Article | Published:

Whole-genome sequence variation, population structure and demographic history of the Dutch population

Nature Genetics volume 46, pages 818825 (2014) | Download Citation

Abstract

Whole-genome sequencing enables complete characterization of genetic variation, but geographic clustering of rare alleles demands many diverse populations be studied. Here we describe the Genome of the Netherlands (GoNL) Project, in which we sequenced the whole genomes of 250 Dutch parent-offspring families and constructed a haplotype map of 20.4 million single-nucleotide variants and 1.2 million insertions and deletions. The intermediate coverage (13×) and trio design enabled extensive characterization of structural variation, including midsize events (30–500 bp) previously poorly catalogued and de novo mutations. We demonstrate that the quality of the haplotypes boosts imputation accuracy in independent samples, especially for lower frequency alleles. Population genetic analyses demonstrate fine-scale structure across the country and support multiple ancient migrations, consistent with historical changes in sea level and flooding. The GoNL Project illustrates how single-population whole-genome sequencing can provide detailed characterization of genetic variation and may guide the design of future population studies.

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Acknowledgements

We wish to dedicate this work to the memory of David R. Cox, an enthusiastic supporter of human genetic research in the Netherlands for many years. The GoNL Project is funded by the BBMRI-NL, a research infrastructure financed by the Netherlands Organization for Scientific Research (NWO project 184.021.007). We acknowledge additional financial support from eBioGrid, CTMM/TraIT, the Ubbo Emmius Fund, the Netherlands Bioinformatics Center (NBIC) and EU-BioSHARE. We thank the individual participants of the biobanks; M. Depristo, E. Banks, R. Poplin and G. del Angel from the Broad Institute for expert advice on setting up our alignment and calling pipeline; K. Garimella for the initial implementation of PhaseByTransmission; G. Strikwerda, W. Albers, R. Teeninga, H. Gankema and H. Wind of the Groningen Center for Information Technology (see URLs) for support of the compute cluster and Target storage; E. Valentyn and R. Williams of Target (see URLs) for hosting project data on IBM GPFS storage; T. Visser and I. Nooren of BiG Grid (see URLs) and SURFsara for providing backup storage, additional computing capacity and expert advice; the team from MOLGENIS (see URLs) for software development support; H. Lauvenberg for handling data access requests; K. Zych for design of the GoNL logo; L. Franke, H.-J. Westra and J. Gutierrez-Achury for useful discussions; and S. Raychaudhuri and B. Neale for their critical reading of the manuscript. Target is supported by Samenwerkingsverband Noord Nederland, the European Fund for Regional Development, the Dutch Ministry of Economic Affairs, Pieken in de Delta and the provinces of Groningen and Drenthe. Target operates under the auspices of Sensor Universe. BiG Grid and the Life Science Grid are financially supported by the Netherlands Organization for Scientific Research (NWO). A.A. is funded by the Center for Medical Systems Biology-2, and D.I.B. is funded by the European Research Council (ERC 230374). A.S. and P.I.W.d.B. are recipients of VIDI awards (NWO projects 016.138.318 and 016.126.354, respectively).

Author information

Author notes

    • LifeLines Cohort Study

    A full list of members appears in the Supplementary Note.

    • David R Cox

    Deceased.

    • Laurent C Francioli
    • , Androniki Menelaou
    • , Sara L Pulit
    •  & Freerk van Dijk

    These authors contributed equally to this work.

    • Paul I W de Bakker
    • , Morris A Swertz
    •  & Cisca Wijmenga

    These authors jointly directed this work.

Affiliations

  1. Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Laurent C Francioli
    • , Androniki Menelaou
    • , Sara L Pulit
    • , Clara C Elbers
    • , Wigard P Kloosterman
    • , Jessica van Setten
    • , Isaäc J Nijman
    • , Ivo Renkens
    •  & Paul I W de Bakker
  2. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

    • Freerk van Dijk
    • , Pieter B T Neerincx
    • , Patrick Deelen
    • , Alexandros Kanterakis
    • , Martijn Dijkstra
    • , Heorhiy Byelas
    • , K Joeri van der Velde
    • , Mathieu Platteel
    • , Morris A Swertz
    •  & Cisca Wijmenga
  3. Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

    • Freerk van Dijk
    • , Pieter B T Neerincx
    • , Patrick Deelen
    • , Alexandros Kanterakis
    • , Martijn Dijkstra
    • , Heorhiy Byelas
    • , K Joeri van der Velde
    • , Morris A Swertz
    •  & Cisca Wijmenga
  4. Department of Computer Science, Columbia University, New York, New York, USA.

