Is ApoE4 Neanderthal?

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
mike
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Re: Is ApoE4 Neanderthal?

Post by mike »

Verax wrote:Homo sapiens and the other two humanoids have intermixed periodically since (outside Africa) in a trellis-like history. A paper in Science (behind a paywall) "The phenotypic legacy of admixture between modern humans and Neandertals" links Neanderthal DNA to hypercoagulation, actinic keratosis, depression, and nicotine addiction, but not to lipid defects. http://science.sciencemag.org/content/351/6274/737.
Would be nice to get whole article... Does anyone know if all Neanderthal affected genes have been identified? Folks have mentioned they have a certain % of genes with Neanderthal variants - where is this coming from - 23andMe?
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Re: Is ApoE4 Neanderthal?

Post by Verax »

Following up on this intriguing question about ApoE4 and 23andMe's report on Neanderthal genes, I see that 23andMe does give some scientific details, see https://permalinks.23andme.com/pdf/23-0 ... erence.pdf which you can retrieve from your 23andMe Neanderthal report Scientific Details.

This 2015 report cautions that 23andMe does not scan the entire genome but only a subset to determine genotypes. The purpose is to report traits, ancestry and some health. The Neanderthal and Denisovan studies were of mtDNA, but 23andMe is not of mtDNA nor the Y chromosome. 23andMe chose selected alleles to determine traits and so the "percent Neanderthal" is misleading: "...it is important to note that [the selected variants tested for in the Neanderthal report] represent only a fraction of the total amount of Neanderthal ancestry an individual carries."

23andMe happens to report traits associated with Neandethal genes such as height, hair, and so on, maybe because there was selection pressure in modern humans to discard other Neanderthal genes not beneficial. For example, my report states I have 274 Neanderthal variants, but only one significant variant, predicting height less than average (rs7544462(C;A) in the MEAF6 gene, which happens not to be true in my phenotype. Sankararaman, et al. (2014) "The genomic landscape of Neanderthal ancestry in present-day humans," doi: 10.1038/nature12961. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4072735/

The white paper authors state they obtained a list of some variants from the authors of the Nature paper, but the SNPs are not listed in full in either location, and as published do not contain Apoe4.
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Re: Is ApoE4 Neanderthal?

Post by Verax »

Mike, one of the articles I referenced does give evidence that only humans have E4/E4, and that chimps and other primates do not have E4, they have a different form of the gene without alleles such as E4 or E3.

Apparently humans were E4/E4 a million years ago but the ancestry of Neanderthals is still unclear, as it might be a different lineage from modern humans, for example, from Homo erectus through Homo heidelbergensis. That some Denisovians were E4 proves nothing about Neanderthals.

There is evidence of course that there was genetic mixture around the same time E3 and E2 alleles arose, but only speculation about association with meat eating, which as you point out. The other article speculates that longevity had something to do with why E4 was so common, but the article also discusses other theories.

I notice a few articles recently about the FADS genes (FADS1, FADS2, FADS3) which are associated in both Europeans and Han Chinese with north-south gradients and may be related to diet or climate. We have long known of a similar association with lactose intolerance. Likely these genetic changes were due to selective pressure, but the causes might be complicated. The mixture may have been in the Middle East before modern Europeans replaced Neanderthals. It is unwise to blame these matters on single genes when there is gene-environment interaction as well as gene-gene.

In any case, I suspect it is unlikely or unproven that E4 genes were from the tiny residual of Neanderthal DNA in modern humans.
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Re: Is ApoE4 Neanderthal?

Post by circular »

See two new papers in Cell:

https://www.ncbi.nlm.nih.gov/m/pubmed/?term=neanderthal

I saw a writeup about these in the CNN Health section the other day.
ApoE 3/4 > Thanks in advance for any responses made to my posts.
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Re: Is ApoE4 Neanderthal?

Post by mike »

Verax, as I wrote that about primates having E4, was feeling I should reread the article...but didn't.

I see circular just put up new articles, but thought I would respond to you first. The NIH article was interesting, and It felt like the first study really trying to answer my question. The math was beyond me, but I felt pelted by their efforts to prove that they probably got most Neanderthal variants. Have you ever played Battleship as a kid? This study is like a common strategy used in that game; you set up a search pattern hoping that you make it coarse enough to be efficient, but likely to find all ships most of the time...but sometimes the small PT boat is missed. How many 4/4s are there? Seems like a needle in a haystack, unless you are looking for it specifically. Why do they know ApoE variant for one type of early man outside Africa, but not for Neanderthal... I believe E4 helps with feast / famine cycle needed for northern europe at the time, and that is where modern man's E3 tuber/carb advantage was least and Neanderthal held out the longest. And where the gene, at least for 4/3s was not as much of an evolutionary disadvantage.

E4 was/is on the way out evolution-wise. These various studies have looked for areas where Neanderthal genes won out. This is a case where it did not win out, but the time has been too short, and it is still exists out there.
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Re: Is ApoE4 Neanderthal?

Post by mike »

I got my new 23andMe results - still 4/4 (I could hope...) and now it says I have 310 Neanderthal variants, more than 93% of other 23andMe, and it gives what I think is a standard <4% of my DNA is Neanderthal. Nothing there to answer my questions. I did tell 23andMe in a survey about the report that they should look specifically at APOE...
Last edited by mike on Thu Oct 11, 2018 10:51 am, edited 1 time in total.
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Re: Is ApoE4 Neanderthal?

