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

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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Figure 1: Discovery of SNVs and structural variation.
Figure 2: De novo mutation detection.
Figure 3: Imputation accuracy.
Figure 4: Population genetic analyses in the Dutch population.

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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).

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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.

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Correspondence to Paul I W de Bakker or Cisca Wijmenga.

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The Genome of the Netherlands Consortium. Whole-genome sequence variation, population structure and demographic history of the Dutch population. Nat Genet 46, 818–825 (2014). https://doi.org/10.1038/ng.3021

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