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Jovialis
05-10-17, 22:25
Here's the full paper:

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

http://science.sciencemag.org/content/early/2017/10/04/science.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 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-1), 2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-2)) and have shown that Neandertals mixed with the ancestors of present-day people living outside sub-Saharan Africa (3 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-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 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-4)–8 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-8)) but some appear to have been beneficial and were positively selected (9 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-9)); among people today, alleles derived from Neandertals are associated with both susceptibility and resistance to diseases (7 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-7), 10 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-10)–12 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-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 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-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 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-3)), while a Neandertal genome from Mezmaiskaya Cave in the Caucasus (2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-2)) is of even lower quality (~0.5-fold coverage). In addition, chromosome 21 (13 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-13)) and exome sequences (14 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-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 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-3), 15 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-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 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-16)), a Neandertal genome (3 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-3)), exome and chromosome 21 sequences (13 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-13), 14 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-14)).
To generate DNA suitable for deep sequencing, we extracted DNA (17 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-17)) and generated DNA libraries (18 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-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 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-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 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20), 21 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-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.
We estimated present-day human DNA contamination among the DNA fragments (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). First, using positions in the mtDNA where present-day humans differ from Neandertals we estimated an mtDNA contamination rate of 1.4-1.7%. Similarly, using positions in the autosomal genome where all present-day humans carry derived variants whereas all archaic genomes studied to date carry ancestral variants we estimated a nuclear contamination rate of 0.17-0.48%. Because the coverage of the X chromosome is similar to that of the autosomes we inferred that the Vindija 33.19 individual is a female, allowing us to use DNA fragments that map to the Y chromosome to estimate a male DNA contamination of 0.74% (between 0.70-0.78% for each of the nine sequencing libraries). Finally, using a likelihood method (2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-2), 3 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-3)) we estimated the autosomal contamination to 0.18-0.23%. We conclude that the nuclear DNA contamination rate among the DNA fragments sequenced is less than 1%. After genotyping this will result in contamination that is much lower than 1%.
Because ~76% of the DNA fragments were not UDG-treated, they carry C to T substitutions throughout their lengths. This causes standard genotyping software to generate false heterozygous calls. To overcome this we implemented snpAD, a genotyping software that incorporates a position-dependent error-profile to estimate the most likely genotype for each position in the genome. This results in genotypes of comparable quality to UDG-treated ancient DNA given our genomic coverage (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). The high-coverage of the Vindija genome also allowed for characterization of longer structural variants and segmental duplications (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)).
To gauge whether the Vindija 33.19 bone might stem from a previously sequenced individual from Vindija Cave we compared heterozygous sites in the Vindija 33.19 genome to DNA fragments sequenced from the other bones. The three bones from which a low-coverage composite genome has been generated (Vindija 33.16, 33.25 and 33.26) do not share variants with Vindija 33.19 at a level compatible with deriving from the same individual. In contrast, over 99% of heterozygous sites in the chromosome 21 sequence from Vindija 33.15 (13 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-13)) are shared with Vindija 33.19, indicating that they come from the same individual (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). Additionally, two of the other three bones may come from individuals that shared a maternal ancestor to Vindija 33.19 relatively recently in their family history because all carry identical mtDNAs.
In addition to the Altai Neandertal genome, a genome from a Denisovan, an Asian relative of Neandertals, has been sequenced to high coverage (~30-fold) from Denisova Cave. These two genomes are similar in that their heterozygosity is about one fifth of that of present-day Africans and about one third of that of present-day Eurasians. We estimated the heterozygosity of the Vindija 33.19 autosomal genome to 1.6x10−5; similar to the Altai Neandertal genome and slightly lower than the Denisovan genome (1.8 x10−5) (Fig. 1A (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F1)). Thus, low heterozygosity may be a feature typical of archaic hominins, suggesting that they lived in small and isolated populations with an effective population size of around 3,000 individuals (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). In addition to low over-all heterozygosity, the Altai Neandertal genome carried segments of many megabases (Mb) (>10 centimorgans (cM)) without any differences between its two chromosomes, indicating that the parents of that individual were related at the level of half-sibs (2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-2)). Such segments are almost totally absent in the Vindija genome (Fig. 1B (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F1)), suggesting that the extreme inbreeding between the parents of the Altai Neandertal was not ubiquitous among Neandertals. We note, however, that the Vindija genome carries extended homozygous segments (>2.5cM) comparable to what is seen in some isolated Native American populations today (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)).