    • Pier Francesco Palamara
    •  & Itsik Pe'er
  5. The Genome Institute, Washington University, St. Louis, Missouri, USA.

    • Kai Ye
  6. Section of Molecular Epidemiology, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.

    • Kai Ye
    • , Eric-Wubbo Lameijer
    • , Matthijs H Moed
    • , Marian Beekman
    • , Anton J M de Craen
    • , H Eka D Suchiman
    •  & P Eline Slagboom
  7. European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

    • Victor Guryev
  8. Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands.

    • Abdel Abdellaoui
    • , Jouke Jan Hottenga
    • , Mathijs Kattenberg
    • , Gonneke Willemsen
    •  & Dorret I Boomsma
  9. Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.

    • Elisabeth M van Leeuwen
    • , Lennart C Karssen
    • , Najaf Amin
    • , Fernando Rivadeneira
    • , Aaron Isaacs
    • , Albert Hofman
    • , André G Uitterlinden
    •  & Cornelia M van Duijn
  10. Department of Forensic Molecular Biology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.

    • Mannis van Oven
    •  & Manfred Kayser
  11. Leiden Genome Technology Center, Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.

    • Martijn Vermaat
    • , Jeroen F J Laros
    •  & Johan T den Dunnen
  12. Netherlands Bioinformatics Center, Nijmegen, the Netherlands.

    • Martijn Vermaat
    • , Jeroen F J Laros
    • , David van Enckevort
    •  & Hailiang Mei
  13. Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.

    • Mingkun Li
    •  & Mark Stoneking
  14. Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, the Netherlands.

    • Barbera D C van Schaik
  15. SURFsara, Science Park, Amsterdam, the Netherlands.

    • Jan Bot
  16. Centrum Wiskunde & Informatica, Life Sciences Group, Amsterdam, the Netherlands.

    • Tobias Marschall
    •  & Alexander Schönhuth
  17. Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.

    • Jayne Y Hehir-Kwa
  18. Center for Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.

    • Jayne Y Hehir-Kwa
  19. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Robert E Handsaker
    • , Paz Polak
    • , Mashaal Sohail
    • , Dana Vuzman
    • , Karol Estrada
    • , Steven A McCarroll
    •  & Shamil R Sunyaev
  20. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Robert E Handsaker
    •  & Steven A McCarroll
  21. Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Paz Polak
    • , Mashaal Sohail
    • , Dana Vuzman
    •  & Shamil R Sunyaev
  22. Department of Genome Sciences, University of Washington, Seattle, Washington, USA.

    • Fereydoun Hormozdiari
  23. Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.

    • Vyacheslav Koval
    • , Fernando Rivadeneira
    • , Karol Estrada
    • , Carolina Medina-Gomez
    •  & André G Uitterlinden
  24. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Karol Estrada
  25. Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.

    • Ben Oostra
  26. Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Jan H Veldink
    •  & Leonard H van den Berg
  27. Rinat-Pfizer, Inc., South San Francisco, California, USA.

    • Steven J Pitts
    • , Shobha Potluri
    • , Purnima Sundar
    •  & David R Cox
  28. Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.

    • Johan T den Dunnen
  29. Forensic Laboratory for DNA Research, Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.

    • Peter de Knijff
  30. BGI-Shenzhen, Shenzhen, China.

    • Qibin Li
    • , Yingrui Li
    • , Yuanping Du
    • , Ruoyan Chen
    • , Hongzhi Cao
    •  & Jun Wang
  31. BGI-Europe, Copenhagen, Denmark.

    • Ning Li
    •  & Sujie Cao
  32. Department of Biology, University of Copenhagen, Copenhagen, Denmark.

