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Reconstructing the genetic history of late Neanderthals

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Abstract

Although it has previously been shown that Neanderthals contributed DNA to modern humans1,2, not much is known about the genetic diversity of Neanderthals or the relationship between late Neanderthal populations at the time at which their last interactions with early modern humans occurred and before they eventually disappeared. Our ability to retrieve DNA from a larger number of Neanderthal individuals has been limited by poor preservation of endogenous DNA3 and contamination of Neanderthal skeletal remains by large amounts of microbial and present-day human DNA3,4,5. Here we use hypochlorite treatment6 of as little as 9 mg of bone or tooth powder to generate between 1- and 2.7-fold genomic coverage of five Neanderthals who lived around 39,000 to 47,000 years ago (that is, late Neanderthals), thereby doubling the number of Neanderthals for which genome sequences are available. Genetic similarity among late Neanderthals is well predicted by their geographical location, and comparison to the genome of an older Neanderthal from the Caucasus2,7 indicates that a population turnover is likely to have occurred, either in the Caucasus or throughout Europe, towards the end of Neanderthal history. We find that the bulk of Neanderthal gene flow into early modern humans originated from one or more source populations that diverged from the Neanderthals that were studied here at least 70,000 years ago, but after they split from a previously sequenced Neanderthal from Siberia2 around 150,000 years ago. Although four of the Neanderthals studied here post-date the putative arrival of early modern humans into Europe, we do not detect any recent gene flow from early modern humans in their ancestry.

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Figure 1: Specimen information and the effects of 0.5% hypochlorite treatment.
Figure 2: Phylogenetic relationships of late Neanderthals.
Figure 3: Proximity to the introgressing Neanderthal populations in present-day and ancient humans calculated using D(Neanderthal1, Neanderthal2; non-African, African).

Accession codes

Primary accessions

European Nucleotide Archive

NCBI Reference Sequence

Change history

  • 28 March 2018

    In the original PDF version of this Letter, Extended Data Tables 1-4 were corrupted; this has been corrected online.

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Acknowledgements

We thank A. Weihmann and B. Höber for their help with DNA sequencing, U. Stenzel for computational support and advice for data analysis, R. Barr for the help with the graphics, V. Slon for helpful discussions and comments on the manuscript. Q.F. is funded in part by NSFC (91731303, 41672021, 41630102), CAS (QYZDB-SSW-DQC003, XDB13000000, XDA19050102, XDPB05) and the Howard Hughes Medical Institute (grant number 55008731). D.R. is supported by the US National Science Foundation (grant BCS-1032255) and by an Allen Discovery Center of the Paul Allen Foundation and is an investigator of the Howard Hughes Medical Institute. This study was funded by the Max Planck Society and the European Research Council (grant agreement number 694707 to S.P.). M.So. thanks the owner of Les Cottés, and the French Ministry of Culture for financial support and excavation permits.

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Authors and Affiliations

Authors

Contributions

M.H., M.M. and S.P. conceived the study. M.Sl., N.P., D.R., K.P., M.M., S.P. and J.Ke. supervised the study. M.H., P.K., S.N. and B.N. performed ancient DNA laboratory work. H.R., I.C., P.Se., M.So., S.T., J.-J.H., I.G., Ž.K., P.R., L.V.G., V.B.D., C.P. and J.Kr. provided and analysed archaeological material. M.H., Q.F., A.H., M.P., F.M., S.G., P.Sk. and V.N. analysed ancient DNA data. M.H., M.M., S.P. and J.Ke. wrote the manuscript with the input of all co-authors.

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Correspondence to Mateja Hajdinjak, Svante Pääbo or Janet Kelso.

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Reviewer Information Nature thanks C. Lalueza-Fox, C. Stringer and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Figure 1 Frequency of nucleotide substitutions at the beginning and the end of nuclear alignments for the final dataset of Les Cottés Z4-1514, Goyet Q56-1, Mezmaiskaya 2, Vindija 87 and Spy 94a.

Only fragments of at least 35 bp that mapped to the human reference genome with a mapping quality of at least 25 (MQ ≥ 25) were used for this analysis. Solid lines depict all fragments and dashed lines the fragments that have a C-to-T substitution at the opposing end (‘conditional’ C-to-T substitutions). All other types of substitutions are marked in grey.

Extended Data Figure 2 Fragment size distribution of fragments longer than 35 bp mapped to the human reference genome with MQ ≥ 25 for each of the five late Neanderthals.

All fragments are depicted in solid lines and fragments with C-to-T substitutions to the reference genome (putatively deaminated fragments) are depicted with dashed lines.

Extended Data Figure 3 Sex determination based on the number of fragments aligning to the X chromosome and the autosomes.

The expected ratios of X to (X + autosomal) fragments for a female and a male individual are depicted as dashed lines. The results were concordant for all fragments (in red) and for deaminated fragments only (in grey).

Extended Data Figure 4 Principal component analysis of the genomes of Vindija 33.19, Altai, the Denisovan individual, five late Neanderthals and Mezmaiskaya 1.

Genomes of the high-coverage archaics were used to estimate the eigenvectors of the genetic variation and low-coverage Neanderthals were projected onto the plane. Only transversion polymorphisms and bi-allelic sites were considered for the analysis, to a total of 1,010,417 sites as defined by the high-coverage genomes. PC, principal component.

Extended Data Table 1 Amount of data generated for Les Cottés Z4-1514, Goyet Q56-1, Mezmaiskaya 2, Vindija 87 and Spy 94a
Extended Data Table 2 Relationship of the late Neanderthals and Mezmaiskaya 1 to the Altai and Vindija 33.19 Neanderthals calculated as D(Altai, Vindija 33.19, Neanderthal, outgroup) for all fragments and deaminated fragments, restricted to transversions
Extended Data Table 3 The fraction of derived alleles among putatively deaminated fragments that each of the low-coverage individuals shares with the Altai Neanderthal, Vindija 33.19, the Denisovan individual and a present-day human genome
Extended Data Table 4 Time of separation of late Neanderthals and Mezmaiskaya 1 (A) from the ancestor with the high-coverage genomes of Altai and Vindija 33.19 Neanderthals, Denisovan individual and a present-day human (B), when measured in terms of time of split from the B individual (split A–B), or time from present (split-time + branch shortening)

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Supplementary Information

This file contains Supplementary Sections 1-12, Supplementary Tables and Supplementary References – see contents page for details. (PDF 4507 kb)

Supplementary Table 1

An assessment of the catalog of modern-human-specific fixed derived changes in the late Neandertals. (CSV 1793 kb)

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Hajdinjak, M., Fu, Q., Hübner, A. et al. Reconstructing the genetic history of late Neanderthals. Nature 555, 652–656 (2018). https://doi.org/10.1038/nature26151

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