The high quality of the three archaic genome sequences allows their approximate ages to be estimated from the number of new nucleotide substitutions they carry relative to present-day humans when compared to the inferred ancestor shared with apes (1 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-1)). Using this approach, we estimate that the Vindija 33.19 individual lived 52 thousand years ago (kya), the Altai Neandertal individual 122kya, and the Denisovan individual 72kya (Fig. 2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F2)) (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). Many factors make such absolute age estimates tentative. Among these are uncertainty in generation times and mutation rates. Nevertheless, these results indicate that the Altai Neandertal lived about twice as far back in time as the Vindija 33.19 Neandertal, while the Denisovan individual lived after the Altai but before the Vindija Neandertal.


We next estimated when ancestral populations that gave rise to the three archaic genomes and to modern humans split from each other based on the extent to which they share genetic variants (1 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-1)–3 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-3), 20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). The estimated population split time between the Vindija Neandertal and the Denisovan is 390-440kya and between the Vindija Neandertal and modern humans 520-630kya, in agreement with previous estimates using the Altai Neandertal (2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-2)). The split time between the Vindija and the Altai Neandertals is estimated to 130-145kya. To estimate the population split time to the Mezmaiskaya 1 Neandertal previously sequenced to 0.5-fold coverage, we prepared and sequenced libraries yielding an additional 1.4-fold coverage. Because the present-day human DNA contamination of these libraries is in the order of 2-3% (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)), we estimated the population split time to the Vindija 33.19 individual with and without restricting the analysis of the Mezmaiskaya 1 individual to fragments that show evidence of deamination. The resulting split time estimates are 100kya for the deaminated fragments and 80kya for all fragments (Fig. 2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F2)).
It has been suggested that Denisovans received gene flow from a human lineage that diverged prior to the common ancestor of modern humans, Neandertals and Denisovans (2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-2)). In addition, it has been suggested that the ancestors of the Altai Neandertal received gene flow from early modern humans that may not have affected the ancestors of European Neandertals (13 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-13)). In agreement with these studies, we find that the Denisovan genome carries fewer derived alleles that are fixed in Africans, and thus tend to be older, than the Altai Neandertal genome while the Altai genome carries more derived alleles that are of lower frequency in Africa, and thus younger, than the Denisovan genome (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). However, the Vindija and Altai genomes do not differ significantly in the sharing of derived alleles with Africans indicating that they may not differ with respect to their putative interactions with early modern humans (Fig. 3A (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F3) & B). Thus, in contrast to earlier analyses of chromosome 21 data for the European Neandertals (13 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-13)), analyses of the full genomes suggest that the putative early modern human gene flow into Neandertals occurred prior to the divergence of the populations ancestral to the Vindija and Altai Neandertals ~130-145 thousand years ago (Fig. 2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F2)). Coalescent simulations show that a model with only gene flow from a deeply diverged hominin into Denisovan ancestors explains the data better than one with only gene flow from early modern humans into Neandertal ancestors, but that a model involving both gene flows explains the data even better. It is likely that gene flow occurred between many or even most hominin groups in the late Pleistocene and that more such events will be detected as more ancient genomes of high quality become available.


A proportion of the genomes of all present-day people whose roots are outside Africa derives from Neandertals (2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-2), 3 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-3), 22 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-22)). We tested if any of the three sequenced Neandertals falls closer to the lineage that contributed DNA to present-day non-Africans by asking if any of them shares more alleles with present-day non-Africans than the others (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20), 23 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-23)). The Vindija 33.19 and Mezmaiskaya 1 genomes share more alleles with non-Africans than the Altai Neandertal, and there is no indication that the former two genomes differ in the extent of their allele-sharing with present-day people (Fig. 3C (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F3)). Using a likelihood approach we estimate the proportion of Neandertal DNA in present-day populations that is closer to the Vindija than the Altai genomes to be 99%-100% (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). Thus, the majority of Neandertal DNA in present-day populations appears to come from Neandertal populations that diverged from the Vindija and Mezmaiskaya 1 Neandertals prior to their divergence from each other some 80-100kya.
The two high-coverage Neandertal genomes allow us to estimate the proportion of the genomes of present-day people that derive from Neandertals with greater accuracy than was hitherto possible. We asked how many derived alleles non-Africans share with the Altai Neandertal relative to how many derived alleles the Vindija Neandertal shares with the Altai Neandertal - essentially asking how close non-Africans are to being 100% Neandertal (24 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-24)). We find that non-African populations outside Oceania carry between 1.8-2.6% Neandertal DNA (Fig. 4A (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F4)), higher than previous estimates of 1.5-2.1% (2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-2)). As described (25 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-25)), East Asians carry somewhat more Neandertal DNA (2.3-2.6%) than people in Western Eurasia (1.8-2.4%).


