December 19, 2011

Neandertal admixture: why I remain skeptical

The announcement by 23andMe of a Neandertal admixture feature of their commercial test gives me an opportunity to revisit the question of Neandertal admixture in general. At the outset, let me state that I'm still on the fence on whether there has been such admixture in Eurasians. The evidence that has appeared since the publication of Green et al. (2010) provides arguments both in favor and against the Neandertal admixture hypothesis.

Let's begin by examining the case for Neandertal introgression into Eurasians. This case boils down to the fact that modern Eurasians are more similar to Neandertals than modern Africans are. If Neandertals were an irrelevant outgroup, this is an unexpected finding.

The above statement in bold is the fact. But, this fact does not admit to the single interpretation of Neandertal admixture in the ancestors of Eurasians.

At the very beginning, I suggested that this fact could be explained by archaic admixture in Africans. Both genetics and paleoanthropology has furnished evidence in favor of my idea. It is no longer tenable to propose that Eurasians are shifted towards Neandertals only because of Neandertal admixture: in fact some of the shift may be due to Africans being shifted away from Neandertals because of admixture with archaic African hominins. Any future work on the issue must take this possibility into account.

A different pitfall is in the direction of gene flow: whether Neandertals donated genes to the Eurasian gene pool or vice versa. Again, I have contended that it is more likely for a successful expanding species to donate to a contracting species, rather than opposite. However, Green et al. proposed an ingenuous argument against that direction of gene flow:

The main idea is the following:

- Yoruba Nigerians are closer to Eurasians than San are.
- If the Neandertal genome is Proto-Eurasian-admixed, then it should be shifted towards Yoruba relative to San
- It does not appear to be, hence, on balance, gene flow was from Neandertals to modern humans, rather than the opposite.

The idea is fleshed out in the supplement of the Green et al. paper. It exploits the fact that modern human populations are not equidistant to each other, to show that an archaic hominin that was admixed with a subset of modern humans (Eurasians) would not only be shifted towards that population, but would also appear closer to populations close to Eurasians (=Yoruba), rather to those who are not (=San).

All this depends, of course, on the idea that the people who interbred with Neandertals were Proto-Eurasians, i.e., a subset of Africans who left the continent and went on to become modern Eurasians.


This idea is not as secure as it formerly appeared to be. The recognition of the real possibility of Out-of-Arabia means that the people who admixed with Neandertals may not have been Proto-Eurasians, but, rather undifferentiated Proto-Humans. In other words, they were not necessarily closer to modern Eurasians than to modern Africans, but, rather, common ancestors to both.

In conclusion:
  • The inference of Neandertal admixture in modern Eurasians in terms of the D-statistic is proven to be a simplification that ignores archaic admixture in Africa
  • The inference of Neandertal-to-modern admixture is based on the assumption that moderns admixing with Neandertals were already Eurasian-like, but the mounting evidence for a major human expansion Out-of-Arabia may mean that they were not. 
Many mysteries about human origins will be solved thanks to the advent of full genome sequencing. Hammer et al. found archaic admixture in Africans on just 61 genomic regions, each about ~20kb in length.

I'm willing to bet that once scientists turn their attentions to full genomes, they will have substantial and indisputable evidence for genetic divergence between stretches of human DNA that simply too deep to be explained in a conventional Out-of-Africa timeframe.

If there was substantial archaic admixture in Africa c. 35ka, according to Hammer et al.'s estimate, and coinciding with the (intrusive?) appearance of Upper Paleolithic modern humans such as Hofmeyr, then full genome sequencing will provide the smoking gun evidence for it. Such an event would simultaneously solve many mysteries about the African population, such as its apparent higher effective population size, greater allele diversity, and recombination rate.

It may very well be that some level of Neandertal admixture will remain part of the story. We shall see.

23 comments:

Razib said...

I'm willing to bet that once scientists turn their attentions to full genomes,

how much are you willing to bet? and what odds are you willing to take?

Dienekes said...

Just entering my prediction on the public record.

I've been pushing the "African genetic diversity is due to admixture between deeply divergent human populations" theory for six years now. Time will tell if I'm right.

