# Population Genetics > Paleogenetics > Paleolithic & Mesolithic >  A high-coverage Neandertal genome from Vindija Cave in Croatia

## Jovialis

Here's the full paper:

Looks like they've released the paper to the public now:

http://science.sciencemag.org/conten...cience.aao1887




> *Abstract*
> 
> To date the only Neandertal genome that has been sequenced to high quality is from an individual found in Southern Siberia. We sequenced the genome of a female Neandertal from ~50 thousand years ago from Vindija Cave, Croatia to ~30-fold genomic coverage. She carried 1.6 differences per ten thousand base pairs between the two copies of her genome, fewer than present-day humans, suggesting that Neandertal populations were of small size. Our analyses indicate that she was more closely related to the Neandertals that mixed with the ancestors of present-day humans living outside of sub-Saharan Africa than the previously sequenced Neandertal from Siberia, allowing 10-20% more Neandertal DNA to be identified in present-day humans, including variants involved in LDL cholesterol levels, schizophrenia and other diseases.
> 
> 
> Neandertals are the closest evolutionary relatives identified to date of all present-day humans and therefore provide a unique perspective on human biology and history. In particular, comparisons of genome sequences from Neandertals with those of present-day humans have allowed genetic features unique to modern humans to be identified (_1_, _2_) and have shown that Neandertals mixed with the ancestors of present-day people living outside sub-Saharan Africa (_3_). Many of the DNA sequences acquired by non-Africans from Neandertals were likely detrimental and were purged from the human genome via negative selection (_4_–_8_) but some appear to have been beneficial and were positively selected (_9_); among people today, alleles derived from Neandertals are associated with both susceptibility and resistance to diseases (_7_, _10_–_12_).
> However, our knowledge about the genetic variation among Neandertals is still limited. To date genome-wide DNA sequences of five Neandertals have been determined. One of these, the “Altai Neandertal”, found in Denisova Cave in the Altai Mountains in southern Siberia, the eastern-most known reach of the Neandertal range, yielded a high quality genome sequence (~50-fold genomic coverage) (_2_). In addition, a composite genome sequence from three Neandertal individuals has been generated from Vindija Cave in Croatia in southern Europe but is of low quality (~1.2-fold total coverage) (_3_), while a Neandertal genome from Mezmaiskaya Cave in the Caucasus (_2_) is of even lower quality (~0.5-fold coverage). In addition, chromosome 21 (_13_) and exome sequences (_14_) have been generated from a different individual from Vindija Cave and one from Sidron Cave in Spain. The lack of high-quality Neandertal genome sequences, especially from the center of their geographical range and from the time close to when they were estimated to have mixed with modern humans, limits our ability to reconstruct their history and the extent of their genetic contribution to present-day humans.
> Neandertals lived in Vindija Cave in Croatia until relatively late in their history (_3_, _15_). The cave has yielded Neandertal and animal bones, many of them too fragmentary to determine from their morphology from what species they derive. Importantly, DNA preservation in Vindija Cave is relatively good and allowed the determination of Pleistocene nuclear DNA from a cave bear (_16_), a Neandertal genome (_3_), exome and chromosome 21 sequences (_13_, _14_).
> To generate DNA suitable for deep sequencing, we extracted DNA (_17_) and generated DNA libraries (_18_) from 12 samples from Vindija 33.19, one of 19 bone fragments from Vindija Cave determined to be of Neandertal origin by mitochondrial (mt) DNA analyses (_19_). In addition, 567 mg (mg) were removed for radiocarbon dating and yielded a date of greater than 45.5 thousand years before present (OxA 32,278). One of the DNA extracts, generated from 41 mg of bone material, contained more hominin DNA than the other extracts. We created additional libraries from this extract, but to maximize the number of molecules retrieved from the specimen we omitted the uracil-DNA-glycosylase (UDG) treatment (_20_, _21_). A total of 24 billion DNA fragments were sequenced and approximately 10% of these could be mapped to the human genome. Their average length was 53 base pairs (bp) and they yielded 30-fold coverage of the approximately 1.8 billion bases of the genome to which such short fragments can be confidently mapped.
> ...