We also identified (8 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-8)) regions of Neandertal-ancestry in present-day Europeans and Asians using the Vindija and the Altai Neandertal genomes (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). The Vindija genome allows us to identify ~10% more Neandertal DNA sequences per individual than the Altai Neandertal genome (e.g. 40.4 Mb vs 36.3 Mb in Europeans) due to the closer relationship between the Vindija genome and the introgressing Neandertal populations. In Melanesians, the increased power to distinguish between Denisovan and Neandertal DNA sequences results in the identification of 20% more Neandertal DNA (Fig. 4B (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F4)).
Many Neandertal variants associated with phenotypes and susceptibility to diseases have been identified in present-day non-Africans (6 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-6), 7 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-7), 10 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-10)–12 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-12)). The fact that the Vindija Neandertal genome is more closely related to the introgressing Neandertals allows ~15% more such variants to be identified (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). Among these are variants associated with plasma levels of LDL cholesterol (rs10490626) and vitamin D (rs6730714), eating disorders (rs74566133), visceral fat accumulation (rs2059397), rheumatoid arthritis (45475795), schizophrenia (rs16977195) and the response to antipsychotic drugs (rs1459148). This adds to mounting evidence that Neandertal ancestry influences disease risk in present-day humans, particularly with respect to neurological, psychiatric, immunological, and dermatological phenotypes (7 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-7)).



https://i.imgur.com/KVogluy.jpg

Fig. 1Heterozygosity and inbreeding in the Vindija Neandertal.
(A) Distribution of heterozygosity over all autosomes in the three archaic hominins, 12 Non-Africans and 3 Africans. Each dot represents the heterozygosity measured for one autosome. The center bar indicates the mean heterozygosity across the autosomal genome. (B) Genome covered by shorter (2.5-10cM, red) and longer (>10cM, yellow) runs of homozygosity in the three archaic hominins.
https://i.imgur.com/HeSQZRx.jpg

Fig. 2Approximate ages of specimens and population split times.
Age estimates for the genomes estimated from branch shortening, i.e. the absence of mutations in the archaic genomes, are indicated by dashed lines. Population split time estimates are indicated by dashed lines. The majority of Neandertal DNA in present-day people comes from a population that split from the branch indicated in red. All reported ages assume a human-chimpanzee divergence of 13 million years. Numbers show ranges over point estimates (split times), or ranges over different data filters (branch shortening).

https://i.imgur.com/Ha2QY8I.jpg

Fig. 3Allele sharing between archaic and modern humans.
(A) Derived allele-sharing in percent of 19 African populations with the Altai and Denisovan, and Vindija and Denisovan genomes, respectively. (B) Sharing of derived alleles in each of the 19 African populations with the Vindija and Altai genomes. (C) Allele sharing of Neandertals with non-Africans and Africans. Points show derived allele sharing in percent for all pairwise comparisons between non-Africans (OAA: French, Sardinian, Han, Dai, Karitiana, Mixe, Australian, Papuan) and Africans (AFR: San, Mbuti, Yoruba). Mezmaiskaya 1 data were restricted to sequences showing evidence of deamination to reduce the influence of present-day human DNA contamination. Lines show two standard errors from the mean in all plots.

https://i.imgur.com/uOJp0KV.jpg

Fig. 4Estimates of fraction of Neandertal DNA for present-day populations.
(A) Colors indicate Neandertal ancestry estimates (20). Oceanian populations show high estimates due to Denisovan ancestry that is difficult to distinguish from Neandertal ancestry. (B) Amount of Neandertal sequence in present-day Europeans, South Asians and East Asians (20).


//

http://science.sciencemag.org/content/early/2017/10/04/science.aao1887.full (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/2017/10/your-neandertal-dna-making-your-belly-fat-ancient-genome-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 inScience (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887.full) 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 (http://science.sciencemag.org/content/328/5979/680) 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 (http://science.sciencemag.org/content/351/6274/648) 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 (http://www.cell.com/ajhg/fulltext/S0002-9297(17)30379-8), 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.

