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<p>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%.</p>

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The Platinum Pedigree: a long-read benchmark for genetic variants

  • 期刊论文

  • 发表日期：

    2025年8月4日

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  • Zev Kronenberg,
  • Cillian Nolan,
  • David Porubsky,
  • Tom Mokveld,
  • William J. Rowell,
  • Sangjin Lee,
  • Egor Dolzhenko,
  • Pi-Chuan Chang,
  • James M. Holt,
  • Christopher T. Saunders,
  • Nathan D. Olson,
  • Cody J. Steely,
  • Sean McGee,
  • Andrea Guarracino,
  • Nidhi Koundinya,
  • William T. Harvey,
  • W. Scott Watkins,
  • Katherine M. Munson,
  • Kendra Hoekzema,
  • Khi Pin Chua,
  • Xiao Chen,
  • Cairbre Fanslow,
  • Christine Lambert,
  • Harriet Dashnow,
  • Erik Garrison,
  • Joshua D. Smith,
  • Peter M. Lansdorp,
  • Justin M. Zook,
  • Andrew Carroll,
  • Lynn B. Jorde,
  • Deborah W. Neklason,
  • Aaron R. Quinlan,
  • Evan E. Eichler,
  • Michael A. Eberle

摘要

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%.