//

http://science.sciencemag.org/content/early/2017/10/04/science.aao1887.full

Looks like its behind a paywall.

But here's the article I read that linked it.




> http://www.sciencemag.org/news/2017/...e-offers-clues
> 
> The insult "You're a Neandertal!" has taken on dramatic new meaning in the past few years, as researchers have begun to identify the genes many of us inherited from our long-extinct relatives. By sequencing a remarkably complete genome from a 50,000-year-old bone fragment of a female Neandertal found in Vindija Cave in Croatia, researchers report online today in_Science_ a new trove of gene variants that living people outside of Africa obtained from Neandertals. Some of this DNA could influence cholesterol levels, the accumulation of belly fat, and the risk of schizophrenia and other diseases.The genome is only the second from a Neandertal sequenced to such high quality that it can reliably reveal when, where, and what DNA was passed from Neandertals to modern humans—and which diseases it may be causing or preventing today. "It's really exciting because it's more than two times better to have two Neandertal genomes," says evolutionary genomicist Tony Capra of Vanderbilt University in Nashville.
> The first Neandertal genome was a composite drawn from three individuals from Vindija Cave. Then, over the past few years, ancient DNA researchers sequenced two more Neandertal genomes, including another high-quality sequence from an individual that lived 122,000 years ago in the Altai Mountains of Siberia. Together, the genomes showed that living Europeans and Asians carry traces of DNA from Neandertals who mated with members of _Homo sapiens_ soon after our species left Africa. (Most Africans lack Neandertal DNA as a result.)
> 
> A key question has been: What does this archaic DNA do in living humans? Drawing largely on the Altai genome, researchers have published on about two dozen Neandertal gene variants that influence living humans' risk of allergies, depression, blood clots, skin lesions, immunological disorders, and other diseases.
> 
> In a separate study published in the _American Journal of Human Genetics_ today, Janet Kelso of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and her team scanned more detail genetic and physical trait data from more than 112,000 participants in the UK Biobank pilot study to find out what Neandertal DNA they had inherited. *They report that the Neandertal genes (drawn from the Altai Neandertal) influence how people respond to sunlight exposure, such as how easily they tan, their hair color, sleep patterns, and mood.*
> 
> ...

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## Angela

Two in one day on Neanderthals. This one is from the Eske group.

It's hard to know if there's disagreement since we only have access to one

http://www.cell.com/ajhg/fulltext/S0002-9297(17)30379-8

"*The Contribution of Neanderthals to Phenotypic Variation in Modern Humans"*
Michael Dannemann et al


"Assessing the genetic contribution of Neanderthals to non-disease phenotypes in modern humans has been difficult because of the absence of large cohorts for which common phenotype information is available. Using baseline phenotypes collected for 112,000 individuals by the UK Biobank, we can now elaborate on previous findings that identified associations between signatures of positive selection on Neanderthal DNA and various modern human traits but not any specific phenotypic consequences.* Here, we show that Neanderthal DNA affects skin tone and hair color, height, sleeping patterns, mood, and smoking status in present-day Europeans. Interestingly, multiple Neanderthal alleles at different loci contribute to skin and hair color in present-day Europeans, and these Neanderthal alleles contribute to both lighter and darker skin tones and hair color, suggesting that Neanderthals themselves were most likely variable in these traits*."

" Strikingly, more than half of the significantly associated alleles that we identified are related to skin and hair traits, consistent with previous evidence that genes associated with skin and hair biology are over-represented in introgressed archaic regions."