But the Vindija Neandertal lived closer than the Altai one to the time and place where Eurasians' ancestors mated with Neandertals—likely 50,000 to 60,000 years ago, perhaps in the Middle East. So its DNA promised better insight, especially with recently improved methods to extract and sequence ancient DNA. Evolutionary geneticist Kay Prüfer of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and colleagues sequenced each base of the female's genome (http://science.sciencemag.org/content/337/6098/1028) about 30 times on average. The team also used radiocarbon and genetic methods to date the bone.

As expected, this Neandertal's genome is more closely related to today's Europeans and Asians than that of the Altai Neandertal. And Prüfer and his colleagues already have discovered 16 new Neandertal gene variants passed on to living humans. These include changes in genes already known to govern levels of cholesterol and vitamin D, and to influence the risk—for better or worse—of developing eating disorders, rheumatoid arthritis, and schizophrenia, as well as the response to antipsychotic drugs. Researchers will now more closely study how each Neandertal version tips the balance in living people.

The new Vindija genome also allowed the researchers to better calculate how much Neandertal DNA different groups of humans outside of Africa have inherited. East Asians, with 2.3%–2.6% of Neandertal DNA, topped people from western Asia and Europe, who had 1.8%–2.4%. Prüfer and his colleagues confirmed that the ancestors of the 122,000-year-old Altai Neandertal had also interbred with H. sapiens in a much earlier encounter that took place more than 130,000 years ago.

The Altai and Vindija genomes are remarkably similar and that limited genetic diversity suggests that Neandertals lived in small, isolated populations of about 3000 individuals of reproductive age, Prüfer says. "This speaks to debates about why they went extinct," Capra says. "They probably were less robust in their response to disease, starvation, and changes in climate."

Angela
05-10-17, 23:28
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 (http://omim.org/entry/607139)), SPIRE2 (MIM: 609217 (http://omim.org/entry/609217)), TCF25 (MIM: 612326 (http://omim.org/entry/612326)), MC1R (MIM: 155555 (http://omim.org/entry/155555)), and TUBB3 (MIM: 602661 (http://omim.org/entry/602661)) (rs62052168, p = 3.7 × 10−202; Figure 1 (http://www.cell.com/cms/attachment/2110355287/2083170103/gr1.jpg) and Table 1 (http://www.cell.com/ajhg/fulltext/S0002-9297(17)30379-8#tbl1)). MC1Ris 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 (http://www.cell.com/cms/attachment/2110355287/2083170107/mmc1.pdf)). 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 (http://www.cell.com/cms/attachment/2110355287/2083170107/mmc1.pdf)). 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 (http://omim.org/entry/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 (http://www.cell.com/cms/attachment/2110355287/2083170107/mmc1.pdf) and Figure 1 (http://www.cell.com/cms/attachment/2110355287/2083170103/gr1.jpg)) 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 (http://www.cell.com/ajhg/fulltext/S0002-9297(17)30379-8#tbl1)). 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 (http://www.cell.com/cms/attachment/2110355287/2083170107/mmc1.pdf)) shows strong associations with darker skin pigmentation in individuals with British ancestry in the UK Biobank cohort (p = 1.6 × 10−14; Figure 1 (http://www.cell.com/cms/attachment/2110355287/2083170103/gr1.jpg) and Table 1 (http://www.cell.com/ajhg/fulltext/S0002-9297(17)30379-8#tbl1)). 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 (http://www.cell.com/ajhg/fulltext/S0002-9297(17)30379-8#tbl1)). Individuals with blonde hair show a higher frequency of the Neanderthal haplotype at chr6: 503,851–544,833 (overlapping EXOC2 [MIM: 615329 (http://omim.org/entry/615329)]), whereas individuals with darker hair color show higher Neanderthal ancestry at chr14: 92,767,097–92,801,297 (overlapping SLC24A4 [MIM: 609840 (http://omim.org/entry/609840)]). Two further archaic haplotypes on chromosomes 6 (chr6: 45,533,261–45,680,205, overlapping RUNX2 [MIM: 600211 (http://omim.org/entry/600211)]) and 11 (chr11: 89,996,325–90,041,511; nearest gene: CHORDC1 [MIM: 604353 (http://omim.org/entry/604353)]) are both significantly associated with lighter skin color (Table 1 (http://www.cell.com/ajhg/fulltext/S0002-9297(17)30379-8#tbl1)). 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 (http://www.cell.com/cms/attachment/2110355287/2083170107/mmc1.pdf)). 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 (http://www.cell.com/cms/attachment/2110355287/2083170107/mmc1.pdf)), indicating that introgressed Neanderthal alleles contribute less than frequency-matched non-archaic alleles to these traits."