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Verax wrote:Apparently humans were E4/E4 a million years ago but the ancestry of Neanderthals is still unclear, as it might be a different lineage from modern humans, for example, from Homo erectus through Homo heidelbergensis. That some Denisovians were E4 proves nothing about Neanderthals.
Verax, how could they be anything else? The E3 variant is thought to have appeared around 220,000 years ago. Neanderthal left Africa prior to that - I get different dates, but in general seems to be 300,000 to 600,000 ago. This means that when they left Africa, they would have been E4/E4. There was genetic mixture in Europe/Asia, but little evidence that there was between Europe/Asia and Africa. It appears that small bands came out of Africa periodically (twice?), but there are gene variants in Neanderthal that never made it back to Africa. For Neanderthal to be anything but E4/E4, they would have had the same genetic mutation in isolation, or some other wave came out of Africa after the Neanderthal but before 45,000 years ago when modern man emerged out of Africa. I haven't heard of any other migrations... But I agree that this proves little. How hard would it be to get someone to test some of the Neanderthal DNA?
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Re: Is ApoE4 Neanderthal?

Post by Verax »

Since the ancestral ApoE4 is preserved in about 15% of modern humans, there must be some evolutionary advantage, else prevalence would be smaller and recede. ApoE4 is thought to modulate immunity and to increase Vitamin D levels more than the other alleles. ApoE4 prevalence is higher at higher latitudes (as is pale skin). So it would seem that as Neanderthal and Denisovan species moved from Africa to Europe and Asia they would retain ApoE4 and their skin pigmentation would lighten. Then when they interbred with modern Homo sapiens who came later, they would pass on those favorable genes.

But it turns out to be a complex story. It appears that modern humans in Europe did not change from African skin colors to pale skin until long after the Neanderthals died out. https://www.newscientist.com/article/dn ... nderthals/ And the Neanderthals in the west and north had light skin genes, while Denisovans in north Asia had dark skins. Melanesians in Papua New Guinea retain some 6% Denisovan genes, while modern Europeans have much less Neanderthal.

The recently recovered nuclear DNA from the most early Neanderthals is too fragmentary to conclude anything about ApoE4 or pigmentation, but indicates Neanderthals and H. heidelbergensis diverged from the modern human species much earlier than previously thought. https://www.nature.com/news/oldest-anci ... ls-1.19557

One possible explanation is that the interbreeding happened later in the middle East, where the Neanderthals had darker skin. Then there were further evolutionary changes when humans moved into Europe and climate and diet changed. Tropical infections became less important and skin paler for Vitamin D, and agriculture brought meat and grains requiring genetic adaptation to ApoE and FADS. In Asia, Tibetans reused Denisovan genes to adapt to higher altitudes.

How can we turn ApoE4 into advantage for us and our descendants?
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Re: Is ApoE4 Neanderthal?

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Verax wrote:Since the ancestral ApoE4 is preserved in about 15% of modern humans, there must be some evolutionary advantage, else prevalence would be smaller and recede.
Thanks for the reading material Verax, I look forward to it! My immediate question is how quickly does something get lost in genetics? 40,000 years doesn't sound that long, in evolutionary terms... Homozygous ApoE4 only happens 2%? What is the cost/benefit ratio for only one ApoE4 gene? And if most negatives happen after childbearing, and you are only dealing with potential social / grand mother theory kind of stuff, then I would think the pressure evolutionary-wise would be less...
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Re: Is ApoE4 Neanderthal?

Post by mike »

It is amazing how quick this field is changing. I think this March 2018 article is beginning to unlock this period a bit more. You need to pay for anything more than the abstract.

https://www.nature.com/articles/nature26151

Abstract
Although it has previously been shown that Neanderthals contributed DNA to modern humans, not much is known about the genetic diversity of Neanderthals or the relationship between late Neanderthal populations at the time at which their last interactions with early modern humans occurred and before they eventually disappeared. Our ability to retrieve DNA from a larger number of Neanderthal individuals has been limited by poor preservation of endogenous DNA and contamination of Neanderthal skeletal remains by large amounts of microbial and present-day human DNA. Here we use hypochlorite treatment of as little as 9 mg of bone or tooth powder to generate between 1- and 2.7-fold genomic coverage of five Neanderthals who lived around 39,000 to 47,000 years ago (that is, late Neanderthals), thereby doubling the number of Neanderthals for which genome sequences are available. Genetic similarity among late Neanderthals is well predicted by their geographical location, and comparison to the genome of an older Neanderthal from the Caucasus indicates that a population turnover is likely to have occurred, either in the Caucasus or throughout Europe, towards the end of Neanderthal history. We find that the bulk of Neanderthal gene flow into early modern humans originated from one or more source populations that diverged from the Neanderthals that were studied here at least 70,000 years ago, but after they split from a previously sequenced Neanderthal from Siberia around 150,000 years ago. Although four of the Neanderthals studied here post-date the putative arrival of early modern humans into Europe, we do not detect any recent gene flow from early modern humans in their ancestry.

So, the reason we can't find the research, is because it hasn't happened yet...i was under the impression they had already been able to get DNA from Neanderthal, but in reality it is just starting...
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