Admixture between early modern humans and Neandertals approximately 50,000-60,000 years ago has resulted in 1.5-4% Neandertal ancestry in the genomes of present-day non-Africans. Evidence is ...accumulating that some of these archaic alleles are advantageous for modern humans, while others are deleterious; however, the major mechanism by which these archaic alleles act has not been fully explored.
Here we assess the contributions of introgressed non-synonymous and regulatory variants to modern human protein and gene expression variation. We show that gene expression changes are more often associated with Neandertal ancestry than expected, and that the introgressed non-synonymous variants tend to have less predicted functional effect on modern human proteins than mutations that arose on the human lineage. Conversely, introgressed alleles contribute proportionally more to expression variation than non-introgressed alleles.
Our results suggest that the major influence of Neandertal introgressed alleles is through their effects on gene regulation.
Natural selection that affected modern humans early in their evolution has likely shaped some of the traits that set present-day humans apart from their closest extinct and living relatives. The ...ability to detect ancient natural selection in the human genome could provide insights into the molecular basis for these human-specific traits. Here, we introduce a method for detecting ancient selective sweeps by scanning for extended genomic regions where our closest extinct relatives, Neandertals and Denisovans, fall outside of the present-day human variation. Regions that are unusually long indicate the presence of lineages that reached fixation in the human population faster than expected under neutral evolution. Using simulations, we show that the method is able to detect ancient events of positive selection and that it can differentiate those from background selection. Applying our method to the 1000 Genomes data set, we find evidence for ancient selective sweeps favoring regulatory changes and present a list of genomic regions that are predicted to underlie positively selected human specific traits.
We sequenced the genome of a Neandertal from Chagyrskaya Cave in the Altai Mountains, Russia, to 27-fold genomic coverage. We show that this Neandertal was a female and that she was more related to ...Neandertals in western Eurasia Prüfer et al., Science 358, 655–658 (2017); Hajdinjak et al., Nature 555, 652–656 (2018) than to Neandertals who lived earlier in Denisova Cave Prüfer et al., Nature 505, 43–49 (2014), which is located about 100 km away. About 12.9% of the Chagyrskaya genome is spanned by homozygous regions that are between 2.5 and 10 centiMorgans (cM) long. This is consistent with the fact that Siberian Neandertals lived in relatively isolated populations of less than 60 individuals. In contrast, a Neandertal from Europe, a Denisovan from the Altai Mountains, and ancient modern humans seem to have lived in populations of larger sizes. The availability of three Neandertal genomes of high quality allows a view of genetic features that were unique to Neandertals and that are likely to have been at high frequency among them. We find that genes highly expressed in the striatum in the basal ganglia of the brain carry more aminoacid- changing substitutions than genes expressed elsewhere in the brain, suggesting that the striatum may have evolved unique functions in Neandertals.
Neanderthals and Denisovans are extinct groups of hominins that separated from each other more than 390,000 years ago
. Here we present the genome of 'Denisova 11', a bone fragment from Denisova Cave ...(Russia)
and show that it comes from an individual who had a Neanderthal mother and a Denisovan father. The father, whose genome bears traces of Neanderthal ancestry, came from a population related to a later Denisovan found in the cave
. The mother came from a population more closely related to Neanderthals who lived later in Europe
than to an earlier Neanderthal found in Denisova Cave
, suggesting that migrations of Neanderthals between eastern and western Eurasia occurred sometime after 120,000 years ago. The finding of a first-generation Neanderthal-Denisovan offspring among the small number of archaic specimens sequenced to date suggests that mixing between Late Pleistocene hominin groups was common when they met.
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 ~50,000 years ago from ...Vindija Cave, Croatia, to ~30-fold genomic coverage. She carried 1.6 differences per 10,000 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 to 20% more Neandertal DNA to be identified in present-day humans, including variants involved in low-density lipoprotein cholesterol concentrations, schizophrenia, and other diseases.
The study of ancient DNA is hampered by degradation, resulting in short DNA fragments. Advances in laboratory methods have made it possible to retrieve short DNA fragments, thereby improving access ...to DNA preserved in highly degraded, ancient material. However, such material contains large amounts of microbial contamination in addition to DNA fragments from the ancient organism. The resulting mixture of sequences constitutes a challenge for computational analysis, since microbial sequences are hard to distinguish from the ancient sequences of interest, especially when they are short.
