The complete genome sequence of a Neanderthal from the Altai Mountains

Abstract

We present a high-quality genome sequence of a Neanderthal woman from Siberia. We show that her parents were related at the level of half-siblings and that mating among close relatives was common among her recent ancestors. We also sequenced the genome of a Neanderthal from the Caucasus to low coverage. An analysis of the relationships and population history of available archaic genomes and 25 present-day human genomes shows that several gene flow events occurred among Neanderthals, Denisovans and early modern humans, possibly including gene flow into Denisovans from an unknown archaic group. Thus, interbreeding, albeit of low magnitude, occurred among many hominin groups in the Late Pleistocene. In addition, the high-quality Neanderthal genome allows us to establish a definitive list of substitutions that became fixed in modern humans after their separation from the ancestors of Neanderthals and Denisovans.

Figure 1. Toe phalanx and location of Neandertal samples for which genome-wide data are available

a, The toe phalanx found in the East Gallery of Denisova Cave in 2010. Left: dorsal view; Right: left view. b, Map of Eurasia showing the location of Vindija cave, Mezmaiskaya cave and Denisova cave.

Figure 2. Phylogenetic relationships of the Altai Neandertal

a, Bayesian tree of mitochondrial sequences of the toe phalanx, the Denisovan finger phalanx, six Neandertals, and five present-day humans. Posterior probabilities are given for branches whose support is less than one (SI 2b). b, Neighbor-joining tree based on autosomal transversion differences among the toe phalanx, four Neandertals, the Denisova genome, and seven present-day human individuals. Bootstrap values are shown for branches supported by less than 100% of 1,000 bootstrap replicates (SI 6).

Figure 3. Indications of inbreeding in the Altai Neandertal individual

a, Time since the most recent common ancestor in log-scale for the two alleles of a French, the Denisovan and the Altai Neandertal individual (SI 12) along 40 Mb of chromosome 21. b, Pedigrees showing four possible scenarios of parental relatedness for the Altai Neandertal (i.e. the child at the bottom of each pedigree). Two additional scenarios can be derived by switching the sex of the parents for the panels marked with an asterisk. c, Fraction of the genome in runs of homozygosity between 2.5 and 10cM in length for Altai Neandertal, Denisovan and the three present-day human individuals with the largest fractions (grey bars). The fractions for the Altai Neandertal (bottom four bars) are reduced by the fraction expected from the four inbreeding scenarios in a.

Figure 4. Inference of population size change over time

The y-axis specifies a number proportional to the population size Ne. The x-axis specifies time in units of divergence per base pair (along the top in years for mutation rates of 0.5 × 10⁻⁹ to 1.0 × 10⁻⁹ per site per year). The analysis assumes that the Neandertal and Denisova remains are of the same age, whereas archaeological evidence and the branch shortening suggest that the Neandertal bone is older than the Denisovan bone. However, because the exact difference in ages is not known, it is not possible to determine whether the reduction in population size experienced by both archaic groups (but not by modern humans) coincided in time.

Figure 5. Relatedness of introgressing archaic and sequenced archaic samples

Divergence of phased present-day human genomes to archaic genomes in windows of size 0.01cM with a minimum of 25,000 analysed bases. Windows are sorted by sequence divergence measured on the archaic side of the tree (SI 13) and the y-axis reports the divergence relative to human-chimpanzee divergence for cumulative fractions of the sorted windows over the entire genomes. Regions of low divergence between non-Africans and Neandertals (a) and between Oceanians and Denisovans (b) indicate gene flow between these groups and the relative divergences between the introgressing archaic and sequenced archaic samples.

Figure 6. Neandertal gene flow into Siberian Denisovans

Divergence in 0.01cM sized windows with at least 50kb analyzed bases between a “test”-archaic genome and effectively haploid regions of the other archaic genome archaic plotted against the most recent-common ancestor of the two alleles of the “test”-archaic. The plot shows 50 equally sized bins of windows for the “test”-archaic Denisovan against the effectively haploid Neandertal (red) and for the “test”-archaic Altai Neandertal against the effectively haploid Denisovan (blue). Divergence is given as percentage of human-chimpanzee divergence. Windows that show a close relationship between the effective haploid Altai Neandertal and the closest inferred Denisovan haplotype show a deep divergence to the second Denisovan haplotype, indicating gene flow from Neandertal into Denisovan.

Figure 7. Altai and Denisovan allele sharing with Africans stratified by African allele frequency

The plot shows the D-statistic of the form D(Neandertal, Denisova; Africa, Chimpanzee) binned by derived allele count in 10 deeply sequenced African genomes. Error-bars represent ± 1 standard error. High-frequency and fixed derived alleles in Africa are more often shared with the Neandertal than with Denisovan genome.

Figure 8. A possible model of gene flow events in the late Pleistocene

The direction and estimated magnitude of inferred gene flow events are shown. Branch lengths and ages gene flows are not drawn to scale. The dashed line indicates that it is uncertain if Denisovan gene flow into modern humans occurred once or more times. D.I. denotes the introgressing Denisovan, N.I. the introgressing Neandertal. Note that the age of the archaic genomes precludes detection of gene-flow from modern humans into the archaic hominins.

Extended Data Figure 1

Heterozygosity estimates for the Altai Neandertal individual, the Denisovan individual, non-Africans and Africans. The bars for the latter two give the range of heterozygosity observed among 15 non-African and 10 African individuals, respectively (SI 9).

Extended Data Figure 2

Neandertal-introgressed loci in Denisova Divergence of the Altai Neandertal to the most closely related Denisovan haplotype in windows of at least 200kb on chromosome 6. Divergence is given as percentage of human-chimpanzee divergence and bars represent ± 1 standard error.