LeBrok
06-10-17, 01:42
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.

Fire Haired14
06-10-17, 02:58
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.

Angela
06-10-17, 04:10
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.

Angela
06-10-17, 04:29
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 (http://www.cell.com/cms/attachment/2110355287/2083170107/mmc1.pdf)). 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.

Jovialis
06-10-17, 04:52
Here are the figures from the Eske group, Angela shared.

https://i.imgur.com/IUY4JbV.png

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.

https://i.imgur.com/b66nf59.png

https://i.imgur.com/QxYTkvU.png

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.

https://i.imgur.com/tjNtvcl.png


https://i.imgur.com/OJUGV2Z.png

bicicleur
06-10-17, 08:01
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.

Angela
06-10-17, 15:14
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."

LeBrok
06-10-17, 15:58
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.

LeBrok
06-10-17, 16:07
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.

Angela
06-10-17, 16:10
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.

LeBrok
06-10-17, 16:11
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.

Jovialis
06-10-17, 16:39
https://i.imgur.com/AosglwX.png

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

Angela
06-10-17, 16:47
https://i.imgur.com/AosglwX.png

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?

Jovialis
06-10-17, 16:50
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.

bicicleur
06-10-17, 16:50
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

Angela
06-10-17, 16:51
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.

Jovialis
06-10-17, 18:12
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.

Jovialis
06-10-17, 20:32
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 (https://phys.org/tags/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.

The Altai Neanderthal's genes showed that her parents had been related, perhaps on the level of half-siblings or an aunt-nephew or uncle-niece pairing.

"The Altai Neanderthal lived in a small group of close relatives—and was the kid of close relatives—and many people thought that this was the typical Neanderthal behavior," said Marcia Ponce de Leon, collection curator and senior lecturer at the Anthropological Institute and Museum, University of Zurich.

However, the present study shows that Neanderthals from the area of Vindija, Croatia, "lived in much more open groups, probably similar to what we know from modern hunter-gatherers," she told AFP in an email, praising the work for its "important new insights."

Neanderthals disappeared from the Earth about 35,000 years ago. Just what forced them into extinction is a mystery, but they were known to be living in relatively small groups of around 3,000 people.

Long caricatured as dim-witted cave dwellers, researchers now know that Neanderthals practised rituals, decorated jewelry, cared for elders, used primitive medicines—and may have resorted to cannibalism.

Lead author Kay Pruefer said he was most surprised to discover that the two high-quality specimens appeared to have been closely related themselves, despite vast distances of geography and time.

"This shows that Neanderthals must have had a small population size," he told AFP.

DNA insights


A second paper in Science analyzed the genomes of four anatomically modern humans who lived around 34,000 years ago and were found at the Sunghir burial site, in Russia.


The four males were not related to each other, and their genes showed no signs of inbreeding, suggesting that these hunter-gatherers mated outside their clans.


"They have a population structure that appears to be really outbred compared to Neanderthals, and that may have something to do with why modern humans succeeded—we were able to maintain broader social networks," explained John Hawks, professor of anthropology at the University of Wisconsin Madison.


Hawks, who was not involved in the research, said the work "is not transforming the way we look at Neanderthals, but it is giving us a much better ability to look at what they shared with us."


The latest genome is closer to the human mixture than the older one and includes "new gene variants in the Neandertal genome that are influential in modern day humans," said the report.


These include variants related to plasma levels of bad (LDL) cholesterol and vitamin D, eating disorders, fat accumulation, rheumatoid arthritis, schizophrenia and responses to antipsychotic drugs, said the report.

Researchers also now believe that Neanderthal DNA is slightly more prevalent in modern people—with the exception of Africans whose ancestors did not breed with Neanderthals—than previously thought.

Most non-African people today carry between 1.8-2.6 percent Neanderthal DNA, higher than earlier estimates of 1.5-2.1 percent, researchers said.

"East Asians carry somewhat more Neanderthal DNA (2.3-2.6 percent) than people in Western Eurasia (1.8-2.4 percent)," said the report.

As to the reported Neanderthal links to disease, Ponce de Leon urged skepticism.

"In my view, this is a statistical artifact resulting from the fact that genome sequencing has a strong clinical bias. As an effect, disease-related genes get into the focus of interest," she said in an email.

