A complete Neandertal mtDNA genome

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In 1997 the first successful extraction of Neandertal DNA was announced to great fanfare (Krings et al. 1997). This DNA was not from the nuclear DNA (from cell nuclei) which determines most of our physical characteristics, but mitochondrial DNA (mtDNA) from the small energy-producing organelles which are inside all of our cells 1. It so happens that mtDNA is easier to extract from ancient bones than is nuclear DNA. Krings et al reconstructed a 379 base sequence from the Neandertal mtDNA, out of the full mtDNA length of more than 16,000 bases. Since then, many other researchers have also extracted mtDNA sequences from Neandertal bones (and one team has even recovered some nuclear DNA).

Now, for the first time, a complete mtDNA sequence has been recovered, from a 38,000 year old Neandertal fossil from the Vindija cave in Croatia. The results were published in August 2008 in the journal Cell: A Complete Neandertal Mitochondrial Genome Sequence Determined by High-Throughput Sequencing (Green et al. 2008).

Here is one of the most important conclusions from the paper’s summary:

Green et al. 2008 Wrote:

Analysis of the assembled sequence unequivocally establishes that the Neandertal mtDNA falls outside the variation of extant human mtDNAs, and allows an estimate of the divergence date between the two mtDNA lineages of 660,000 ± 140,000 years.

The Neandertal mtDNA sequence was compared with mtDNA from chimpanzees and 53 modern humans. The human mtDNA sequences had between 2 and 118 differences from each other. The number of differences between the human mtDNAs and the Neandertal mtDNA varied from 201 to 234. This graph shows the differences between the human, Neandertal and chimp groups, and the human group:

fullmtdnacomp.jpg

Green: human/human; Red: human/N’tal; Blue: human/chimp. 2
X axis, the number of sequence differences
Y axis, the fraction of pairwise comparisons. (Green et al. 2008)

This is not unexpected; it confirms the conclusion from the earlier Krings et al. 1997 paper (you can see the equivalent graph from that paper here). In that paper, the 994 human sequences had between 1 and 24 differences from each other (over a partial mtDNA sequence). The number of differences between the human sequences and the Neandertal sequence varied from 22 to 36. Because the minimum distance between any human and the Neandertal (22) was slightly less than the maximum distance between any two modern humans (24), some creationists (e.g. Lubenow 1998) misinterpreted these figures to claim that the 1997 Neandertal mtDNA was within the modern human range. (It was a misinterpretation because it was comparing apples (a minimum distance between N’tals and any human) with oranges (a maximum distance between any two humans)). As an alternative explanation of the data, Lubenow suggested that maybe early humans formed a large population which had far greater genetic variability, most of which had since been lost. This was, at the time, a conceivable conjecture, though not one I would have wanted to bet on. But further study has disproved it; all the subsequent Neandertal mtDNA sequences which have been recovered have been similar to each other, and dissimilar to modern humans.

Now that we have a complete Neandertal mtDNA genome, the distinction between the Neandertal and modern human mtDNA is even more striking. It strengthens the view that Neandertals should be designated a separate species Homo neanderthalensis, because even if they could interbreed with the ancestors of modern humans (and they probably could, and possibly did on occasion 3) there does not seem to have been a significant amount of genetic interflow happening between the two populations. We don’t find Neandertal mtDNA in modern humans, and vice versa. Humans and Neandertals seem to have split off around 600,000 years ago and developed separately thereafter.

For a more in-depth analysis of this paper, see John Hawks’ blog entry Complete Neandertal mitochondrial sequence, and selection on human (not Neandertal) mtDNA.

Footnotes

1. mtDNA also has the intruiging property that it is always (or almost always; there is some dispute over this) inherited only from the mother, and not the father. This means that it is useful for determining relationships through maternal lines.

2. The graph shows the Neandertal group between the human and chimp groups. This does not mean that Neandertals are intermediate between humans and chimps. In fact, both are about equally distant from chimps (which is what we would expect from evolutionary theory). The Neandertal group is in the middle because the graph compares each group with modern humans. If instead it had compared each group with the Neandertal mtDNA, then the human group would have been between the Neandertals and the chimps.

3. Just because two individuals can breed does not mean they belong to the same species. Although there are many competing concepts as to what constitutes a 'species', usually it is considered to be a population of individuals that successfully interbreed in the wild. Populations that could interbreed in theory but don't in practice are therefore different species.

