Evaluation of GRCh38 and de novo haploid genome assemblies demonstrates the enduring quality of the reference assembly

  1. Deanna M. Church1,14
  1. 1National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA;
  2. 2McDonnell Genome Institute at Washington University, St. Louis, Missouri 63018, USA;
  3. 3Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom;
  4. 4European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom;
  5. 5National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;
  6. 6Pacific Biosciences, Menlo Park, California 94025, USA;
  7. 7Broad Institute, Cambridge, Massachusetts 02142, USA;
  8. 8Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA;
  9. 9Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA
  1. Corresponding author: schneiva{at}ncbi.nlm.nih.gov
  • Present addresses: 10Nationwide Children's Hospital, Columbus, OH 43205, USA; 11King's College London, London WC2R 2LS, UK; 12Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3; 13Department of Computer Science, University of Toronto, Toronto, Ontario, Canada M5S 2E4; 1410X Genomics, Pleasanton, CA 94566, USA

Abstract

The human reference genome assembly plays a central role in nearly all aspects of today's basic and clinical research. GRCh38 is the first coordinate-changing assembly update since 2009; it reflects the resolution of roughly 1000 issues and encompasses modifications ranging from thousands of single base changes to megabase-scale path reorganizations, gap closures, and localization of previously orphaned sequences. We developed a new approach to sequence generation for targeted base updates and used data from new genome mapping technologies and single haplotype resources to identify and resolve larger assembly issues. For the first time, the reference assembly contains sequence-based representations for the centromeres. We also expanded the number of alternate loci to create a reference that provides a more robust representation of human population variation. We demonstrate that the updates render the reference an improved annotation substrate, alter read alignments in unchanged regions, and impact variant interpretation at clinically relevant loci. We additionally evaluated a collection of new de novo long-read haploid assemblies and conclude that although the new assemblies compare favorably to the reference with respect to continuity, error rate, and gene completeness, the reference still provides the best representation for complex genomic regions and coding sequences. We assert that the collected updates in GRCh38 make the newer assembly a more robust substrate for comprehensive analyses that will promote our understanding of human biology and advance our efforts to improve health.

Footnotes

  • [Supplemental material is available for this article.]

  • Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.213611.116.

  • Freely available online through the Genome Research Open Access option.

  • Received July 29, 2016.
  • Accepted March 14, 2017.

This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.

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