"However, the 'obesity/arthritis/schizophrenia-causing Neanderthal' is likely more fiction than fact."




Read more at: https://phys.org/news/2017-10-incest-neanderthal-woman-genome.html#jCp

bicicleur
06-10-17, 20:57
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/2016/feb/17/oldest-known-case-of-neanderthal-human-sex-revealed-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

Jovialis
09-10-17, 17:34
Looks like they've released the paper to the public now:

http://science.sciencemag.org/content/early/2017/10/04/science.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 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-1), 2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-2)) and have shown that Neandertals mixed with the ancestors of present-day people living outside sub-Saharan Africa (3 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-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 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-4)–8 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-8)) but some appear to have been beneficial and were positively selected (9 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-9)); among people today, alleles derived from Neandertals are associated with both susceptibility and resistance to diseases (7 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-7), 10 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-10)–12 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-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 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-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 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-3)), while a Neandertal genome from Mezmaiskaya Cave in the Caucasus (2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-2)) is of even lower quality (~0.5-fold coverage). In addition, chromosome 21 (13 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-13)) and exome sequences (14 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-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 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-3), 15 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-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 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-16)), a Neandertal genome (3 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-3)), exome and chromosome 21 sequences (13 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-13), 14 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-14)).
To generate DNA suitable for deep sequencing, we extracted DNA (17 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-17)) and generated DNA libraries (18 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-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 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-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 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20), 21 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-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.
We estimated present-day human DNA contamination among the DNA fragments (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). First, using positions in the mtDNA where present-day humans differ from Neandertals we estimated an mtDNA contamination rate of 1.4-1.7%. Similarly, using positions in the autosomal genome where all present-day humans carry derived variants whereas all archaic genomes studied to date carry ancestral variants we estimated a nuclear contamination rate of 0.17-0.48%. Because the coverage of the X chromosome is similar to that of the autosomes we inferred that the Vindija 33.19 individual is a female, allowing us to use DNA fragments that map to the Y chromosome to estimate a male DNA contamination of 0.74% (between 0.70-0.78% for each of the nine sequencing libraries). Finally, using a likelihood method (2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-2), 3 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-3)) we estimated the autosomal contamination to 0.18-0.23%. We conclude that the nuclear DNA contamination rate among the DNA fragments sequenced is less than 1%. After genotyping this will result in contamination that is much lower than 1%.
Because ~76% of the DNA fragments were not UDG-treated, they carry C to T substitutions throughout their lengths. This causes standard genotyping software to generate false heterozygous calls. To overcome this we implemented snpAD, a genotyping software that incorporates a position-dependent error-profile to estimate the most likely genotype for each position in the genome. This results in genotypes of comparable quality to UDG-treated ancient DNA given our genomic coverage (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). The high-coverage of the Vindija genome also allowed for characterization of longer structural variants and segmental duplications (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)).
To gauge whether the Vindija 33.19 bone might stem from a previously sequenced individual from Vindija Cave we compared heterozygous sites in the Vindija 33.19 genome to DNA fragments sequenced from the other bones. The three bones from which a low-coverage composite genome has been generated (Vindija 33.16, 33.25 and 33.26) do not share variants with Vindija 33.19 at a level compatible with deriving from the same individual. In contrast, over 99% of heterozygous sites in the chromosome 21 sequence from Vindija 33.15 (13 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-13)) are shared with Vindija 33.19, indicating that they come from the same individual (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). Additionally, two of the other three bones may come from individuals that shared a maternal ancestor to Vindija 33.19 relatively recently in their family history because all carry identical mtDNAs.
In addition to the Altai Neandertal genome, a genome from a Denisovan, an Asian relative of Neandertals, has been sequenced to high coverage (~30-fold) from Denisova Cave. These two genomes are similar in that their heterozygosity is about one fifth of that of present-day Africans and about one third of that of present-day Eurasians. We estimated the heterozygosity of the Vindija 33.19 autosomal genome to 1.6x10−5; similar to the Altai Neandertal genome and slightly lower than the Denisovan genome (1.8 x10−5) (Fig. 1A (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F1)). Thus, low heterozygosity may be a feature typical of archaic hominins, suggesting that they lived in small and isolated populations with an effective population size of around 3,000 individuals (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). In addition to low over-all heterozygosity, the Altai Neandertal genome carried segments of many megabases (Mb) (>10 centimorgans (cM)) without any differences between its two chromosomes, indicating that the parents of that individual were related at the level of half-sibs (2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-2)). Such segments are almost totally absent in the Vindija genome (Fig. 1B (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F1)), suggesting that the extreme inbreeding between the parents of the Altai Neandertal was not ubiquitous among Neandertals. We note, however, that the Vindija genome carries extended homozygous segments (>2.5cM) comparable to what is seen in some isolated Native American populations today (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)).