References

Krings M., Stone A., Schmitz R.W., Krainitzki H., Stoneking M., and Pääbo S. (1997): Neandertal DNA sequences and the origin of modern humans. Cell, 90:19-30.

Green R., Malaspinas A-S, Krause J., Briggs A., et al. (2008) A Complete Neandertal Mitochondrial Genome Sequence Determined by High-Throughput Sequencing. Cell, 134:416-426.

Lubenow M. (1998), Recovery of Neandertal mtDNA: an evaluation. Technical Journal, 12(1):87-97

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64 Comments

Personally, I think this is fascinating. I wonder what we can learn about these extinct cousins of ours just from the mtDNA. It’s amazing to think we went from mediocre mtDNA fragments to a full sequence in just over a decade.

Of course, AiG will probably just put a little blurb in their “News to Note” about how this evidence is biased by evolutionary preconceptions or similar nonsense. Ah well, we’ll let the little bugs dance on the end of the stick, it doesn’t change the fact that we skewered ‘em.

Gentlemen, on the basis of this news, let me be the first to proudly say: “I ain’t no kin to no Neandertal.”

Can I ask what will seem to the geneticists here a very stupid question?

On the basis of this new evidence - as we have it - would this mean that the Neaderthals are a different species to us? So that the genus Homo would be made up of at least four species, three of them extinct: sapiens, neanderthalis, erectus and habilis (ergastor)?

Dave Luckett said:

Can I ask what will seem to the geneticists here a very stupid question?

On the basis of this new evidence - as we have it - would this mean that the Neaderthals are a different species to us? So that the genus Homo would be made up of at least four species, three of them extinct: sapiens, neanderthalis, erectus and habilis (ergastor)?

That depends on which definition (the number of which exceeds the number of species) of species you use.

Even if you use a particular definition of ‘species’, it’s damn near impossible to say how many species of humans existed. Are sapiens, neanderthalensis, antecessor, erectus, ergaster, heidelbergensis, habilis and rudolfensis all different species? You can’t easily apply the definition given above (or any definition) to species known only from scanty fossil remains. And genera don’t have fixed boundaries in any case - some people would put habilis and rudolfensis in the genus Australopithecus.

I just realised that it is a stupid question, since it is actually asking to draw a boundary that doesn’t really exist as a boundary, a line.

It’s like the boundary between sea and land. Where do you draw it? At the bottom of the tide, or the top? Where the highest waves break or along the points that are always covered? Is that tidal lagoon part of the sea or not? Is that half-tide rock an island?

But if the boundary can’t be drawn as a line, does that mean that there is no meaning to the terms “land” and “sea”? Of course not.

Dave Luckett said:

It’s like the boundary between sea and land. Where do you draw it? At the bottom of the tide, or the top? Where the highest waves break or along the points that are always covered?

Now *those questions actually have answers.… Where do you draw the line? It depends on what coast you’re on. On East and Gulf Coasts of the US, the line is drawn at mean low water (the average height of all low tides). On the West Coast of the US, the line is drawn at mean lower low water (the average of the lower low tide on each day). This is, by the way, why you can get a low tide with a negative value, though it’s less common on the West Coast than on the East or Gulf Coasts.

The point is that the line is drawn because of a convention that has been agreed to. That convention is perfectly reasonable, but it is a convention. The fact that a different convention has been adopted for the two coasts is a demonstration that we are dealing with a human construction, not a division that exists in nature. The same for species. Where we draw the dividing line depends on a human convention, not on nature.

Jim Foley Wrote:

2. The graph shows the Neandertal group between the human and chimp groups. This does not mean that Neandertals are intermediate between humans and chimps. In fact, both are about equally distant from chimps (which is what we would expect from evolutionary theory). The Neandertal group is in the middle because the graph compares each group with modern humans. If instead it had compared each group with the Neandertal mtDNA, then the human group would have been between the Neandertals and the chimps.

That cannot be overemphasized. I have asked people such questions, and they usually get them wrong. The reason is that they think “ladder” not “tree.” I can recall thinking that way too.

Frank J said: That cannot be overemphasized. I have asked people such questions, and they usually get them wrong. The reason is that they think “ladder” not “tree.” I can recall thinking that way too.

Agreed!

Lets complete the trio. How would the graph look if it had compared each homo group to chimps?

