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A high-coverage Neandertal genome from Chagyrskaya Cave
Significance
We present the third high-quality genome to be determined from a Neandertal. Patterns of variation in the genome suggest that her ancestors lived in relatively isolated populations of less than 60 individuals. When we analyze this genome together with two previously sequenced Neandertal genomes, we find that genes expressed in the striatum of the brain may have changed especially much, suggesting that the striatum may have evolved unique functions in Neandertals.
Abstract
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 amino-acid-changing substitutions than genes expressed elNeandertals and Denisovans are the closest evolutionary relatives of present-day humans. Analyses of their genomes showed that they contributed genetically to present-day people outside sub-Saharan Africa (1, 2). However, to date, the genomes of only two Neandertals and one Denisovan have been sequenced to high quality. One of these Neandertal genomes (Vindija 33.19) comes from an individual found in Vindija Cave in Croatia (3), whereas the other Neandertal genome (Denisova 5 or the “Altai Neandertal”) (4) and the Denisovan genome (Denisova 3) (5) both come from specimens discovered in Denisova Cave, in the Altai mountains in Siberia.
A number of archaic genomes of moderate quality (one- to threefold genomic coverage) have yielded additional insights into Neandertal history. For example, genome sequences from five late Neandertals from Europe have shown that they carried little genetic variation (6, 7) and were more closely related to the Vindija 33.19 than to the Denisova 5 Neandertal. A genome sequence from a morphologically undiagnostic bone from Denisova Cave, Denisova 11, belonged to the direct offspring of a Neandertal mother and a Denisovan father (8), indicating that the two groups met in the Altai region. The Neandertal mother of Denisova 11 was more closely related to Vindija 33.19 than to Denisova 5, indicating that a replacement of Neandertal populations in the Altai Mountains occurred (8).
Here, we present the high-coverage genome sequence of a Neandertal from Chagyrskaya Cave, located 106 km to the west of Denisova Cave (9⇓⇓–12) (Fig. 1). This genome provides insights into Neandertal population structure and history and allows the identification of genomic features unique to Neandertals.
Fig. 1.
The Chagyrskaya 8 Neandertal and its relationship with other archaic individuals. (Top) Locations of Chagyrskaya Cave and other sites where archaic specimens analyzed here were found are indicated. (Bottom) Schematic illustration of the relationship among archaic genomes. The gray outline describes relationships between high-coverage genomes (SI Appendix 7). Population split times estimated using the F(A|B) statistics (3, 4, 8) (SI Appendix 7) between high-coverage and low-coverage genomes are indicated by horizontal dashed line. Within the gray outlines, colored silhouettes schematically indicate population sizes (Ne) over time as estimated in SI Appendix 6. Neandertals are indicated in blue, Denisovans in red. Genomes determined to high genomic coverage (>27-fold) are indicated by large circles. The genomes from Spy, Goyet, and Les Cottés are reported in ref. 6, Scladina and Holehnstein-Stadel in ref. 13, other genomes in refs. 2⇓⇓⇓–6, 8.
Results
Genome Sequencing and Age Estimates.
We sampled 100 mg of bone powder from Chagyrskaya 8, a phalanx found in 2011 at Chagyrskaya Cave in layer 6b (SI Appendix 1). The DNA extracted (14) allowed the nuclear genome to be sequenced (SI Appendix 2) to an average coverage of 27.6-fold (SI Appendix 3). Less than 1% of the DNA fragments sequenced were estimated to originate from contamination by present-day modern human DNA (SI Appendixes 4 and 5).
We estimated the age of Chagyrskaya 8 using two different methods (SI Appendix 6). First, we counted the proportion of “missing” derived substitutions compared to present-day genomes (3⇓–5, 15). We also used a method similar to Fu et al. (15) that takes advantage of the shared evolutionary history of the three high-coverage Neandertal genomes. Under the assumption that Neandertals had the same mutation rate (1.45 × 10−8 mutations per generation per base pair) (15) and generation time as present-day humans (29 y), both methods suggest that Chagyrskaya 8 lived ∼80 kya (1,000 y ago), i.e., ∼30 ky (1,000 y) after Denisova 5 and ∼30 ky before Vindija 33.19. This estimate is older than the optically stimulated luminescence dates of ∼60 kya (10, 12) for the archaeological layer in which Chagyrskaya 8 was found. Excluding redeposition from lower, older layers (10, 12), this might indicate that the genetic dates, based on the current mutation rate in humans, are incorrect. Possible explanations could be that Neandertals had a lower mutation rate than modern humans or that that the modern human mutation rate decreased recently (16). Additional high-quality genomes determined from well-dated Neandertal remains are needed to address these possibilities. Nevertheless, the Chagyrskaya 8 Neandertal and the Denisovan Denisova 3 display similar proportions of missing mutations relative to present-day humans, suggesting that they lived approximately at the same time (SI Appendix 6).