Here, we develop a method to quantify spurious alignments based on the presence or absence of rare variants. We find that spurious alignments are enriched for mismatches and insertion/deletion differences and lack substitution patterns typical of ancient DNA. The impact of spurious alignments can be reduced by filtering on these features and by imposing a sample-specific minimum length cutoff. We apply this approach to sequences from four ~ 430,000-year-old Sima de los Huesos hominin remains, which contain particularly short DNA fragments, and increase the amount of usable sequence data by 17-150%. This allows us to place a third specimen from the site on the Neandertal lineage.
Our method maximizes the sequence data amenable to genetic analysis from highly degraded ancient material and avoids pitfalls that are associated with the analysis of ultra-short DNA sequences.
We present a DNA library preparation method that has allowed us to reconstruct a high-coverage (30×) genome sequence of a Denisovan, an extinct relative of Neandertals. The quality of this genome ...allows a direct estimation of Denisovan heterozygosity indicating that genetic diversity in these archaic hominins was extremely low. It also allows tentative dating of the specimen on the basis of "missing evolution" in its genome, detailed measurements of Denisovan and Neandertal admixture into present-day human populations, and the generation of a near-complete catalog of genetic changes that swept to high frequency in modern humans since their divergence from Denisovans.
Denisovans, a sister group of Neandertals, have been described on the basis of a nuclear genome sequence from a finger phalanx (Denisova 3) found in Denisova Cave in the Altai Mountains. The only ...other Denisovan specimen described to date is a molar (Denisova 4) found at the same site. This tooth carries a mtDNA sequence similar to that ofDenisova 3. Here we present nuclear DNA sequences fromDenisova 4and a morphological description, as well as mitochondrial and nuclear DNA sequence data, from another molar (Denisova 8) found in Denisova Cave in 2010. This new molar is similar toDenisova 4in being very large and lacking traits typical of Neandertals and modern humans. Nuclear DNA sequences from the two molars form a clade withDenisova 3. The mtDNA ofDenisova 8is more diverged and has accumulated fewer substitutions than the mtDNAs of the other two specimens, suggesting Denisovans were present in the region over an extended period. The nuclear DNA sequence diversity among the three Denisovans is comparable to that among six Neandertals, but lower than that among present-day humans.
Fossils and molecular data are two independent sources of information that should in principle provide consistent inferences of when evolutionary lineages diverged. Here we use an alternative ...approach to genetic inference of species split times in recent human and ape evolution that is independent of the fossil record. We first use genetic parentage information on a large number of wild chimpanzees and mountain gorillas to directly infer their average generation times. We then compare these generation time estimates with those of humans and apply recent estimates of the human mutation rate per generation to derive estimates of split times of great apes and humans that are independent of fossil calibration. We date the human–chimpanzee split to at least 7–8 million years and the population split between Neanderthals and modern humans to 400,000–800,000 y ago. This suggests that molecular divergence dates may not be in conflict with the attribution of 6- to 7-million-y-old fossils to the human lineage and 400,000-y-old fossils to the Neanderthal lineage.
Small insertions and deletions occur in humans at a lower rate compared to nucleotide changes, but evolve under more constraint than nucleotide changes. While the evolution of insertions and ...deletions have been investigated using ape outgroups, the now available genome of a Neandertal can shed light on the evolution of indels in more recent times.
We used the Neandertal genome together with several primate outgroup genomes to differentiate between human insertion/deletion changes that likely occurred before the split from Neandertals and those that likely arose later. Changes that pre-date the split from Neandertals show a smaller proportion of deletions than those that occurred later. The presence of a Neandertal-shared allele in Europeans or Asians but the absence in Africans was used to detect putatively introgressed indels in Europeans and Asians. A larger proportion of these variants reside in intergenic regions compared to other modern human variants, and some variants are linked to SNPs that have been associated with traits in modern humans.
Our results are in agreement with earlier results that suggested that deletions evolve under more constraint than insertions. When considering Neandertal introgressed variants, we find some evidence that negative selection affected these variants more than other variants segregating in modern humans. Among introgressed variants we also identify indels that may influence the phenotype of their carriers. In particular an introgressed deletion associated with a decrease in the time to menarche may constitute an example of a former Neandertal-specific trait contributing to modern human phenotypic diversity.
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