The high quality of the three archaic genome sequences allows their approximate ages to be estimated from the number of new nucleotide substitutions they carry relative to present-day humans when compared to the inferred ancestor shared with apes (1 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-1)). Using this approach, we estimate that the Vindija 33.19 individual lived 52 thousand years ago (kya), the Altai Neandertal individual 122kya, and the Denisovan individual 72kya (Fig. 2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F2)) (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). Many factors make such absolute age estimates tentative. Among these are uncertainty in generation times and mutation rates. Nevertheless, these results indicate that the Altai Neandertal lived about twice as far back in time as the Vindija 33.19 Neandertal, while the Denisovan individual lived after the Altai but before the Vindija Neandertal.


We next estimated when ancestral populations that gave rise to the three archaic genomes and to modern humans split from each other based on the extent to which they share genetic variants (1 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-1)–3 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-3), 20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). The estimated population split time between the Vindija Neandertal and the Denisovan is 390-440kya and between the Vindija Neandertal and modern humans 520-630kya, in agreement with previous estimates using the Altai Neandertal (2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-2)). The split time between the Vindija and the Altai Neandertals is estimated to 130-145kya. To estimate the population split time to the Mezmaiskaya 1 Neandertal previously sequenced to 0.5-fold coverage, we prepared and sequenced libraries yielding an additional 1.4-fold coverage. Because the present-day human DNA contamination of these libraries is in the order of 2-3% (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)), we estimated the population split time to the Vindija 33.19 individual with and without restricting the analysis of the Mezmaiskaya 1 individual to fragments that show evidence of deamination. The resulting split time estimates are 100kya for the deaminated fragments and 80kya for all fragments (Fig. 2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F2)).
It has been suggested that Denisovans received gene flow from a human lineage that diverged prior to the common ancestor of modern humans, Neandertals and Denisovans (2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-2)). In addition, it has been suggested that the ancestors of the Altai Neandertal received gene flow from early modern humans that may not have affected the ancestors of European Neandertals (13 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-13)). In agreement with these studies, we find that the Denisovan genome carries fewer derived alleles that are fixed in Africans, and thus tend to be older, than the Altai Neandertal genome while the Altai genome carries more derived alleles that are of lower frequency in Africa, and thus younger, than the Denisovan genome (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). However, the Vindija and Altai genomes do not differ significantly in the sharing of derived alleles with Africans indicating that they may not differ with respect to their putative interactions with early modern humans (Fig. 3A (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F3) & B). Thus, in contrast to earlier analyses of chromosome 21 data for the European Neandertals (13 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-13)), analyses of the full genomes suggest that the putative early modern human gene flow into Neandertals occurred prior to the divergence of the populations ancestral to the Vindija and Altai Neandertals ~130-145 thousand years ago (Fig. 2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F2)). Coalescent simulations show that a model with only gene flow from a deeply diverged hominin into Denisovan ancestors explains the data better than one with only gene flow from early modern humans into Neandertal ancestors, but that a model involving both gene flows explains the data even better. It is likely that gene flow occurred between many or even most hominin groups in the late Pleistocene and that more such events will be detected as more ancient genomes of high quality become available.


A proportion of the genomes of all present-day people whose roots are outside Africa derives from Neandertals (2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-2), 3 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-3), 22 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-22)). We tested if any of the three sequenced Neandertals falls closer to the lineage that contributed DNA to present-day non-Africans by asking if any of them shares more alleles with present-day non-Africans than the others (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20), 23 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-23)). The Vindija 33.19 and Mezmaiskaya 1 genomes share more alleles with non-Africans than the Altai Neandertal, and there is no indication that the former two genomes differ in the extent of their allele-sharing with present-day people (Fig. 3C (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F3)). Using a likelihood approach we estimate the proportion of Neandertal DNA in present-day populations that is closer to the Vindija than the Altai genomes to be 99%-100% (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). Thus, the majority of Neandertal DNA in present-day populations appears to come from Neandertal populations that diverged from the Vindija and Mezmaiskaya 1 Neandertals prior to their divergence from each other some 80-100kya.
The two high-coverage Neandertal genomes allow us to estimate the proportion of the genomes of present-day people that derive from Neandertals with greater accuracy than was hitherto possible. We asked how many derived alleles non-Africans share with the Altai Neandertal relative to how many derived alleles the Vindija Neandertal shares with the Altai Neandertal - essentially asking how close non-Africans are to being 100% Neandertal (24 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-24)). We find that non-African populations outside Oceania carry between 1.8-2.6% Neandertal DNA (Fig. 4A (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F4)), higher than previous estimates of 1.5-2.1% (2 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-2)). As described (25 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-25)), East Asians carry somewhat more Neandertal DNA (2.3-2.6%) than people in Western Eurasia (1.8-2.4%).