Unknown said...

A few comments.
- "All this depends, of course, on the idea that the people who interbred with Neandertals were Proto-Eurasians, i.e., a subset of Africans who left the continent and went on to become modern Eurasians "

If Neanderthal admixture took place with a population ancestral to both modern Eurasian and modern Africans, it would not show in the D-statistics.

- In the same spirit ; archaic admixture into Africa could indeed create the same D-statistics as Neanderthal admixture into non-Africans. However, it is the case ONLY if archaic admixture in Africans occure AFTER the split with non-Africans.

To summarize, archaic admixture into populations ancestral to both modern Africans and modern Eurasians would NOT bias D-statistics.

Eric Durand said...

Previous comment is by me, sorry.

Dienekes said...

- In the same spirit ; archaic admixture into Africa could indeed create the same D-statistics as Neanderthal admixture into non-Africans. However, it is the case ONLY if archaic admixture in Africans occure AFTER the split with non-Africans.

I don't see how that follows.
Archaic admixture in Africans may have happened e.g., as early as 200,000 years ago or as recently as 10,000 years ago.

In both cases it could show up in the D-statistics. If admixture was recent, then it would certainly show in the D-statistic, since Eurasians had certainly differentiated from Africans since at least 40-50 thousand years ago. If it was very old, it could also show, provided that the African population was structured, and Eurasians share common ancestors with an African population that did not admix with archaics rather than a panmictic African population.

Eric Durand said...

True if you're ready to assume ancient population structure lasting for tens of thousands of years. I'd rather go for the more parsimonious, "one admixture pulse" model. Unless I see some very convincing evidence proving otherwise, of course.

It is always possible to construct (more) complicated alternative models that fit the data.

Dienekes said...

The palaeoanthropological record is consistent with a structured African population all the way to well after the Upper Paleolithic revolution. Archaic African hominins persist down to 13,000 years ago

http://dienekes.blogspot.com/2011/09/chris-stringer-video-on-bbc-on-iwo.html

A panmictic African population is inconsistent with the anthropological evidence. Omo from 195,000 years ago is more modern morphologically than these skulls from 13,000 years ago.

eurologist said...

Eric,

Would you say that the projection onto the Chimpanzee/Denisovan/Neanderthal principal component axes (that you are now using to estimate Neanderthal fraction) makes a clearer case for factual Neanderthal admixture?

Also, John Hawks has shown on his blog that looking at sited where Neanderthals have derived SNPs (compared to Chimpanzees), Eurasians share significantly more of those than Africans. So, even if a large fraction of these are due to incomplete lineage sorting, it does not make sense to me that Eurasians have more - unless they have factual admixture.

I would be interested to see if one removed such shared African SNP sites from Eurasians, if one could (i) better estimate the admixture percentage, and (ii)(by looking at the size of surrounding overlap) better estimate admixture date(s).

karl00 said...

Averages by 23andMe

2.0% North African
0.5% West African
1.0% East African
1.6% South African
2.5% North American
2.4% Central American
2.4% South American
2.5% Central Asian
2.6% East Asian
2.3% South Asian
2.6% North European
2.5% East European
2.5% South European
2.3% Near Easterner
2.6% Oceanian

2.5% 23andMe customer
2.9% Mine

The average percentages are fairly equal among non-Africans.

Paper behind tool: https://23andme.https.internapcdn.net/res/pdf/jZxKxwC6liHimK59hqd1HQ_23-05_Neanderthal_Ancestry.pdf

German Dziebel said...

"I'm willing to bet that once scientists turn their attentions to full genomes, they will have substantial and indisputable evidence for genetic divergence between stretches of human DNA that simply too deep to be explained in a conventional Out-of-Africa timeframe.