"The strongest association we found in this study was an archaic allele under-represented among red-haired individuals. This archaic allele is on an introgressed haplotype composed of 71 aSNPs and encompassing five genes: _FANCA_ (MIM: 607139), _SPIRE2_ (MIM: 609217), _TCF25_ (MIM: 612326), _MC1R_ (MIM: 155555), and _TUBB3_ (MIM: 602661) (rs62052168, p = 3.7 × 10−202; Figure 1 and Table 1). _MC1R_is a key genetic determinant of pigmentation and hair color and is therefore a good candidate for this association. More than 20 variants in _MC1R_ have been shown to alter hair color in humans.21,22,23,24,25,26,27,28 None of the variants resulting in red hair in modern humans are present in either of the two high-coverage Neanderthal genomes that have been sequenced (Table S5). Therefore, Neanderthals appear not to carry any of the variants associated with red hair in modern humans. Further, a Neanderthal-specific variant (p.Arg307Gly) postulated to reduce the activity of MC1R and result in red hair was identified by PCR amplification of _MC1R_ in two Neanderthals.29 However, this putative Neanderthal-specific variant is also not present in the Neanderthals genomes that have been sequenced to date, suggesting that if this variant was present in Neanderthals, it was rare. Using the high-coverage Neanderthal genomes, we identified only one additional Neanderthal-specific MC1R amino acid change for which the effect on hair color is unknown. However, it is polymorphic among Neanderthals, indicating that any phenotype that it confers was variable in Neanderthals (Table S5). Finally, because the introgressed haplotype we identified in this cohort is under-represented among red-haired individuals, we conclude that if variants contributing to red hair were present in Neanderthals, they were probably not at high frequency."

I guess it's time to change back all those red-haired Neanderthal reconstructions again. This is why I don't take the pigmentation on those things too seriously, although the Mycenaean one turns out to have been correct.

"We also identified strongly associated archaic alleles on two unlinked introgressed haplotypes near _BNC2_ (MIM: 608669), a gene that has been previously associated with skin pigmentation in Europeans.30 The first archaic haplotype (chr9: 16,720,122–16,804,167) is tagged by an archaic allele (rs10962612) that has a frequency of more than 66% in European populations (Table S6 and Figure 1) and is associated with increased incidence of childhood sunburn (p = 1.5 × 10−9) and poor tanning (p = 1.6 × 10−22) in the UK Biobank cohort (Table 1). A Neanderthal haplotype in this region was previously identified by Vernot and Akey,11 and the association with sun sensitivity is consistent with the previous finding that Neanderthal alleles on this haplotype result in an increased risk of keratosis.12 All of the Neanderthal-like SNPs overlapping _BNC2_ on this haplotype have significant scores in a test for recent positive selection in Europeans31 (singleton density score > 3), perhaps indicating their importance in recent local adaptation.Interestingly, a second, less-frequent (19%) archaic haplotype near _BNC2_ (chr9: 16,891,561–16,915,874; rs62543578; Table S6) shows strong associations with darker skin pigmentation in individuals with British ancestry in the UK Biobank cohort (p = 1.6 × 10−14; Figure 1 and Table 1). These results suggest that multiple alleles in and near _BNC2_, some of which are contributed by Neanderthals, have different effects on pigmentation in modern humans. Our analysis identified six additional associations (p < 1.0 × 10−8) contributing to variation in skin and hair biology at other introgressed loci (Table 1). Individuals with blonde hair show a higher frequency of the Neanderthal haplotype at chr6: 503,851–544,833 (overlapping _EXOC2_ [MIM: 615329]), whereas individuals with darker hair color show higher Neanderthal ancestry at chr14: 92,767,097–92,801,297 (overlapping _SLC24A4_ [MIM: 609840]). Two further archaic haplotypes on chromosomes 6 (chr6: 45,533,261–45,680,205, overlapping _RUNX2_ [MIM: 600211]) and 11 (chr11: 89,996,325–90,041,511; nearest gene: _CHORDC1_ [MIM: 604353]) are both significantly associated with lighter skin color (Table 1). The apparent variation in the phenotypic effects of Neanderthal alleles in this cohort demonstrates that it is difficult to confidently predict Neanderthal skin and hair color."

As I've been saying ad nauseam:
"Given the large number of associations with skin and hair traits, it is tempting to speculate that Neanderthals might have had an outsized contribution to these phenotypes. However, the number of significant associations that can be identified for a trait is dependent on how polygenic the traits are and how they are measured. Power to measure the contribution of an allele depends also on the minor allele frequency. "

". For the majority of phenotypes (130/136), we found no difference between the relative contribution of archaic alleles and that of non-archaic alleles, indicating that for most phenotypes measured here, Neanderthal alleles contribute phenotypic variation proportionally to non-archaic SNPs at similar frequencies (Table S3). We detected six phenotypes where there was a significant difference between the p values distributions for archaic alleles and those for non-archaic alleles (FDR < 0.05). Neanderthal alleles contributed more variation in four behavioral phenotypes influencing sleep, mood, and smoking behaviors, suggesting that Neanderthal alleles contribute more to these traits than expected from their frequency in modern humans. Conversely, for two associations (ease of skin tanning and pork intake), non-archaic alleles showed lower association p values (Table S3), indicating that introgressed Neanderthal alleles contribute less than frequency-matched non-archaic alleles to these traits."