Relationship to Other Neandertals and Denisovans.
Chagyrskaya 8 shares more derived alleles with Vindija 33.19 and other later Neandertals in the Caucasus and in Europe than with the older Denisova 5 Neandertal from the Altai (Fig. 2). With the Denisovan Denisova 3, Chagyrskaya 8 shares fewer derived alleles than does Denisova 5.
Fig. 2.
Relative sharing of derived allele among the Chagyrskaya 8 and other archaic genomes. Positive values in the D statistic indicate more allele sharing with Chagyrskaya 8 than with Denisova 5 (A) or than with Vindija 33.19 (B). Error bars indicate one SE. One asterisk indicates Z > 2; two asterisks indicate Z > 3. Late Neandertals of low genomic coverage refer to the genomes in ref. 6.
When compared to Vindija 33.19 (Fig. 2), Chagyrskaya 8 shares fewer derived alleles with other Neandertals that lived in Europe ∼50 kya, i.e., approximately at the same time as Vindija 33.19. However, Chagyrskaya 8 shares more derived alleles than Vindija 33.19 with Denisova 11, a first-generation Neandertal–Denisovan offspring (8). Since Vindija 33.19 and Chagyrskaya 8 do not differ in their sharing of derived alleles with the Denisovan Denisova 3, this indicates that Chagyrskaya 8 is most closely related among currently known Neandertal to the mother of Denisova 11 found at Denisova Cave (Fig. 1 and SI Appendix 7).
Significance
We present the third high-quality genome to be determined from a Neandertal. Patterns of variation in the genome suggest that her ancestors lived in relatively isolated populations of less than 60 individuals. When we analyze this genome together with two previously sequenced Neandertal genomes, we find that genes expressed in the striatum of the brain may have changed especially much, suggesting that the striatum may have evolved unique functions in Neandertals.
Abstract
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 amino-acid-changing substitutions than genes expressed elNeandertals and Denisovans are the closest evolutionary relatives of present-day humans. Analyses of their genomes showed that they contributed genetically to present-day people outside sub-Saharan Africa (1, 2). However, to date, the genomes of only two Neandertals and one Denisovan have been sequenced to high quality. One of these Neandertal genomes (Vindija 33.19) comes from an individual found in Vindija Cave in Croatia (3), whereas the other Neandertal genome (Denisova 5 or the “Altai Neandertal”) (4) and the Denisovan genome (Denisova 3) (5) both come from specimens discovered in Denisova Cave, in the Altai mountains in Siberia.
A number of archaic genomes of moderate quality (one- to threefold genomic coverage) have yielded additional insights into Neandertal history. For example, genome sequences from five late Neandertals from Europe have shown that they carried little genetic variation (6, 7) and were more closely related to the Vindija 33.19 than to the Denisova 5 Neandertal. A genome sequence from a morphologically undiagnostic bone from Denisova Cave, Denisova 11, belonged to the direct offspring of a Neandertal mother and a Denisovan father (8), indicating that the two groups met in the Altai region. The Neandertal mother of Denisova 11 was more closely related to Vindija 33.19 than to Denisova 5, indicating that a replacement of Neandertal populations in the Altai Mountains occurred (8).
Here, we present the high-coverage genome sequence of a Neandertal from Chagyrskaya Cave, located 106 km to the west of Denisova Cave (9⇓⇓–12) (Fig. 1). This genome provides insights into Neandertal population structure and history and allows the identification of genomic features unique to Neandertals.
Fig. 1.