If there was substantial archaic admixture in Africa c. 35ka, according to Hammer et al.'s estimate, and coinciding with the (intrusive?) appearance of Upper Paleolithic modern humans such as Hofmeyr,"

I completely agree with you, Dienekes. This is fully consistent with my out-of-America model - although you don't want to associate yourself with it or admit its explanatory power. Allele diversity and effective population size progressively increase from the New World to the Old World. This is consistent with the deepening of archaic admixture with the colonization of the Old World. In America, where there were no archaic hominids, allele diversity has remained low, which is consistent with the recency of our species and the founding bottleneck. On the other hand, linguistic diversity decreases from America into Africa and Europe, which indicates the progressive modernization of the Old World in the past 40,000 years. Africa was colonized by modern humans some 40,000 years ago in accordance with Hammer's dates for the African admixture event and with the date of the Hofmeyr skull.

Your out-of-Arabia model has no backing from linguistics and hence is untenable.

Marcel F. Williams said...

Modern Eurasians are more similar to Neanderthals than sub-Saharan Africans for the simple reason that there was only one out-of-Africa event more than 2 million years ago in the form of Homo habilis. In other words, modern Eurasians and Neanderthals had an ancient common ancestor to the exclusion of sub-Saharan Africans.

Homo has always been just one species since it first appeared in sub-Saharan Africa nearly 2.6 million years ago. And no regional member of Homo on Earth has ever been isolated long enough for true speciation to occur.

Clifford Jolly probably wrote the best analysis of the likely-hood of true speciation within the genus Homo:

Am J Phys Anthropol. 2001;Suppl 33:177-204.
A proper study for mankind: Analogies from the Papionin monkeys and their implications for human evolution.
Jolly CJ.

Beastmanager said...

I am not quite sure what do you mean by "out of arabia". It is obvious that modern humans appeared first in Africa. Out of Arabia changes nothing, it is just the way out of Africa for the "Out of Africa Tribe". Am I missing something?

Dienekes said...

I am not quite sure what do you mean by "out of arabia". It is obvious that modern humans appeared first in Africa. Out of Arabia changes nothing, it is just the way out of Africa for the "Out of Africa Tribe". Am I missing something?

Out of Arabia does not mean that Arabia was just the crossing point for Out-of-Africans. It means that the major human expansion from which modern humans derive from originated in Arabia, or more generally Asia. This expansion replaced pre-existing Eurasian populations (with some admixture in Australasia, and, possibly with Neandertals), and it absorbed pre-existing African populations, which, as far as palaeoanthropology goes, were not homogeneous AMH, but included a wide variety of forms.

There is a disconnect between the traditional OoA proposed by geneticists and the palaeoanthropological record.

Traditional OoA proposed total replacement of all human populations by expanding modern humans. We've only tested 2 types of archaic Eurasians so far (Neandertals/Denisovans) and they've proven not to be irrelevant to the human story. Hence, I tend to the belief that the archaic Africans themselves will not be proven to be irrelevant as well.

Beastmanager said...

Well, if that is Out of Arabia, I find it unlikely, given for example that the San bushmen live in south africa and are consistently rooted basally in all genetic tests, including mtDNA and Y-chromosome haplotypes, that lack significant recombination. Also biombos cave in South Africa is an archeological evidence much more compelling than the arabian archeology.
I have no problem with african admixture, but that does not need to be linked to the out of arabia extreme hypothesis. They likely came from the south of africa.

Carlos said...

Perhaps I'm missing something, but if Neanderthal admixture indeed took place where are the YDNA or MTDNA haplogroups related to them? Have they got extinct in homo sapiens too?

Dienekes said...

They could have been lost by either drift or natural selection. A recent paper argued against the possibility of drift:

http://dienekes.blogspot.com/2011/08/no-evidence-for-neandertal-admixture.html

In other words: if Neandertals did admix with humans at the levels predicted, the complete absence of Neandertal mtDNA in modern humans seems unlikely to be due to random extinction of Neandertal mtDNA.

Selection is a more promising hypothesis, but there's really no specific evidence for it.

Carlos said...

Thanks for the explanation and clarification, Dienekes!
My point is that if the hybridization was so successful that now all Eurasians supposedly have a certain amount of Neanderthal admixture (in my case 2.8%) it seems strange, to say the least, that ALL Neanderthal-related YDNA and MTDNA lines went extinct...

terryt said...

"The inference of Neandertal-to-modern admixture is based on the assumption that moderns admixing with Neandertals were already Eurasian-like, but the mounting evidence for a major human expansion Out-of-Arabia may mean that they were not".