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## LeBrok

Great. I always maintained that HSS picked up skin lightening genes from Neanderthal. This idea was shot down by first research, which didn't confirm that and hoards of Neanderthal haters picking up on it. I said let's wait. Thanks to this statistical analyzes we know better now, and new skin colour affecting alleles were discovered in the proces. Good stuff.
I'm guessing that they were light brown, and HSS were black or dark brown at first mating contact, probably in Near East. I guess we need to wait a 5-10 years or so for the knowledge about skin colour to settle down and first true recreation, together with other correct anatomical and phenotypical details. Can't wait.

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## Fire Haired14

But is it really such a big surprise or a sign of cultural achievement that brothers and sisters and close relatives didn't have kids? I really don't see the big deal here.

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## Angela

> But is it really such a big surprise or a sign of cultural achievement that brothers and sisters and close relatives didn't have kids? I really don't see the big deal here.


I think you're in the wrong thread. I'll move it.

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## Angela

> Great. I always maintained that HSS picked up skin lightening genes from Neanderthal. This idea was shot down by first research, which didn't confirm that and hoards of Neanderthal haters picking up on it. I said let's wait. Thanks to this statistical analyzes we know better now, and new skin colour affecting alleles were discovered in the proces. Good stuff.
> I'm guessing that they were light brown, and HSS were black or dark brown at first mating contact, probably in Near East. I guess we need to wait a 5-10 years or so for the knowledge about skin colour to settle down and first true recreation, together with other correct anatomical and phenotypical details. Can't wait.


Maybe I'm reading it incorrectly, but I don't think that's their conclusion. They seem pretty certain they weren't red-haired, but as for pigmentation, they claim there was probably variation among them, and their specific snp for pigmentation which we've inherited contributes to some lightening in some of us, and some darkening in others. 

It's still a work in progress as far as pigmentation is concerned, whereas the disease associations seem more solid. 

"We conclude that if variants contributing to red hair were present in Neanderthals, they were probably not at high frequency."

As for the BNC2 area, there are two versions, and while one lightens, the other seems to darken. Some of us get one and some the other. They conclude there must have been variation in Neanderthals. At any rate, these are not major effect snps. None of the major effect genes in us were present in Neanderthals. 

Also, there is this: " *For the majority of phenotypes (130/136), we found no difference between the relative contribution of archaic alleles and that of non-archaic alleles, indicating that for most phenotypes measured here, Neanderthal alleles contribute phenotypic variation proportionally to non-archaic SNPs at similar frequencies* (Table S3). We detected *six phenotypes where there was a significant difference between the p values distributions for archaic alleles and those for non-archaic alleles (FDR < 0.05). Neanderthal alleles contributed more variation in four behavioral phenotypes influencing sleep, mood, and smoking behaviors, suggesting that Neanderthal alleles contribute more to these traits than expected from their frequency in modern humans.**

*Looking at it from a personal angle, I guess I can blame the fact that I get such terrible sunburns and can't tan on them, as well as the fact that I've had a few small keratosis lesions that I've had to have removed! Interestingly, 23andme picked that up, but also told me I'm low risk for melanoma, so it could be worse.

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## Jovialis

Here are the figures from the Eske group, Angela shared.



Figure 1


Archaic Haplotypes Associated with Skin and Hair Phenotypes


(A–D) Neanderthal allele frequency in percentage (x axis) and the number of individuals in the UK Biobank cohort for four aSNPs that show strong associations with skin and hair phenotypes (y axis): chr9: 16,904,635 (rs62543578) associated with skin color (A), chr9: 16,804,167 (rs10962612) associated with ease of skin tanning (B) and incidence of childhood sunburn (C) (illustrated are the average numbers of childhood sunburns for individuals with the three genotypes), and chr16: 89,947,203 (rs62052168) associated with hair color (D).