Frank J said:

Jim Foley Wrote:

2. The graph shows the Neandertal group between the human and chimp groups. This does not mean that Neandertals are intermediate between humans and chimps. In fact, both are about equally distant from chimps (which is what we would expect from evolutionary theory). The Neandertal group is in the middle because the graph compares each group with modern humans. If instead it had compared each group with the Neandertal mtDNA, then the human group would have been between the Neandertals and the chimps.

That cannot be overemphasized. I have asked people such questions, and they usually get them wrong. The reason is that they think “ladder” not “tree.” I can recall thinking that way too.

eric said:

Lets complete the trio. How would the graph look if it had compared each homo group to chimps?

Oops, never mind, Jim already answered that; they’re approximately equidistant.

Dave,

The answer to your question is absolutely yes:

Dave Luckett said:

Can I ask what will seem to the geneticists here a very stupid question?

On the basis of this new evidence - as we have it - would this mean that the Neaderthals are a different species to us? So that the genus Homo would be made up of at least four species, three of them extinct: sapiens, neanderthalis, erectus and habilis (ergastor)?

Human evolutionary history is quite complicated to say the least.

John

Frank J said:

That cannot be overemphasized. I have asked people such questions, and they usually get them wrong. The reason is that they think “ladder” not “tree.” I can recall thinking that way too.

Neanderthals are not intermediate between humans and chimps. However, that is not the only possible misinterpretation of the graph.

The graph appears to indicate that the distribution among humans is rather wide as compared both to the Neanderthal group and to the chimpanzee group. This was exactly my first impression. I thought that it was due to the limited number of individuals (one?) in the Neanderthal group, but surely there should be mtDNA available from chimps.

Only later I realized that this graph does not tell much about the variation within the Neanderthal group (in this study), or about the variation within modern chimpanzees. It tells that the locations in mtDNA that differ between two human individuals are likely to be different between any human and either a Neanderthal or a chimp.

The graph does tell, however, that the distance between humans and chimps is about tenfold compared to the distance between any two humans.

We still need a study of mtDNA from late Homo erectus in Asia (which, despite the species name, may be just as far removed evolutionarily from early Home erectus as Neanderthals and modern humans).

Has someone sent a PDF over to the DI? Since they don’t bother with such unfruitful activities as actually reading the literature, they probably aren’t aware yet. I can’t wait to hear their (and AiG’s) response to this.

KP, AIG has already commented on prior mitochrondial DNA studies of neanderthals( http://www.answersingenesis.org/tj/[…]i1/mtdna.asp ) I suspect they will rehash the points made there.

Now onto more substantative issues: Can someone explain why mitochrondial DNA is easier to recover than nucleic DNA? There’s no obvious reason to the non-experts like me. The only thing that occurred to me is there are many copies of the same mitochrondrial DNA in each given cell but it isn’t clear to me that will be substantial enough to make a difference.

We have to be careful when comparing modern sequences to ancient sequences. The proper comparison is not between Neanderthals and present humans, but rather between Neaderthals and the our ancestors that are contemporaneous with them. Due to the process of coalescence our mt genomes can (and will) be rather divergent from our ancestors, therefore it is difficult to draw conclusions without the additional information about what the variation in our ancestors was like as well.

Very cool article. Some pop-sci questions for the experts:

1) What is the likelihood that nuclear Neanderthal DNA will ever be sequenced in full (is it “just a matter of time”, or are there obstacles which might conceivably leave the Neanderthal genome lost to history)?

2) If Neanderthal DNA were sequenced, would there be ethical objections to cloning one?

3) Is there archaeological reason to expect the Neanderthal to have significantly less (or approximately the same) cognitive capacity / language skills of Homo sapiens?

Kevin said:

Very cool article. Some pop-sci questions for the experts:

3) Is there archaeological reason to expect the Neanderthal to have significantly less (or approximately the same) cognitive capacity / language skills of Homo sapiens?

The likely answer is that they were probably pretty comparable to us. They had a complex clan structure and intentional burial of the dead (and perhaps a belief in the afterlife) and similarities in the FOXP2 gene suggest that they possessed complex language skills like our own.

http://www.cell.com/current-biology[…]2(07)02065-9

re Kevin

until 1983 or so it was believed that Neanderthals could not possibly have similar language skills vs. H. sapiens - because there were no examples of Neanderthal hyoid bones; essential for fine motor control of larynx and tongue. An example of a Neanderthal hyoid was found in 1983 and it is very similar to the hyoid in H. sapiens. Between this evidence and brain case casts there is currently no reason not to believe that Neanderthals (at least anatomically) had vastly different cognitive/ language capabilities. There does seem to big vast cultural differences between Neanderthal and H. sapiens populations that were contemporaneous- there are not many examples of Neanderthal art for example.

