Abstract
Recent advances in genome sequencing have improved variant calling in complex regions of the human genome. However, it is difficult to quantify variant calling performance because existing standards often focus on specificity, neglecting completeness in difficult-to-analyze regions. To create a more comprehensive truth set, we used Mendelian inheritance in a large pedigree (CEPH-1463) to filter variants across PacBio high-fidelity (HiFi), Illumina and Oxford Nanopore Technologies platforms. This generated a variant map with over 4.7 million single-nucleotide variants, 767,795 insertions and deletions (indels), 537,486 tandem repeats and 24,315 structural variants, covering 2.77 Gb of the GRCh38 genome. This work adds ~200 Mb of high-confidence regions, including 8% more small variants, and introduces the first tandem repeat and structural variant truth sets for NA12878 and her family. As an example of the value of this improved benchmark, we retrained DeepVariant using these data to reduce genotyping errors by ~34%.
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Data availability
For the open consent samples, the data are released on Amazon Open Data. The Amazon S3 bucket contains the sequencing data, assemblies, variant calls and additional files documented here: https://github.com/Platinum-Pedigree-Consortium/Platinum-Pedigree-Datasets The full dataset, including controlled samples, was deposited at https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs003793.v1.p1
Code availability
The code associated with this work can be found at https://github.com/Platinum-Pedigree-Consortium/Platinum-Pedigree-Inheritance. The code is open source and MIT licensed.
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Acknowledgements
The authors thank D. Baker (PacBio) for exploration of the SV merging methods and T. Brown (University of Washington) for assistance with the manuscript. This work was supported, in part, by US National Institutes of Health (NIH) grants R01HG002385 and R01HG010169 to E.E.E. (an investigator of the Howard Hughes Medical Institute). Certain commercial equipment, instruments or materials are identified to specify experimental conditions or reported results. Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology, nor does it imply that the equipment, instruments or materials identified are necessarily the best available for the purpose. The authors also thank the Amazon Open Data program for hosting the data. The following cell lines were obtained from the NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research: GM12877, GM12878, GM12879, GM12881, GM12882, GM12883, GM12884, GM12885, GM12886, GM12887, GM12889, GM12890, GM12891, GM12892 (ref. 11).
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Z.K., C.N., D.P., T.M., W.J.R., S.L., E.D., A.C., J.M.H., C.T.S., E.E.E. and M.A.E. wrote the manuscript. Z.K., C.N., D.P., T.M., W.J.R., S.L., E.D., N.K., W.T.H., A.C., J.M.H., C.J.S., P.-C.C., S.M., A.G., J.M.Z, X.C., N.D.O., C.T.S. and K.P.C. processed the data and carried out analyses. K.M.M., K.H., W.S.W., C.F. and C.L. generated sequencing data. Z.K., D.P., A.C., H.D., J.M.Z., P.M.L., E.G., J.D.S., P.M.L., D.W.N., L.B.J., A.R.Q., E.E.E. and M.A.E. provided oversight and designed the experiments.
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Z.K., C.N., T.M., W.J.R., S.L., E.D., J.M.H., C.T.S., K.P.C., C.F., C.L., X.C. and M.A.E. are employees and shareholders of PacBio. Z.K. holds private equity in Phase Genomics. P.-C.C. and A.C. are employees and shareholders of Google LLC. E.E.E. is a scientific advisory board (SAB) member of Variant Bio, Inc. All other authors have no competing interests.
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Nature Methods thanks the anonymous reviewers for their contribution to the peer review of this work. Peer reviewer reports are available. Primary Handling Editor: Lei Tang, in collaboration with the Nature Methods team.
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Kronenberg, Z., Nolan, C., Porubsky, D. et al. The Platinum Pedigree: a long-read benchmark for genetic variants. Nat Methods 22, 1669–1676 (2025). https://doi.org/10.1038/s41592-025-02750-y
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DOI: https://doi.org/10.1038/s41592-025-02750-y
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