The repetitive nature and complexity of some medically relevant genes poses a challenge for their accurate analysis in a clinical setting. The Genome in a Bottle Consortium has provided variant benchmark sets, but these exclude nearly 400 medically relevant genes due to their repetitiveness or polymorphic complexity. Here, we characterize 273 of these 395 challenging autosomal genes using a haplotype-resolved whole-genome assembly. This curated benchmark reports over 17,000 single-nucleotide variations, 3,600 insertions and deletions and 200 structural variations each for human genome reference GRCh37 and GRCh38 across HG002. We show that false duplications in either GRCh37 or GRCh38 result in reference-specific, missed variants for short- and long-read technologies in medically relevant genes, including CBS, CRYAA and KCNE1. When masking these false duplications, variant recall can improve from 8% to 100%. Forming benchmarks from a haplotype-resolved whole-genome assembly may become a prototype for future benchmarks covering the whole genome.
Justin Wagner, Nathan D. Olson, Lindsay Harris, Jennifer McDaniel, Haoyu Cheng, Arkarachai Fungtammasan, Yih-Chii Hwang, Richa Gupta, Aaron M. Wenger, William J. Rowell, Ziad M. Khan, Jesse Farek, Yiming Zhu, Aishwarya Pisupati, Medhat Mahmoud, Chunlin Xiao, Byunggil Yoo, Sayed Mohammad Ebrahim Sahraeian, Danny E. Miller, David Jáspez, José M. Lorenzo-Salazar, Adrián Muñoz-Barrera, Luis A. Rubio-Rodríguez, Carlos Flores, Giuseppe Narzisi, Uday Shanker Evani, Wayne E. Clarke, Joyce Lee, Christopher E. Mason, Stephen E. Lincoln, Karen H. Miga, Mark T. W. Ebbert, Alaina Shumate, Heng Li, Chen-Shan Chin, Justin M. Zook & Fritz J. Sedlazeck
Material Measurement Laboratory, National Institute of Standards and Technology, Gaithersburg, MD, USA
Justin Wagner, Nathan D. Olson, Lindsay Harris, Jennifer McDaniel & Justin M. Zook
Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
Haoyu Cheng & Heng Li
DNAnexus, Inc., Mountain View, CA, USA
Arkarachai Fungtammasan, Yih-Chii Hwang, Richa Gupta & Chen-Shan Chin
Pacific Biosciences, Menlo Park, CA, USA
Aaron M. Wenger & William J. Rowell
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
Ziad M. Khan, Jesse Farek, Yiming Zhu, Aishwarya Pisupati, Medhat Mahmoud & Fritz J. Sedlazeck
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA
Chunlin Xiao
Genomic Medicine Center, Children’s Mercy Kansas City, Kansas City, MO, USA
Byunggil Yoo
Roche Sequencing Solutions, Santa Clara, CA, USA
Sayed Mohammad Ebrahim Sahraeian
Department of Pediatrics, Division of Genetic Medicine, University of Washington and Seattle Children’s Hospital, Seattle, WA, USA
Danny E. Miller
Department of Genome Sciences, University of Washington, Seattle, WA, USA
Danny E. Miller
Genomics Division, Instituto Tecnológico y de Energías Renovables (ITER), Santa Cruz de Tenerife, Spain
David Jáspez, José M. Lorenzo-Salazar, Adrián Muñoz-Barrera, Luis A. Rubio-Rodríguez & Carlos Flores
CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
Carlos Flores
Research Unit, Hospital Universitario N.S. de Candelaria, Santa Cruz de Tenerife, Spain
Carlos Flores
New York Genome Center, New York, NY, USA
Giuseppe Narzisi, Uday Shanker Evani & Wayne E. Clarke
Bionano Genomics, San Diego, CA, USA
Joyce Lee
Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
Christopher E. Mason
Invitae, San Francisco, CA, USA
Stephen E. Lincoln
UC Santa Cruz Genomics Institute, University of California, Santa Cruz, Santa Cruz, CA, USA
Karen H. Miga
Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA
Mark T. W. Ebbert
Department of Internal Medicine, Division of Biomedical Informatics, University of Kentucky, Lexington, KY, USA
Mark T. W. Ebbert
Department of Neuroscience, University of Kentucky, Lexington, KY, USA
Mark T. W. Ebbert
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
Alaina Shumate
Center for Computational Biology, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA
Alaina Shumate
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