Kevin said:

1) What is the likelihood that nuclear Neanderthal DNA will ever be sequenced in full (is it “just a matter of time”, or are there obstacles which might conceivably leave the Neanderthal genome lost to history)?

2) If Neanderthal DNA were sequenced, would there be ethical objections to cloning one?

3) Is there archaeological reason to expect the Neanderthal to have significantly less (or approximately the same) cognitive capacity / language skills of Homo sapiens?

1. A fair chance, I think. As is said, some nuclear Neandertal DNA has already been sequenced, by Green and his team in fact. That was a sequence of over a million base pairs, and somewhere recently I read they’re working on the full nuclear Neandrtal genome.

2. I think you’d have the exact same ethical considerations as with cloning a modern human.

3. Opinions differ. Neandertals used fire, make sophisticated tools, would have been able to talk and make clothes, buried their dead, so are undoubtedly human in many respects. However they don’t seem to have been as innovative with tools, or have done much in the way of art, so there’s a widespread suspicion, which I cautiously share, that they weren’t quite as smart or inventive as modern humans.

Kevin said:

Very cool article. Some pop-sci questions for the experts:

1) What is the likelihood that nuclear Neanderthal DNA will ever be sequenced in full (is it “just a matter of time”, or are there obstacles which might conceivably leave the Neanderthal genome lost to history)?

I heard the senior author Svante Paabo (sorry I don’t know how to add umlauts to the two “a”s) talk about this work this past October, so I can share some information about the first question - Svante said their studies show that DNA degradation and chemical modification begins immediately after death and that all the DNA from an organism is completely deteriorated by one million years after death. 40,000 YO DNA is degraded to pieces averaging 70bp in length. Sequencing of Neanderthal nuclear DNA is ongoing, some work already published, but assembling a 3 billion base sequence from 70bp pieces will take time. My personal guess is that 20 fold coverage will be required to assure accuracy. Svante’s conclusion from all the completed DNA sequencing is that there was very little “mixing of DNA” (a weaker way of saying “interbreeding”) between Neanderthals and our ancestors.

Vaughn

Reed A. Cartwright Wrote:

The proper comparison is not between Neanderthals and present humans, but rather between Neaderthals and the our ancestors that are contemporaneous with them.

Another good point, if only to dispel the “ladder” misconception. Ideally the “chimp” DNA should be a ~30K year old ancestor too. But AIUI, they left few if any fossils, let alone partially preserved DNA, from that era.

I often wonder what a field day creationists would have had if for some reason other hominid/hominoid branches fossilized well and Australopithecus/Homo branches didn’t.

Yeah, I guess it’s just luck that we’re in a genus in which the odds of fossilization are apparently better than one per trillion individuals (although maybe worse than one per billion, if my rough estimates aren’t too far off).

Henry

You were just joking around, Curmudgeon, I’m sure. Still, it fascinates me to conceptualise common ancestry in terms of genealogy.

Thus, on the basis of this news, one of my many-times-great grandmothers who lived about 0.7 Mya, had a child whose descendants are known to us as Neandertals.

Given the common ancestry of all known living species on the planet, I can only conclude that you are admitting to being an alien. If so, I’d love to study this further with you. When can we schedule an autopsy? Er, I mean compete physical exam.

Now, we have to try to figure out what the common ancestral population that the 0.66 Mya mtDNA common ancestral sequence came from, and what that population might have become before the Neandertal and modern human lineages split. Was this ancestral population Homo erectus like or more Neandertal or generic Homo sapien? The question of whether we evolved from Neandertals is still open in a sense. As far as I know we do not know what that common ancestral population looked like. Comparing erectus like skulls to Neandertal and modern humans I’d expect that those common ancestors would have looked more like Neandertals than modern humans. What would their classification be?

JimF said:

2) If Neanderthal DNA were sequenced, would there be ethical objections to cloning one?