The Chagyrskaya 8 Neandertal and its relationship with other archaic individuals. (Top) Locations of Chagyrskaya Cave and other sites where archaic specimens analyzed here were found are indicated. (Bottom) Schematic illustration of the relationship among archaic genomes. The gray outline describes relationships between high-coverage genomes (SI Appendix 7). Population split times estimated using the F(A|B) statistics (3, 4, 8) (SI Appendix 7) between high-coverage and low-coverage genomes are indicated by horizontal dashed line. Within the gray outlines, colored silhouettes schematically indicate population sizes (Ne) over time as estimated in SI Appendix 6. Neandertals are indicated in blue, Denisovans in red. Genomes determined to high genomic coverage (>27-fold) are indicated by large circles. The genomes from Spy, Goyet, and Les Cottés are reported in ref. 6, Scladina and Holehnstein-Stadel in ref. 13, other genomes in refs. 2⇓⇓⇓–6, 8.
Results
Genome Sequencing and Age Estimates.
We sampled 100 mg of bone powder from Chagyrskaya 8, a phalanx found in 2011 at Chagyrskaya Cave in layer 6b (SI Appendix 1). The DNA extracted (14) allowed the nuclear genome to be sequenced (SI Appendix 2) to an average coverage of 27.6-fold (SI Appendix 3). Less than 1% of the DNA fragments sequenced were estimated to originate from contamination by present-day modern human DNA (SI Appendixes 4 and 5).
We estimated the age of Chagyrskaya 8 using two different methods (SI Appendix 6). First, we counted the proportion of “missing” derived substitutions compared to present-day genomes (3⇓–5, 15). We also used a method similar to Fu et al. (15) that takes advantage of the shared evolutionary history of the three high-coverage Neandertal genomes. Under the assumption that Neandertals had the same mutation rate (1.45 × 10−8 mutations per generation per base pair) (15) and generation time as present-day humans (29 y), both methods suggest that Chagyrskaya 8 lived ∼80 kya (1,000 y ago), i.e., ∼30 ky (1,000 y) after Denisova 5 and ∼30 ky before Vindija 33.19. This estimate is older than the optically stimulated luminescence dates of ∼60 kya (10, 12) for the archaeological layer in which Chagyrskaya 8 was found. Excluding redeposition from lower, older layers (10, 12), this might indicate that the genetic dates, based on the current mutation rate in humans, are incorrect. Possible explanations could be that Neandertals had a lower mutation rate than modern humans or that that the modern human mutation rate decreased recently (16). Additional high-quality genomes determined from well-dated Neandertal remains are needed to address these possibilities. Nevertheless, the Chagyrskaya 8 Neandertal and the Denisovan Denisova 3 display similar proportions of missing mutations relative to present-day humans, suggesting that they lived approximately at the same time (SI Appendix 6).
Relationship to Other Neandertals and Denisovans.
Chagyrskaya 8 shares more derived alleles with Vindija 33.19 and other later Neandertals in the Caucasus and in Europe than with the older Denisova 5 Neandertal from the Altai (Fig. 2). With the Denisovan Denisova 3, Chagyrskaya 8 shares fewer derived alleles than does Denisova 5.
Fig. 2.
Relative sharing of derived allele among the Chagyrskaya 8 and other archaic genomes. Positive values in the D statistic indicate more allele sharing with Chagyrskaya 8 than with Denisova 5 (A) or than with Vindija 33.19 (B). Error bars indicate one SE. One asterisk indicates Z > 2; two asterisks indicate Z > 3. Late Neandertals of low genomic coverage refer to the genomes in ref. 6.
When compared to Vindija 33.19 (Fig. 2), Chagyrskaya 8 shares fewer derived alleles with other Neandertals that lived in Europe ∼50 kya, i.e., approximately at the same time as Vindija 33.19. However, Chagyrskaya 8 shares more derived alleles than Vindija 33.19 with Denisova 11, a first-generation Neandertal–Denisovan offspring (8). Since Vindija 33.19 and Chagyrskaya 8 do not differ in their sharing of derived alleles with the Denisovan Denisova 3, this indicates that Chagyrskaya 8 is most closely related among currently known Neandertal to the mother of Denisova 11 found at Denisova Cave (Fig. 1 and SI Appendix 7).