    • Jun Wang
  33. The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

    • Jun Wang
  34. Legal Pathways Institute for Health and Bio Law, Aerdenhout, the Netherlands.

    • Jasper A Bovenberg
  35. Department of Systems Biology, Columbia University, New York, New York, USA.

    • Itsik Pe'er
  36. Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.

    • Gert-Jan B van Ommen
  37. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Paul I W de Bakker

Consortia

  1. The Genome of the Netherlands Consortium

Authors

    Contributions

    P.I.W.d.B., D.I.B., J.A.B., C.M.v.D., G.-J.B.v.O., P.E.S., M.A.S. and C.W. (chair) formed the steering committee of the GoNL Project. Biobanks are managed and organized by A.H., A.G.U., C.M.v.D., B.O., F.R., A.I. (for the Rotterdam and Erasmus Rucphen Family studies), D.I.B., G.W. (for the Netherlands Twin Register), P.E.S., M.B., A.J.M.d.C., H.E.D.S. (for the Leiden Longevity Study) and the members of the LifeLines Cohort Study. P.I.W.d.B. and M.A.S. jointly led the analysis group. Sequencing data were generated at BGI (Shenzhen, China) by Q.L., Y.L., Y.D., R.C., H.C., N.L., S.C. and J.W. Additional Complete Genomics sequencing data were generated by S.J.P., S.P., P.S. and D.R.C. through a partnership with Pfizer. F.v.D., P.B.T.N., P.D., L.C.F., A.K., M.D., H.B., K.J.v.d.V. and M.A.S. formed the operational data stewardship and processing center. P.B.T.N., F.v.D. and M.A.S. designed and implemented the compute cluster. M.D., H.B., A.K. and M.A.S. designed and implemented the MOLGENIS computing platform to scale up analysis pipelines for alignment, variant calling and imputation. F.v.D. and L.C.F. performed alignment with help from I.J.N., J.B. and B.D.C.v.S. L.C.F. and F.v.D. called SNVs. L.C.F., S.L.P., A.M., E.M.v.L., L.C.K., M. Sohail, A.A. and M.V. performed quality control. V.G., K.Y., L.C.F., T.M., A.S., R.E.H., S.A.M., W.P.K., F.H., J.Y.H.-K., E.-W.L., A.A., V.K., H.M., M.H.M. and J.B. formed the structural variation subgroup. L.C.F. developed the PhaseByTransmission module in GATK and performed de novo mutation analyses with P.P. A.M. performed haplotype phasing and imputation benchmarks. J.H.V. and L.H.v.d.B. provided Complete Genomics data for imputation benchmarking. W.P.K. and I.R. performed variant validation. C.W. and M.P. generated Immunochip data on all GoNL samples. S.L.P., C.C.E., A.M., P.F.P., I.P., A.A., N.A., M. Sohail, D.V. and S.R.S. performed population genetic analyses. M.v.O., M.V., M.L., J.F.J.L., M. Stoneking, P.d.K. and M. Kayser performed mitochondrial DNA analysis. P.D., A.M., A.K., E.M.v.L., L.C.K., K.E., C.M.-G., J.v.S., M. Kattenberg, J.J.H. and D.v.E. formed the imputation subgroup. P.B.T.N., K.J.v.d.V. and M.A.S. were responsible for the GoNL website and associated services (see URLs). C.W. conceived the GoNL Project. P.I.W.d.B. wrote the initial manuscript with critical input from L.C.F., A.M., S.L.P., P.F.P. and C.C.E. C.W., D.I.B., G.-J.B.v.O., L.C.K., A.A., M.A.S., P.E.S., S.R.S., J.Y.H.-K., I.P., J.H.V., P.d.K., W.P.K., T.M., A.S., V.G., J.T.d.D. and M. Kayser provided critical feedback on the manuscript. All authors have seen and approved the final manuscript.

    Competing interests

    The author declare no competing financial interests.

    Corresponding authors

    Correspondence to Paul I W de Bakker or Cisca Wijmenga.

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    https://doi.org/10.1038/ng.3021

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