Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Toe phalanx and location of Neanderthal samples for which genome-wide data are available.
Figure 2: Phylogenetic relationships of the Altai Neanderthal.
Figure 3: Indications of inbreeding in the Altai Neanderthal individual.
Figure 4: Inference of population size change over time.
Figure 5: Relatedness of introgressing archaic and sequenced archaic samples.
Figure 6: Neanderthal gene flow into Siberian Denisovans.
Figure 7: Altai and Denisovan allele sharing with Africans stratified by African allele frequency.
Figure 8: A possible model of gene flow events in the Late Pleistocene.

Accession codes

Accessions

European Nucleotide Archive

Data deposits

All sequence data have been submitted to the European Nucleotide Archive (ENA) and are available under the following accessions: Altai Neanderthal: ERP002097, Mezmaiskaya Neanderthal: ERP002447. The data from the 25 present-day human genomes and 13 experimentally phased present-day genomes are available as a public dataset from http://aws.amazon.com/datasets/ and from http://cdna.eva.mpg.de/neandertal/altai/.

References

  1. Meyer, M. et al. A high-coverage genome sequence from an archaic Denisovan individual. Science 338, 222–226 (2012)

    CAS  ADS  Article  Google Scholar 

  2. Reich, D. et al. Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature 468, 1053–1060 (2010)

    CAS  ADS  Article  Google Scholar 

  3. Mednikova, M. B. A proximal pedal phalanx of a paleolithic hominin from Denisova cave, Altai. Archaeol. Ethnol. Anthropol. Eurasia 39, 129–138 (2011)

    Article  Google Scholar 

  4. Green, R. E. et al. A complete Neandertal mitochondrial genome sequence determined by high-throughput sequencing. Cell 134, 416–426 (2008)

    CAS  Article  Google Scholar 

  5. Briggs, A. W. et al. Targeted retrieval and analysis of five Neandertal mtDNA genomes. Science 325, 318–321 (2009)

    CAS  ADS  Article  Google Scholar 

  6. Golovanova, L. V., Hoffecker, J. F., Kharitonov, V. M. & Romanova, G. P. Mezmaiskaya cave: A Neanderthal occupation in the Northern Caucasus. Curr. Anthropol. 40, 77–86 (1999)

    Article  Google Scholar 

  7. Gansauge, M. T. & Meyer, M. Single-stranded DNA library preparation for the sequencing of ancient or damaged DNA. Nature Protocols 8, 737–748 (2013)

    Article  Google Scholar 

  8. Kircher, M. Analysis of high-throughput ancient DNA sequencing data. Methods Mol. Biol. 840, 197–228 (2012)

    CAS  Article  Google Scholar 

  9. Briggs, A. W. et al. Patterns of damage in genomic DNA sequences from a Neandertal. Proc. Natl Acad. Sci. USA 104, 14616–14621 (2007)

    CAS  ADS  Article  Google Scholar 

  10. Briggs, A. W. et al. Removal of deaminated cytosines and detection of in vivo methylation in ancient DNA. Nucleic Acids Res. 38, e87 (2010)

    Article  Google Scholar 

  11. Hofreiter, M., Jaenicke, V., Serre, D., von Haeseler, A. & Paabo, S. DNA sequences from multiple amplifications reveal artifacts induced by cytosine deamination in ancient DNA. Nucleic Acids Res. 29, 4793–4799 (2001)

    CAS  Article  Google Scholar 

  12. Green, R. E. et al. A draft sequence of the Neandertal genome. Science 328, 710–722 (2010)

    CAS  ADS  Article  Google Scholar 

  13. Skinner, A. R. et al. ESR dating at Mezmaiskaya Cave, Russia. Appl. Radiat. Isot. 62, 219–224 (2005)

    CAS  Article  Google Scholar 

  14. Kitzman, J. O. et al. Haplotype-resolved genome sequencing of a Gujarati Indian individual. Nature Biotechnol. 29, 59–63 (2011)

    CAS  Article  Google Scholar 

  15. Abecasis, G. R. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010)

    ADS  Article  Google Scholar 

  16. Awadalla, P. et al. Direct measure of the de novo mutation rate in autism and schizophrenia cohorts. Am. J. Hum. Genet. 87, 316–324 (2010)