(E and F) The genomic locations of introgressed haplotypes for the aSNPs showing significant associations in (A)–(D). Gray vertical lines denote the extent of the inferred archaic haplotypes on chromosomes 9 (E) and 16 (F). At the top, we show all aSNPs that are within the inferred archaic haplotypes and are present in any 1000 Genomes individual. The associated tag SNPs directly genotyped by the UK Biobank are marked in red, and other aSNPs within the archaic haplotypes and genotyped in the UK Biobank are marked in orange. The associated tag aSNPs represented in (A)–(D) are marked on the x axis.





Figure 2


Archaic Haplotype Associated with Chronotype


(A) The Neanderthal allele frequency in percentage (x axis) and the number of individuals in the UK Biobank cohort for the four reported chronotype phenotypes (y axis; from top to bottom: definitely an evening person, more an evening than a morning person, more a morning than an evening person, definitely a morning person) for the archaic tag SNP with the strongest association with chronotype (position chr2: 239,316,043 [rs75804782] near ASB1).


(B) Worldwide frequency of the archaic allele (C, blue) and the modern human allele (T, orange) in the Simons Genome Diversity Panel populations.


(C) The association p values (y axis; in the form of −log10(p)) with chronotype for all archaic and non-archaic SNPs (squares) genotyped by the UK Biobank study in the region of the inferred archaic haplotype at chr2: 239,316,043–239,470,654. The tag SNP at chr2: 239,316,043 (rs75804782) is shown in red, other aSNPs are shown in orange, and non-archaic SNPs are shown in black. The genome-wide significance cutoff of p = 1.0 × 10−8 and the extent of the inferred archaic haplotype are illustrated with dashed horizontal and vertical gray lines, respectively. At the top, we show all aSNPs that are within the inferred archaic haplotype and are present in any 1000 Genomes individual. The directly genotyped SNPs from the UK Biobank are illustrated as red (the archaic tag SNP) and orange bars. One archaic allele that leads to a missense mutation in ASB1 is marked as a green bar.



//

Here's a couple screen caps from the Pääbo group paper, Razib Khan posted on Twitter.

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## bicicleur

> Great. I always maintained that HSS picked up skin lightening genes from Neanderthal. This idea was shot down by first research, which didn't confirm that and hoards of Neanderthal haters picking up on it. I said let's wait. Thanks to this statistical analyzes we know better now, and new skin colour affecting alleles were discovered in the proces. Good stuff.
> I'm guessing that they were light brown, and HSS were black or dark brown at first mating contact, probably in Near East. I guess we need to wait a 5-10 years or so for the knowledge about skin colour to settle down and first true recreation, together with other correct anatomical and phenotypical details. Can't wait.


The problem is that Neanderthals went extinct some 40 ka, and that the admixture between modern humans and Neanderthals happened even earlier, some 55-60 ka. Light skin in modern humans appeared much, much later.
If they got it from Neanderthals, these genes must have been slumbering for a very long time.

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## Angela

Razib Khan has chimed in...

See:
https://gnxp.nofe.me/2017/10/05/neanderthals/

"What they are saying is that for a lot of traits *Neanderthals don’t really change the direction of the trait in humans, they just add more variants. This seems to be the case in pigmentation. Entirely unsurprising, Neanderthals were around for hundreds of thousands of years. Of course they had a lot of variation amongst themselves.**But the behavioral traits above shifted the modern humans in the aggregate who had the archaic allele somewhat. That is, being Neanderthal derived made a difference.

*There have long been speculations about the sociality (or lack thereof) of Neanderthals. It would not be surprising if small population sizes meant that Neanderthals were less gregarious than modern humans, and that their lack of gregariousness did not redound to their benefit when they encountered the last wave of moderns."

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## LeBrok

> The problem is that Neanderthals went extinct some 40 ka, and that the admixture between modern humans and Neanderthals happened even earlier, some 55-60 ka. Light skin in modern humans appeared much, much later.


 We would have had a problem if mutations showed up after Neanderthal extinction. I didn't say they had light skin, I said their skin was lighter than HSS.