The admixture may have happened in Arabia, surely. That would be where any humans who emerged from Africa would have first met Neanderthals, or slightly to the north of Arabia.

"It is always possible to construct (more) complicated alternative models that fit the data".

I would be reasonably sure that the real situation is more likely to be complicated rather than being simple.

"there was only one out-of-Africa event more than 2 million years ago in the form of Homo habilis".

As Im said, I think the situation is more likely to be complicated than simple. Movement backwards and forwards around the world has been happening since Homo Habilis/erectus/Australopithecus first emerged from Africa.

"Homo has always been just one species since it first appeared in sub-Saharan Africa nearly 2.6 million years ago. And no regional member of Homo on Earth has ever been isolated long enough for true speciation to occur".

I'm very much inclined to agree with that, but I'm also prepared to accept formation of subspecies.

"We've only tested 2 types of archaic Eurasians so far (Neandertals/Denisovans) and they've proven not to be irrelevant to the human story".

And I'm prepared to bet that if ever SE Asian Homo erectus is tested we'll find a third type not irrelevant to the human story. And possibly so for East Asia Homo erectus as well.

"where are the YDNA or MTDNA haplogroups related to them? Have they got extinct in homo sapiens too?"

Haplogroups tend to be replaced more readily that does aDNA. When a particular haplogroup enters a region it will as often as not breed with residents. The offspring carry the relevant haplogroup but only half of the incoming aDNA. Information regarding cattle breeding demonstrates this remarkably well.

"Selection is a more promising hypothesis, but there's really no specific evidence for it".

Selection is actually likely, but not necessarily genetic selection. Any improved technology will tend to be passed on to sons or nephews at the expense of others, leading to expansion of Y-DNA. Any improved cultural elements will tend to be passed on the daughters or nieces at the expanse of others, leading to expansion of mt-DNA.

German Dziebel said...

@ Carlos

"it seems strange, to say the least, that ALL Neanderthal-related YDNA and MTDNA lines went extinct..."

I doubt they did. The problem lies in the biased mtDNA and Y-DNA phylogenies that have been widely circulated. For example, human mtDNA 16278 and 16223 sites carry the same T allele in the so-called "haplogroup X" as the 3 Neanderthal sequences from Germany, Croatia and the Caucasus. Site 16189 carries a C in human "haplogroup X" exactly like in the 3 Neanderthal sequences. It's assumed that evolution in the human tree went from C > T but it could've gone T > C, or human mtDNA haplogroup X could've been introgressed from Neanderthals.

These sites are hypervariable in humans but fixed in Neanderthals. See Hagelberg 2003 "Recombination or mutation rate heterogeneity" for an interesting discussion.

Carlos said...

@ German Dziebel

Thank you for your comment, fascinating! I'll have to read more about the topic..

Baldric said...

Can it be that a single interbreeding event happened in Arabia within the proto-eurasian tribe, that then spread the genes?
A halfling man who had a daughter.

No more allosomes, and a decent percentage of neanderthal genes to spread into the tribe.


Suppose somewhere in human genomes lie TWO variations that come from neanderthals, that would certainly be a problem. But it is much more a problem to explain why thousands of admixture events left no neanderthal mt/y dna.

David said...

To my knowledge there is more genetic distance between a Neanderthal and Human than Chimpaneze and Human.

Chimpanezes and Humans cannot interbreed. I doubt that Neanderthals and Cro Magnons could interbreed as well.

And if they could, by chance, the results would be that of a mule or a zonky, sterile offspring.

Vilhelmo said...

I found this paper on Human/Neanderthal admixture theory, specifically on the Genomic DNA Sequences:
"Inconsistencies in Neanderthal Genomic DNA Sequences"
http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030175

Although I am not competent to judge the merits if the paper, I found their adstract telling.

"Two recently published papers describe nuclear DNA sequences that were obtained from the same Neanderthal fossil. Our reanalyses of the data from these studies show that they are not consistent with each other and point to serious problems with the data quality in one of the studies, possibly due to modern human DNA contaminants and/or a high rate of sequencing errors."