    CAS  Article  Google Scholar 

  17. Roach, J. C. et al. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328, 636–639 (2010)

    CAS  ADS  Article  Google Scholar 

  18. Kong, A. et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature 488, 471–475 (2012)

    CAS  ADS  Article  Google Scholar 

  19. Campbell, C. D. et al. Estimating the human mutation rate using autozygosity in a founder population. Nature Genet. 44, 1277–1281 (2012)

    CAS  Article  Google Scholar 

  20. Li, H. & Durbin, R. Inference of human population history from individual whole-genome sequences. Nature 475, 493–496 (2011)

    CAS  Article  Google Scholar 

  21. Prado-Martinez, J. et al. Great ape genetic diversity and population history. Nature 499, 471–475 (2013)

    CAS  ADS  Article  Google Scholar 

  22. Kirin, M. et al. Genomic runs of homozygosity record population history and consanguinity. PLoS ONE 5, e13996 (2010)

    ADS  Article  Google Scholar 

  23. Leffler, E. M. et al. Revisiting an old riddle: what determines genetic diversity levels within species? PLoS Biol. 10, e1001388 (2012)

    CAS  Article  Google Scholar 

  24. Reich, D. et al. Denisova admixture and the first modern human dispersals into Southeast Asia and Oceania. Am. J. Hum. Genet. 89, 516–528 (2011)

    CAS  Article  Google Scholar 

  25. Skoglund, P. & Jakobsson, M. Archaic human ancestry in East Asia. Proc. Natl Acad. Sci. USA 108, 18301–18306 (2011)

    CAS  ADS  Article  Google Scholar 

  26. Fu, Q. et al. DNA analysis of an early modern human from Tianyuan Cave, China. Proc. Natl Acad. Sci. USA 110, 2223–2227 (2013)

    CAS  ADS  Article  Google Scholar 

  27. Wall, J. D. et al. Higher levels of Neanderthal ancestry in East Asians than in Europeans. Genetics 194, 199–209 (2013)

    Article  Google Scholar 

  28. Abi-Rached, L. et al. The shaping of modern human immune systems by multiregional admixture with archaic humans. Science 334, 89–94 (2011)

    CAS  ADS  Article  Google Scholar 

  29. Waddell, P. J. & Tan, X. New g%AIC, g%AICc, g%BIC, and power divergence fit statistics expose mating between modern humans, Neanderthals and other archaics. Preprint at http://arxiv.org/abs/1212.6820 (2012)

  30. Wegmann, D., Leuenberger, C., Neuenschwander, S. & Excoffier, L. ABCtoolbox: a versatile toolkit for approximate Bayesian computations. BMC Bioinformatics 11, 116 (2010)

    Article  Google Scholar 

  31. Kumar, R. A. et al. Recurrent 16p11.2 microdeletions in autism. Hum. Mol. Genet. 17, 628–638 (2008)

    CAS  Article  Google Scholar 

  32. Abecasis, G. R. et al. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012)

    ADS  Article  Google Scholar 

  33. Fietz, S. A. & Huttner, W. B. Cortical progenitor expansion, self-renewal and neurogenesis-a polarized perspective. Curr. Opin. Neurobiol. 21, 23–35 (2011)

    CAS  Article  Google Scholar 

  34. Kokovay, E. et al. VCAM1 is essential to maintain the structure of the SVZ niche and acts as an environmental sensor to regulate SVZ lineage progression. Cell Stem Cell 11, 220–230 (2012)

    CAS  Article  Google Scholar 

  35. Wang, C., Liang, C. C., Bian, Z. C., Zhu, Y. & Guan, J. L. FIP200 is required for maintenance and differentiation of postnatal neural stem cells. Nature Neurosci. 16, 532–542 (2013)

    Article  Google Scholar 

  36. Rios, D. et al. A database and API for variation, dense genotyping and resequencing data. BMC Bioinformatics 11, 238 (2010)

    Article  Google Scholar 

  37. Hublin, J. J. Out of Africa: modern human origins special feature: the origin of Neandertals. Proc. Natl Acad. Sci. USA 106, 16022–16027 (2009)

    CAS  ADS  Article  Google Scholar 

  38. Sankararaman, S., Patterson, N., Li, H., Pääbo, S. & Reich, D. The date of interbreeding between Neandertals and modern humans. PLoS Genet. 8, e1002947 (2012)

    CAS  Article  Google Scholar 

  39. Yang, M. A., Malaspinas, A. S., Durand, E. Y. & Slatkin, M. Ancient structure in Africa unlikely to explain Neanderthal and non-African genetic similarity. Mol. Biol. Evol. 29, 2987–2995 (2012)