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## LeBrok

> Razib Khan has chimed in...
> 
> See:
> https://gnxp.nofe.me/2017/10/05/neanderthals/
> 
> "What they are saying is that for a lot of traits *Neanderthals don’t really change the direction of the trait in humans,*


Direction? One would need to assume that HSS leaving Africa were already getting lighter and lighter skin colour. Where are the samples? 
On other hand my assumption is based on a fact that Neanderthal had lived in Europe for few hundred thousand of years. It is hard to imagine that after so long time living in higher latitudes they were still dark in skin colour. Obviously they had lighter skin mutations already developed. Unlike HSS who left Africa much later and obviously didn't have time to developed lighter skin before first contact.

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## Angela

Whatever they looked like, and there seems to have been variation, their BNC2 gene hasn't had much effect on us, and the effect it had went in both directions. Their disproportionate effect is in the brain.

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## LeBrok

One thing is very interesting, the amount of genetic variations they had. What does that mean? Perhaps, Neanderthals didn't travel much and lived in smaller groups in insulation for very long thousands of years? In this case, we might start recognizing subspecies of them very soon.

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## Jovialis

I guess none of these are particularly inaccurate reconstructions. They could have looked like all of them.

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## Angela

> I guess none of these are particularly inaccurate reconstructions. They could have looked like all of them.


While there may have been variation, the authors think red hair was highly unlikely, so wouldn't two of them be out?

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## Jovialis

> While there may have been variation, the authors think red hair was highly unlikely, so wouldn't two of them be out?


I thought those reconstructions were more blondish tbh.

edit: except maybe the top right one.

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## bicicleur

_Then, over the past few years, ancient DNA researchers sequenced two more Neandertal genomes, including another high-quality sequence from an individual that lived 122,000 years ago in the Altai Mountains of Siberia._ 

is this correct?
afaik the oldest Neanderthal in Central Asia is dated 87 ka, and in the Altaï Mts, it is even much later

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## Angela

It seems we purged the variations in the testes pretty quickly, which makes sense, because it probably impacted fertility.

I wonder if the fact that lack of sunlight causes depression in some people is somehow related to all of this.

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## Jovialis

I'm looking forward to when they update the insitome app to account for all of these new discoveries. They had announced on Facebook they would.

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## Jovialis

Here's more coverage on the Pääbo group paper.




> A complete genetic analysis of a Neanderthal woman whose remains were found in a cave in Croatia shows no apparent incest in her ancestry, contrary to a previous specimen, researchers said Thursday.
> 
> As only the second Neanderthal to undergo full, high-quality genome sequencing, the findings in the journal _Science_ offer a broader picture of our extinct ancestors, and also uncovered 16 new Neanderthal gene variants that were passed on to modern humans.
> 
> The results confirm some things that were already known, including that Neanderthals lived in small, isolated populations and inter-bred with Homo sapiens who had migrated north from Africa.
> 
> The latest genome comes from a Neanderthal woman who lived about 52,000 years ago in what is today Eastern Europe.
> Until now, the only high-quality Neanderthal genome came from an individual in the Altai mountains of Siberia, dating back about 122,000 years.
> 
> ...

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## bicicleur

> _Then, over the past few years, ancient DNA researchers sequenced two more Neandertal genomes, including another high-quality sequence from an individual that lived 122,000 years ago in the Altai Mountains of Siberia._ 
> 
> is this correct?
> afaik the oldest Neanderthal in Central Asia is dated 87 ka, and in the Altaï Mts, it is even much later



this is the Neanderthal DNA they are talking about :

https://www.theguardian.com/science/...ed-by-dna-test

it is from 50 ka, not 122 ka

it was admixed 100 ka with modern human DNA, from a branch of modern humans that has gone extinct, probably related to the humans from Skhul and Qafzeh cave in the Levant
those Skhul and Qafzeh skull shapes suggests they are related to the Irhoud skulls in the Atlas Mountains, which recently were dated +/- 315 ka

