years so maybe it could be related to humans at the time eating them which brings to an sooner dating??
https://heartandsoil.co/tommy-wood-md-p ... s-disease/

Regardless or whether E3 appeared 220 kya or more recently, Man has been eating meat for a million years or more, so it does not make sense that E3 is a "meat" gene. I saw an article about the baby mammoth, but didn't follow your point there...