Abstract
Creating a catalogue of early diverged genome variation is critical to determine the true extent of human diversity and associated medical impact. Generating deep whole genome data for 150 Khoe-San (12 groups, 1 unclassified), and 40 regionally comparative Southern Africans (3 groups), we identify ~30 million small-to-large variants - over 1.3 million unknown single nucleotide variants. Representing shared traditionally forager lifestyles and click-speaking languages, we identify San and Damara as separate phylogenetic lineages, contributing two admixture waves to Nama. While San represented modern humans’ deep divergence (~115 thousand years ago), Damara divergence is recent, with both showing high effective population sizes between 45–150 thousand years ago. Developing an assembly-based test we report 1,376 genes under positive selection (dN/dS = 19.46) of which 479 are significantly associated with forager peoples and, therefore, maintained ancestral alleles that differ from derived genetic variation observed in non-African biomedical resources.
Data availability
Raw sequencing data, alignments, germline variant calls (small variants, short tandem repeats and mobile element insertions) and derived datasets are available for general research use for browsing and download through the European Genome Phenome Achieve (EGA) [https://ega-archive.org] via adherence to KSGP Data Access Committee (DAC) EGAC50000000798 policy and approval [https://dac.ega-archive.org/EGAC50000000798/requests] for KSGP under accession number EGAS50000001408. Genomic data for South African participants have previously been deposited at the EGA under accession number EGAD00001009067. The public release of SGDP data is available through the EBI European Nucleotide Archive under accession numbers PRJEB9586 and ERP010710. The Altai Neanderthal genome can be downloaded online [http://cdna.eva.mpg.de/neandertal/altai/AltaiNeandertal/]. Source data are provided with this paper. Access to KSGP and SAPCS sequencing data may be requested via the KSGP or SAPCS Data Access Committee’s (DACs), respectively, and will be made available to researchers with appropriate feasibility and corresponding ethics approvals to ensure the safeguarding of patient genomic information (contact V.M.H. directly). Both DACs include community representation, with all studies directly communicated with community representative partners. Restrictions include (i) no transfer to third parties allowed, (ii) inability of the researchers to adequately articulate their research question at application or the question is deemed culturally inappropriate, (iii) a report of the results of the research to be provided to the respective DACs prior to publication (or when requested), (iv) written DAC approval for publication of final draft, (v) acknowledgment of the KSGP or SAPCS community leaders in publications/presentations, (vi) researchers cannot utilise the data for commercial purposes or any other purposes not approved by the DAC, and (vii) approval will not be given that excludes other researchers from accessing data. Data currently being used for capacity building in under-resourced studies across Sub-Saharan Africa will be given priority and at times may be granted time-limited exclusive rights for no more than a two-year period. Source data are provided in this paper.
Code availability
The core computational pipelines used in this study for read alignment, quality control and variant calling are described in Supplementary Information. Analysis code for assembly-based genome analysis of positive selection is available at GitHub (https://github.com/wjaratlerdsiri/aGATK) or Reference96.
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Acknowledgements
The work presented was supported by a donation provided by the University of Limpopo in South Africa (to V.M.H. and J.M.), the Garvan Institute of Medical Research Foundation and Medical Genome Research Biobank (MGRB) in Australia (to D.M.T.), and by an Australian Medical Research Future Fund (MRFF) Genomics Health Futures Mission Grant (2025/MRF2045394 to V.M.H., W.J., D.M.T. and P.X.Y.S.), while partially supported through the U.S.A. Congressionally Directed Medical Research Programmes (CDMRP) Prostate Cancer Research Programme (PCRP) Health Equity Research and Outcomes Improvement Consortium (HEROIC) Award (PC210168 and PC230673, HEROIC Prostate Cancer Precision Health (PCaPH) Africa1K to V.M.H., M.S.R.B., Peter Ngugi from the University of Nairobi, Kenya and Gail Prins from the University of Illinois at Chicago, U.S.A.). J.J. is supported by a U.S.A. Prostate Cancer Foundation (PCF) PhD Scholarship as part of a Challenge award) 23CHAL18, to V.M.H.) and V.M.H. is supported by the Petre Foundation through the University of Sydney Foundation. We acknowledge the use of the National Computational Infrastructure (NCI), which is supported by the Australian Government, and accessed through the National Computational Merit Allocation Scheme (V.M.H., E.K.F.C. and W.J.), the Intersect Computational Merit Allocation Scheme (V.M.H.), Intersect Australia Limited and the Sydney Informatics Hub, Core Research Facility, and we acknowledge the staff at the Garvan Institute of Medical Research’s Kinghorn Centre for Clinical Genomics (KCCG) core facility for genome sequencing. We thank the study participants and their representative communities who contributed to this study; without their contribution and continued engagement, this research would not be possible. We are in debt to the many local Namibians who have aided during community engagement, providing critical logistical, historical, cultural and linguistic insights, specifically E. Adams, A.A. Collins, R. Friederich, B. G/aq’o, N. /kun, J. /kunta, H. Mische, F. Naque, D. Naque, H. Oosthuizen, E. Oosthuizen, A. Oosthuysen, E. Oosthuysen, D. Roux, J. Sinvula, C. Swau, T. Tauros, T. Tsebe and R. Wilkinson, while we are grateful to C.P. Bennett from Evolving Picture in Sydney (https://evolvingpicture.com/) for providing community recording. We further acknowledge and fondly remember the late Archbishop Emeritus Desmond Tutu (South Africa), who remained an advocate and key participant of the Ubuntu Project, to the late Chief Seth M. Kooitjie (Namibia), past Chairperson of the Nama Traditional Leaders Association for his blessing and critical support, and to Professors Philip A. Venter (University of Limpopo, South Africa) and Christopher F. Heyns (University of Stellenbosch, South Africa) for their respective foundational work in establishing ethical frameworks within South Africa and Namibia, respectively. We are more recently grateful to Professor Lamech Mwapagha, Namibia University of Science & Technology (NUST), for taking on the responsibility of KSGP DAC Chair.
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V.M.H. designed the experiments. Community engagement, recruitments, government and ethic approvals were performed by V.M.H., Z.S., E.H., K.T., H.A.E.F., M.S.R.B. and J.M., with V.M.H. performing all remote community recruitment personally in the boarder of Namibia (see Supplementary Data). Z.S., D.C.P., E.K.F.C., K.T., and V.M.H. performed initial genetic screening for participant inclusion, W.H.G.H. provided Khoe-San linguistic expertise, and D.M.T. provided access and interpretation for Medical Genome Reference Biobank (MGRB). W.J. performed all the bioinformatic analyses and designed the positive selection workflow and codes, with additional support from T.G. and J.J, while P.X.Y.S. performed population substructure analyses. W.J. developed the pipelines and performed high-performance computational variant calling, with further complex variant annotation supported by T.G. and J.J. Both W.J. and V.M.H. performed data interpretation and wrote the manuscript, with further critical culturally relevant interpretation provided by Z.S., D.C.P., E.H., H.A.E.F., M.S.R.B., and J.M.; V.M.H., J.M., M.S.R.B. and D.M.T. acquired the funding. W.J. and P.X.Y.S. generated the figures, while all authors contributed to the final editing and approval of the manuscript.
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Jaratlerdsiri, W., Soh, P.X.Y., Gong, T. et al. A catalogue of early diverged contemporary human genome variation reveals distinct Khoe-San populations. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69269-4
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DOI: https://doi.org/10.1038/s41467-026-69269-4