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## Jovialis

Looks like they've released the paper to the public now:

http://science.sciencemag.org/conten...cience.aao1887




> *Abstract*
> 
> To date the only Neandertal genome that has been sequenced to high quality is from an individual found in Southern Siberia. We sequenced the genome of a female Neandertal from ~50 thousand years ago from Vindija Cave, Croatia to ~30-fold genomic coverage. She carried 1.6 differences per ten thousand base pairs between the two copies of her genome, fewer than present-day humans, suggesting that Neandertal populations were of small size. Our analyses indicate that she was more closely related to the Neandertals that mixed with the ancestors of present-day humans living outside of sub-Saharan Africa than the previously sequenced Neandertal from Siberia, allowing 10-20% more Neandertal DNA to be identified in present-day humans, including variants involved in LDL cholesterol levels, schizophrenia and other diseases.
> 
> 
> Neandertals are the closest evolutionary relatives identified to date of all present-day humans and therefore provide a unique perspective on human biology and history. In particular, comparisons of genome sequences from Neandertals with those of present-day humans have allowed genetic features unique to modern humans to be identified (_1_, _2_) and have shown that Neandertals mixed with the ancestors of present-day people living outside sub-Saharan Africa (_3_). Many of the DNA sequences acquired by non-Africans from Neandertals were likely detrimental and were purged from the human genome via negative selection (_4_–_8_) but some appear to have been beneficial and were positively selected (_9_); among people today, alleles derived from Neandertals are associated with both susceptibility and resistance to diseases (_7_, _10_–_12_).
> However, our knowledge about the genetic variation among Neandertals is still limited. To date genome-wide DNA sequences of five Neandertals have been determined. One of these, the “Altai Neandertal”, found in Denisova Cave in the Altai Mountains in southern Siberia, the eastern-most known reach of the Neandertal range, yielded a high quality genome sequence (~50-fold genomic coverage) (_2_). In addition, a composite genome sequence from three Neandertal individuals has been generated from Vindija Cave in Croatia in southern Europe but is of low quality (~1.2-fold total coverage) (_3_), while a Neandertal genome from Mezmaiskaya Cave in the Caucasus (_2_) is of even lower quality (~0.5-fold coverage). In addition, chromosome 21 (_13_) and exome sequences (_14_) have been generated from a different individual from Vindija Cave and one from Sidron Cave in Spain. The lack of high-quality Neandertal genome sequences, especially from the center of their geographical range and from the time close to when they were estimated to have mixed with modern humans, limits our ability to reconstruct their history and the extent of their genetic contribution to present-day humans.
> Neandertals lived in Vindija Cave in Croatia until relatively late in their history (_3_, _15_). The cave has yielded Neandertal and animal bones, many of them too fragmentary to determine from their morphology from what species they derive. Importantly, DNA preservation in Vindija Cave is relatively good and allowed the determination of Pleistocene nuclear DNA from a cave bear (_16_), a Neandertal genome (_3_), exome and chromosome 21 sequences (_13_, _14_).
> To generate DNA suitable for deep sequencing, we extracted DNA (_17_) and generated DNA libraries (_18_) from 12 samples from Vindija 33.19, one of 19 bone fragments from Vindija Cave determined to be of Neandertal origin by mitochondrial (mt) DNA analyses (_19_). In addition, 567 mg (mg) were removed for radiocarbon dating and yielded a date of greater than 45.5 thousand years before present (OxA 32,278). One of the DNA extracts, generated from 41 mg of bone material, contained more hominin DNA than the other extracts. We created additional libraries from this extract, but to maximize the number of molecules retrieved from the specimen we omitted the uracil-DNA-glycosylase (UDG) treatment (_20_, _21_). A total of 24 billion DNA fragments were sequenced and approximately 10% of these could be mapped to the human genome. Their average length was 53 base pairs (bp) and they yielded 30-fold coverage of the approximately 1.8 billion bases of the genome to which such short fragments can be confidently mapped.
> ...

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## Expredel

> One thing is very interesting, the amount of genetic variations they had. What does that mean? Perhaps, Neanderthals didn't travel much and lived in smaller groups in insulation for very long thousands of years? In this case, we might start recognizing subspecies of them very soon.


http://johnhawks.net/weblog/reviews/...rica-2012.html

I think a North African Neanderthal genome would be the next interesting thing.

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