    CAS  Article  Google Scholar 

  40. Eriksson, A. & Manica, A. Effect of ancient population structure on the degree of polymorphism shared between modern human populations and ancient hominins. Proc. Natl Acad. Sci. USA 109, 13956–13960 (2012)

    CAS  ADS  Article  Google Scholar 

  41. Krause, J. et al. The complete mitochondrial DNA genome of an unknown hominin from southern Siberia. Nature 464, 894–897 (2010)

    CAS  ADS  Article  Google Scholar 

  42. Gabunia, L. et al. Dmanisi and dispersal. Evol. Anthropol. 10, 158–170 (2001)

    Article  Google Scholar 

  43. Asfaw, B. et al. Remains of Homo erectus from Bouri, Middle Awash, Ethiopia. Nature 416, 317–320 (2002)

    ADS  Article  Google Scholar 

  44. Kircher, M., Stenzel, U. & Kelso, J. Improved base calling for the Illumina Genome Analyzer using machine learning strategies. Genome Biol. 10, R83 (2009)

    Article  Google Scholar 

  45. Langergraber, K. E. et al. Generation times in wild chimpanzees and gorillas suggest earlier divergence times in great ape and human evolution. Proc. Natl Acad. Sci. USA 109, 15716–15721 (2012)

    CAS  ADS  Article  Google Scholar 

  46. Scally, A. & Durbin, R. Revising the human mutation rate: implications for understanding human evolution. Nature Rev. Genet. 13, 745–753 (2012)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank M. Hammer, C. Winkler and W. Klitz for sharing DNA samples; W. Huttner and his group, B. Peter, J. G. Schraiber and M. A. Yang for helpful discussions; and A. Lewis and R. Qiu for technical assistance. N.P. and D.R. are grateful for the chance to discuss these results with Peter Waddell who independently found evidence of a deeply diverged hominin admixing into the Denisova genome. D.R. and E.E.E. are Howard Hughes Medical Institute Investigators. D.R. and N.P. were supported by NSF grant number 1032255 and NIH grant GM100233; E.E.E. by NIH grant HG002385; J.S. by grant HG006283 from the National Genome Research Institute (NHGRI); S.S. by a post-doctoral fellowship from the Harvard University Science of the Human Past Program; F.J. and M.S. in part by a grant from the NIH (R01-GM40282); P.H.S. by an HHMI International Student Fellowship. We thank the team at the NIH Intramural Sequencing Center and Alice Young in particular, for generating some of the sequence reported here. This research was supported in part by the Paul G. Allen Family Foundation. Major funding support came from the Presidential Innovation Fund of the Max Planck Society.

Author information

Authors and Affiliations

Authors

Contributions

S.Saw., A.H. and Q.F. performed the experiments; K.P., F.R., N.P., F.J., S.San., S.Saw., A.H., G.R., P.H.S., C.d.F., M.D., Q.F., M.Ki., M.Ku., M.L., M.M., M.O., M.Si., C.T., H.L., S.M., A.T., P.M., J.P., J.C.M., S.H.V., R.E.G., I.H., P.L.F.J., J.O.K., J.S., E.E.E., E.S.L., T.E.B., M.Sl., D.R., J.K., and S.P. analysed genetic data; L.V.G., V.B.D., M.V.S., A.P.D. and B.V. analysed archaeological and anthropological data; H.B. and H.C. provided samples and reagents; K.P., J.K. and S.P. wrote and edited the manuscript with input from all authors.

Corresponding authors

Correspondence to Montgomery Slatkin, David Reich or Svante Pääbo.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Heterozygosity estimates for the Altai Neanderthal 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 (Supplementary Information section 9).

Extended Data Figure 2 Neanderthal-introgressed loci in Denisova.

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

Extended Data Table 1 Neanderthal ancestry estimate
Extended Data Table 2 Selected D-statistics supporting inferences about gene flows
Extended Data Table 3 Lineage-specific segmental duplications along each of the terminal branches and genes encompassed

Supplementary information

Supplementary Information

This file contains Supplementary Text, Tables and Figures – see contents page for details. (PDF 16537 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Prüfer, K., Racimo, F., Patterson, N. et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–49 (2014). https://doi.org/10.1038/nature12886

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature12886

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing