# Population Genetics > mtDNA Haplogroups >  neandertal signitures in human mtdna

## kingjohn

truly amazing ......

http://www.biorxiv.org/content/early/2017/09/18/190363

:)

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## I1a3_Young

Am I reading this wrong or are a handful of those Neanderthals mtDNA haplo H1?

Also, the bank of mondern mtDNA from the phylotree database used to compare is woefully sparse. They chose H1a1, H3, H15, U1a1d, and U6a7a2 as the only H and U samples to compare when we have such a wide variety in Europe.

H1a1, H3, H15, and U6a7a2 (Not the U1a1d) had one of the Neanderthal-exclusive variants. Does this mean that H is older in Europe than we thought?

Since they only chose three H to test, we don't have a lot of info. I wish they would let us hobbyists replicate the calculations using all the other H and U versions.
Nmt.jpg

Also interesting:



> A back to Africa hypothesis has been proposed in which humans from Eurasia returned to Africa and impacted a wide range of sub-Saharan populations (19). Our data shows that Neandertal signatures are present in all major African haplogroups thus confirming that the Back to Africa contribution to the modern mitochondrial African pool was extensive.


Of course we did already know there has been back-migration due to J and the R1b V88 Y haplos, but they are going a step farther.

Instead of single events it was probably a flow mostly one way, but sometimes the opposite.

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## I1a3_Young

They need to run the analysis for more samples throughout human history as well. Some of that stuff seems far fetched and more calculations may help corroborate or dispel their claims.

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## Angela

Young, I didn't get that they tested only certain haplos. Maybe I missed it. Could you find the reference for me? 

Or perhaps they worked backwards, i.e. they knew which mtdna harbored the "markers" for certain diseases and then compared them to the Neanderthal sequences? 

I don't think the age of the mtDNA H in Europe is the issue. H arose in the Middle East, from everything I've ever seen, no matter when a few stray mtDna H women may have arrived in Europe, and the majority came in the Neolithic.

Very interesting that they posit that Africans have more of this Neanderthal mtDna "intrusion" because that particular mating involved an AMH male with a Neanderthal female, whereas it was the other way around in Europe. 

Are the graphs saying a lot of the Amerindian mtDna harbors the Neanderthal variant for depression, or am I reading it incorrectly?

Of course, these kinds of major traits and diseases are probably impacted by a lot of genes, so I doubt it's this simple.

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## bicicleur

I don't get it.
There must be some things in mtDNA I don't know about.
Furthermore the Gibraltar Neanderthals were redated. All European Neanderthals were extinct by ca 40 ka, that is before the Vestonice and Oberkassel anciant H. Sapiens.

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## bicicleur

> Am I reading this wrong or are a handful of those Neanderthals mtDNA haplo H1?
> 
> Also, the bank of mondern mtDNA from the phylotree database used to compare is woefully sparse. They chose H1a1, H3, H15, U1a1d, and U6a7a2 as the only H and U samples to compare when we have such a wide variety in Europe.
> 
> H1a1, H3, H15, and U6a7a2 (Not the U1a1d) had one of the Neanderthal-exclusive variants. Does this mean that H is older in Europe than we thought?
> 
> Since they only chose three H to test, we don't have a lot of info. I wish they would let us hobbyists replicate the calculations using all the other H and U versions.
> Nmt.jpg


If I understand well, this figure is an example and concerns only 1 of the 918 polymorphic positions of the human mtDNA.

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## I1a3_Young

> Comparative analysis of the mitochondrial DNA from present day humans, ancient Homosapiens and Neandertals, 52 sequences of modern human mtDNA, representing all major mitochondrial haplogroups (table S1), were selected from the PhyloTREE database (25) and downloaded from GenBank. Six ancient H. sapiens mtDNA and eight Neandertal mtDNA sequences were downloaded from GenBank (tables S1-S3).


They chose 52 modern samples for comparison of which 3 were H and 3 were U. I just noticed U2 was included in Table S1. They also have one T and three K.

Table S3 has the neanderthal mtDNA samples as H1 or L with the H1 being in Croatia, Germany, and Spain and the L in Russia/Siberia. Do they have a neander-specific tree or are they referring to AMH mtDNA tree here? If so, how can this be?

They say three positions impact IQ but don't say positively or negatively. Of the IQ positions, only some are European and the others are Asian and African. The European mtDNA that have one are T1, U2c, U1ad, V1a, V2, X3, X1a, R0a. X3 is the only European one having two of the IQ mutations.

Major depressive disorder in common with the Neanderthal mutation are these: 
U6a7a2 U1a1d, I1, C1a, C4, C7, D4, E1, G1a1, M20, M29a, M2b, M3b, M8a1, M9a, Q1, Z1

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## Maciamo

I only has a cursory look at the paper, but it seems that they did not find any Neanderthal mtDNA in any modern populations. They are comparing mutations found in Neanderthal mtDNA samples with mutations found in modern human haplogroups. If they are under the impression that they could have somehow be passed on by Neanderthal to Homo sapiens, then they should go back to school, as mtDNA does not recombine. I really don't see the point of comparing the presence of mutations between these populations.

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## I1a3_Young

> I only has a cursory look at the paper, but it seems that they did not find any Neanderthal mtDNA in any modern populations. They are comparing mutations found in Neanderthal mtDNA samples with mutations found in modern human haplogroups. If they are under the impression that they could have somehow be passed on by Neanderthal to Homo sapiens, then they should go back to school, as mtDNA does not recombine. I really don't see the point of comparing the presence of mutations between these populations.


That was the far fetched claim I was referring to. They are suggesting a major revision to our understanding of mtDNA.

Analyses presented here suggest that Neandertal genomic signatures might have been a 
product of rare mtDNA recombination events. Although there is evidence supporting mtDNA 
recombination its weight in phylogenies remain controversial. Some authors contend that due to 
its high mutation rate reverse compensatory mutations can be confounded with recombination in 
mtDNA. Our data supports a mtDNA recombination scenario in which recombination events are 
extremely rare thus producing a small number of Neandertal 
signatures.

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## Maciamo

> Very interesting that they posit that Africans have more of this Neanderthal mtDna "intrusion" because that particular mating involved an AMH male with a Neanderthal female, whereas it was the other way around in Europe.


From what I read it rather sounded like they just found more mtDNA mutations in common between Neanderthal samples and some branches of mt-haplogroup L. That's not surprising considering that early L branches are closer to the ancestral Homo sapiens, and therefore phylogenetically closer to Neanderthal than N and M. But if that's what they mean, that is meaningless and absolutely does not suggest Neanderthal introgression among Africans.

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## Maciamo

> That was the far fetched claim I was referring to. They are suggesting a major revision to our understanding of mtDNA.
> 
> Analyses presented here suggest that Neandertal genomic signatures might have been a 
> product of rare mtDNA recombination events. Although there is evidence supporting mtDNA 
> recombination its weight in phylogenies remain controversial. Some authors contend that due to 
> its high mutation rate reverse compensatory mutations can be confounded with recombination in 
> mtDNA. Our data supports a mtDNA recombination scenario in which recombination events are 
> extremely rare thus producing a small number of Neandertal 
> signatures.


So they really do think that mtDNA can recombine! That's not good publicity for the Federal University of Sao Paulo (not that it was very high to start with). If that get published that's the end of their career.

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## bicicleur

> I only has a cursory look at the paper, but it seems that they did not find any Neanderthal mtDNA in any modern populations. They are comparing mutations found in Neanderthal mtDNA samples with mutations found in modern human haplogroups. If they are under the impression that they could have somehow be passed on by Neanderthal to Homo sapiens, then they should go back to school, as mtDNA does not recombine. I really don't see the point of comparing the presence of mutations between these populations.


that is what I taught
but what are the chances of the same mutations in mtDNA happening in both independant modern human and Neanderthal branches?
they claim there are only 918 polymorphic positions of the modern human/Neanderthal mtDNA
some of the data they present here must be wrong

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## Angela

From a quick search for papers on mtDna recombination:

This is sort of a summary:
http://www.nature.com/hdy/journal/v9.../6800572a.html

"Over the last 5 years, there has been considerable debate as to whether there is recombination in human mitochondrial DNA (mtDNA) (for references, see Piganeau and Eyre-Walker, 2004). That debate appears to have finally come to an end with the publication of some direct evidence of recombination. Schwartz and Vissing (2002), 2 years ago, presented the case of a 28-year-old man who had both maternal and paternally derived mtDNA in his muscle tissue – in all his other tissues he had only maternally derived mtDNA. It was the first time that paternal leakage and, consequently, heteroplasmy was observed in human mtDNA. In a recent paper, Kraytsberg _et al_ (2004) take this observation one step further, and claim to show that there has been recombination between the maternal and paternal mtDNA in this individual.There is a major possibility, in experiments of this nature, that the recombinants have been produced in laboratory, either by PCR, or by some other mistake. However, the authors have gone to great lengths to ensure that the recombinants are genuine, including repeating the experiment with a mix of maternal and paternal mtDNAs. They did not observe any recombination in this latter experiment, so we can be very confident that recombinants that they detected in the muscle tissue are genuine.
The direct demonstration of recombination in human mtDNA has a number of important implications. First, the results show that recombination between maternal and paternal mtDNA is possible. It has been known for sometime that paternal mtDNA enters the egg in humans (see Cummins, 2000), and that mammalian mitochondria contain the enzymes necessary to promote homologous recombination (Thyagarajan _et al_, 1996). However, there are efficient mechanisms that target paternal mtDNA for destruction once it is in the egg (Sutovsky _et al_, 2000), and there is no evidence that different mtDNAs would ever have the chance to recombine. If different mtDNAs are introduced into the same cell in different mitochondria, can be maintained in that state for many generations, without ever appearing in the same mitochondria (Enriquez _et al_, 2000).
Second, the results suggest that human mitochondria have an active recombination pathway. Human mtDNA has a high rate of evolution and this has been attributed to a lack of repair enzymes (Brown, 2001). The possibility of a recombination pathway suggested by these current results may also provide a further reason."

"Although Kraytsberg _et al_ (2004) show very clear evidence of crossing-over in human mtDNA, there is little or no population genetic evidence of recombination. How can this be? There are two possibilities. One possibility is that, although Kraytsberg _et al_ (2004) have detected recombination in a somatic tissue, it never occurs in the germ line. This seems unlikely, however. Alternatively, the explanation may be that recombination is difficult to detect in population genetic data, even if it is occurring at appreciable frequencies. This is because all methods for detecting recombination have low statistical power."

Kraytsberg et al:
http://science.sciencemag.org/content/304/5673/981

Later papers:
https://www.researchgate.net/profile...nheritance.pdf

This is the most recent discussion of it I could find:
"Whether recombination occurs in human mitochondrial DNA (mtDNA) at a level significant enough to alter the evolution of the molecule, and evolutionary analysis based on mtDNA, remains contentious (Slate and Gemmell 2004; reviewed by White et al. 2008). At present, only one definitive case of mtDNA recombination has been detected using direct means (Kraytsberg et al. 2004), in a patient suffering from a mitochondrial myopathy, although the occurrence of tetraplasmy in 10 individuals who carried mutations in both coding and control regions of mtDNA (Zsurka et al. 2005), suggests recombination may be more widespread in somatic tissue. Further, an indirect observation suggests that mtDNA recombinants can reach the germ line in humans, thereby potentially becoming inheritable (Zsurka et al. 2007).

"However, mtDNA recombination has been detected in animals in similar studies (Piganeau et al. 2004; Tsaousis et al. 2005), raising the possibility that the lack of evidence for recombination in human mtDNA is not due to an absence of recombination per se, but rather the ineffectiveness of current tests to detect it."

https://academic.oup.com/mbe/article/26/7/1435/1126800/Can-Indirect-Tests-Detect-a-Known-Recombination


So, still up in the very theoretical realm, in my opinion.

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## Angela

On differential mating patterns:

"Our data is compatible with a scenario in which the AMH-Neandertal crosses occur inEuropeans, East Asians and African lines of descent. However, in the African haplogroups thecrosses between AMH males and Neandertal females would have a higher frequency than inEuropean lines of descent, where the reverse crosses would be predominant. Based on thecomparison of Neandertal signatures in nuclear and mitochondrial genome haplogroups wehypothesize that the African lines of descent would have a higher female Neandertal contribution whereas European lines of descent would have higher male Neandertal contribution."

Maybe I'm not getting their point, but wouldn't this be a more parsimonious explanation? Not that they'd be able to prove it.

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## Expredel

> that is what I taught
> but what are the chances of the same mutations in mtDNA happening in both independant modern human and Neanderthal branches?
> they claim there are only 918 polymorphic positions of the modern human/Neanderthal mtDNA
> some of the data they present here must be wrong


If the split was 600,000 years there should be about 75 mutations differentiating the two lineages.

The chance of having 1 mutation in common with Neanderthal is about 0.5%. 

They however used 8 Neanderthal mtDNAs and 52 divergent human mtDNAs. This totaled up to 250 Neanderthal mutations and 843 human mutations if I read it correctly. Most of those mutations would be African as their mtDNA is more divergent. The expected overlap would be 15 mutations but they found 75.

One (obvious) explanation is that mtDNA mutates more rapidly than expected but that most of these mutations are deleterious.

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## Maciamo

> From a quick search for papers on mtDna recombination:
> This is sort of a summary:
> http://www.nature.com/hdy/journal/v9.../6800572a.html
> "Over the last 5 years, there has been considerable debate as to whether there is recombination in human mitochondrial DNA (mtDNA) (for references, see Piganeau and Eyre-Walker, 2004). That debate appears to have finally come to an end with the publication of some direct evidence of recombination. Schwartz and Vissing (2002), 2 years ago, presented the case of a 28-year-old man who had both maternal and paternally derived mtDNA in his muscle tissue – in all his other tissues he had only maternally derived mtDNA. It was the first time that paternal leakage and, consequently, heteroplasmy was observed in human mtDNA. In a recent paper, Kraytsberg _et al_ (2004) take this observation one step further, and claim to show that there has been recombination between the maternal and paternal mtDNA in this individual.There is a major possibility, in experiments of this nature, that the recombinants have been produced in laboratory, either by PCR, or by some other mistake. However, the authors have gone to great lengths to ensure that the recombinants are genuine, including repeating the experiment with a mix of maternal and paternal mtDNAs. They did not observe any recombination in this latter experiment, so we can be very confident that recombinants that they detected in the muscle tissue are genuine.


Odd that all these papers date from 1996 to 2004. My interest in mtDNA and population genetics started in 2008, so everything I learned since should mention the possibility of mtDNA recombination if these studies were trustworthy and replicable. Yet I have always read (including from recent Harvard and MIT courses) that germline mtDNA doesn't recombine. In fact, that is the basis for mtDNA phylogeny and the whole maternal inheritance line. If recombinations were possible and did happen once in a while, then how could we possibly use mtDNA to trace back maternal ancestry? 

They mention heteroplasmy, i.e. the presence of different types of mtDNA within an individual. This is known to be true, but doesn't prove that maternal and paternal mtDNA can recombine in the germline. Paternal mtDNA can occasionally survive inside the ovum, but the two types of mtDNA coexist side by side. Recombination requires meiosis and chromosomes. Mitochondria are bacteria-like and therefore lack sexual reproduction with recombination. They just divide and inherit their DNA unchanged. In fact, we have seen from ancient DNA samples that some mtDNA lineages have survived without the slightest de novo mutation since the Neolithic (deep clades like N1a1a1a2, H1e1a2, K1a3a3, K1a4a1a2, U5b2a5 or U5b2a2c). 

We could argue that mitochondria swap genes like bacteria, but that would be whole genes, not single point mutations. They do not provide any evidence of that and I haven't seen any mt-haplogroup that suddenly seem to have inherited a whole block of mutations in the same gene from another haplogroup. For example, could there have been a swap of the Coenzyme Q - cytochrome c reductase gene located between positions 14,747 and 15,887 in the mtDNA sequence? This would mean that one mtDNA deep clade suddenly gets reverse mutation for all the accumulated mutations between these positions and get new ones from a completely different haplogroup clade in exchange. Never seen that (but I admit that I didn't actively look for such swaps).

Back to the case of Neanderthal mtDNA swapping genes with H. sapiens mtDNA, that would leave much more obvious traces as the two sets of mtDNA evolved for 600,000 years separately and would have accumulated a lot of diverging mutations. It's much easier to explain those shared mutations as coincidences due to chance mutations that were positively selected due to their beneficial effects in a similar environment (Western Europe in this case). It's all the more likely for the mutations they listed that fall in the hypervariable region (high mutation rate) such as 195, 16093, 16129, 16189 and especially 16183 and 16519, two positions that are so unstable they are known to vary between cells in a same individual, which is why they aren't even used in the mtDNA phylogeny.

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## bicicleur

furthermore the study doesn't mention paternal intrusion in the mtDNA, they explicitely mention maternal mtDNA inheritance :

It has been proposedhowever that there is no contribution of Neandertal mitochondrial DNA to contemporary humangenomes (7). Because of mtDNA matrilineal inheritance this implies that the all intercrossesoccurred between Neandertal males and AMH females. Another possibility is that crossesbetween AMH males and Neandertal females were either extremely rare or yet, produced suchunfavorable traits, via mitonuclear incompatibility (8), that none of its descendants left marks inpresent day human populations.

I don't understand what they mean by this phrasing. As if contribution of Neandertal Y-DNA to contemporary human genomes does exist?

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## bicicleur

> Back to the case of Neanderthal mtDNA swapping genes with H. sapiens mtDNA, that would leave much more obvious traces as the two sets of mtDNA evolved for 600,000 years separately and would have accumulated a lot of diverging mutations. It's much easier to explain those shared mutations as coincidences due to chance mutations that were positively selected due to their beneficial effects in a similar environment (Western Europe in this case). It's all the more likely for the mutations they listed that fall in the hypervariable region (high mutation rate) such as 195, 16093, 16129, 16189 and especially 16183 and 16519, two positions that are so unstable they are known to vary between cells in a same individual, which is why they aren't even used in the mtDNA phylogeny.


That is a possible explanation, but remains to be proven.
If there is positive selection of certain mtDNA mutations whilst others would be deleterious, that would be interesting news to be investigated further.

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