2. I think you’d have the exact same ethical considerations as with cloning a modern human.

That was my initial reaction too, but now I think its wrong. One significant ethical reservation with human reproductive cloning comes from the fact that you are intentionally choosing a reproductive method known to give a very high rate of birth defects when other less risky methods are available. So you are being unnecessarily risky and cruel; you are toying with the potential health of the child for no better reason than to stroke your own ego. And this is not like a difference between, say, a 0.001% chance and 0.01% chance. The chance of a major developmental issue from cloning is still very high (over 50%, I think) in the anmials we clone.

While I’m certain other people can list other ethical problems relevant to this case, the ethical problem with human cloning I’ve cited above is not an issue for Neanderthal because, obviously, there’s no other way to produce them.

Maternal lines… So if Neandertal women were damned ugly, Neadertal men would subsequently choose to mate with human women while human men wouldn’t even think of doing the same with Neandertal women.. And we would still see no sign of interbreeding from the mtDNA. Farfetched?

rijkswaanvijand said: So if Neandertal women were damned ugly,..

What if both women were ugly from others side of view but only sapiens had some fermented juice fruits within and he temporarily saw some very very beautiful Ne-Annes.. ? ;)

Reed A. Cartwright said:

We have to be careful when comparing modern sequences to ancient sequences. The proper comparison is not between Neanderthals and present humans, but rather between Neaderthals and the our ancestors that are contemporaneous with them. Due to the process of coalescence our mt genomes can (and will) be rather divergent from our ancestors, therefore it is difficult to draw conclusions without the additional information about what the variation in our ancestors was like as well.

Perhaps a more detailed explanation of the impact of “coalescence” on the data would clarify Reed’s comment, but why don’t we have mtDNA sequences from a sufficiently wide sample of anatomically modern humans such that we can, in effect, “correct” for this lack of contemporaneity?

Realizing that both anatomically modern humans and Neanderthals go further back in time, let’s still draw the “contemporaneous” horizon at 40,000 to 50,000 BP, representing the period of maximum “overlap” in the respective Eurasian ranges of the two hominids.

Doesn’t the modern human genome contain representative samples of the diversity of that era? After all, Australian aborigines probably took their ancestral copies of human mtDNA into pretty complete isolation > 40 kya, emerging from that isolation only within the last several centuries, a genetic eyeblink. Likewise for the bulk of native americans, who were isolated from the rest of human mtDNA diversity for between 10k and 35k years, depending on which archaeologist you listen to… And subSaharan African mtDNA was relatively isolated from the OoA mtDNA for much of the past 50-60 k years (whence the double peak) – or, perhaps better put, the OoA groups that budded off, and rebudded, and rebudded, from the subSaharan core population, obtained relative isolation from that parental population…

So we have extant populations that effectively split from the parental population, and which went into relatively complete isolation until the Age of “Discovery.” And those lineage splits date back more than 10 ky, and as far back as 40-50-60 ky. Accepting that the mtDNA of all these populations has continued to evolve and differentiate over the interim, one would still think that an ancestral anatomically-modern-human mtDNA genome could be reconstructed for approximately 40 to 60 kya?

And that this reconstructed genome could be usefully compared with the (admittedly much more limited) sample of Neanderthal mtDNA from roughly the same time period.

And, effectively, by modelling the present human variability, isn’t that what this the current paper’s authors have done?

“However they don’t seem to have been as innovative with tools, or have done much in the way of art, so there’s a widespread suspicion, which I cautiously share, that they weren’t quite as smart or inventive as modern humans.” —

How is this any different from saying that humans from cultures that did not use wheels are not as “smart or inventive” as humans from cultures that used wheels?

Without hard, compelling evidence, this sounds like suspiciously like cultural prejudice.

What if their art was using materials that don’t last for thousands of years? In that case we wouldn’t know about it.

Doug Watts said: How is this any different from saying that humans from cultures that did not use wheels are not as “smart or inventive” as humans from cultures that used wheels?

Without hard, compelling evidence, this sounds like suspiciously like cultural prejudice.

Henry J said: What if their art was using materials that don’t last for thousands of years? In that case we wouldn’t know about it.

These objections are why I’m cautious. But, if they were doing art, you’d think they’d have done some of it in durable materials over the course of a couple of hundred thousand years. Ditto, if they really were as inventive as modern humans, you’d think there’d be some sign of it, somewhere, somewhen. Recent cultures that didn’t use wheels did demonstrate their ingenuity in other ways. Not that Neandertals were without it, but the evidence is indicative (I agree, not conclusive!) to me that they weren’t quite on a par with modern humans.

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