We also identified (8 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-8)) regions of Neandertal-ancestry in present-day Europeans and Asians using the Vindija and the Altai Neandertal genomes (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). The Vindija genome allows us to identify ~10% more Neandertal DNA sequences per individual than the Altai Neandertal genome (e.g. 40.4 Mb vs 36.3 Mb in Europeans) due to the closer relationship between the Vindija genome and the introgressing Neandertal populations. In Melanesians, the increased power to distinguish between Denisovan and Neandertal DNA sequences results in the identification of 20% more Neandertal DNA (Fig. 4B (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#F4)).
Many Neandertal variants associated with phenotypes and susceptibility to diseases have been identified in present-day non-Africans (6 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-6), 7 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-7), 10 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-10)–12 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-12)). The fact that the Vindija Neandertal genome is more closely related to the introgressing Neandertals allows ~15% more such variants to be identified (20 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-20)). Among these are variants associated with plasma levels of LDL cholesterol (rs10490626) and vitamin D (rs6730714), eating disorders (rs74566133), visceral fat accumulation (rs2059397), rheumatoid arthritis (45475795), schizophrenia (rs16977195) and the response to antipsychotic drugs (rs1459148). This adds to mounting evidence that Neandertal ancestry influences disease risk in present-day humans, particularly with respect to neurological, psychiatric, immunological, and dermatological phenotypes (7 (http://science.sciencemag.org/content/early/2017/10/04/science.aao1887#ref-7)).



https://i.imgur.com/KVogluy.jpg

Fig. 1Heterozygosity and inbreeding in the Vindija Neandertal.
(A) Distribution of heterozygosity over all autosomes in the three archaic hominins, 12 Non-Africans and 3 Africans. Each dot represents the heterozygosity measured for one autosome. The center bar indicates the mean heterozygosity across the autosomal genome. (B) Genome covered by shorter (2.5-10cM, red) and longer (>10cM, yellow) runs of homozygosity in the three archaic hominins.
https://i.imgur.com/HeSQZRx.jpg

Fig. 2Approximate ages of specimens and population split times.
Age estimates for the genomes estimated from branch shortening, i.e. the absence of mutations in the archaic genomes, are indicated by dashed lines. Population split time estimates are indicated by dashed lines. The majority of Neandertal DNA in present-day people comes from a population that split from the branch indicated in red. All reported ages assume a human-chimpanzee divergence of 13 million years. Numbers show ranges over point estimates (split times), or ranges over different data filters (branch shortening).

https://i.imgur.com/Ha2QY8I.jpg

Fig. 3Allele sharing between archaic and modern humans.
(A) Derived allele-sharing in percent of 19 African populations with the Altai and Denisovan, and Vindija and Denisovan genomes, respectively. (B) Sharing of derived alleles in each of the 19 African populations with the Vindija and Altai genomes. (C) Allele sharing of Neandertals with non-Africans and Africans. Points show derived allele sharing in percent for all pairwise comparisons between non-Africans (OAA: French, Sardinian, Han, Dai, Karitiana, Mixe, Australian, Papuan) and Africans (AFR: San, Mbuti, Yoruba). Mezmaiskaya 1 data were restricted to sequences showing evidence of deamination to reduce the influence of present-day human DNA contamination. Lines show two standard errors from the mean in all plots.

https://i.imgur.com/uOJp0KV.jpg

Fig. 4Estimates of fraction of Neandertal DNA for present-day populations.
(A) Colors indicate Neandertal ancestry estimates (20). Oceanian populations show high estimates due to Denisovan ancestry that is difficult to distinguish from Neandertal ancestry. (B) Amount of Neandertal sequence in present-day Europeans, South Asians and East Asians (20).

Expredel
14-10-17, 21:04
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/neandertals/neandertal_dna/sanchez-quinto-north-africa-2012.html

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