title: Evaluation of GRCh38 and de novo haploid genome assemblies demonstrates the enduring quality of the reference assembly.
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.
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Schneider
authors.affiliation: McDonnell Genome Institute at Washington University, St. Louis, Missouri 63018, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Graves-Lindsay
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Howe
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Bouk
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA.
authors.forename: Hsiu-Chuan
authors.initials: HC
authors.lastname: Chen
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Kitts
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA.
authors.forename: Terence D
authors.initials: TD
authors.lastname: Murphy
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA.
authors.forename: Kim D
authors.initials: KD
authors.lastname: Pruitt
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA.
authors.forename: Françoise
authors.initials: F
authors.lastname: Thibaud-Nissen
authors.affiliation: McDonnell Genome Institute at Washington University, St. Louis, Missouri 63018, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Albracht
authors.affiliation: McDonnell Genome Institute at Washington University, St. Louis, Missouri 63018, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.affiliation: McDonnell Genome Institute at Washington University, St. Louis, Missouri 63018, USA.
authors.forename: Milinn
authors.initials: M
authors.lastname: Kremitzki
authors.affiliation: McDonnell Genome Institute at Washington University, St. Louis, Missouri 63018, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Magrini
authors.affiliation: McDonnell Genome Institute at Washington University, St. Louis, Missouri 63018, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Markovic
authors.affiliation: McDonnell Genome Institute at Washington University, St. Louis, Missouri 63018, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: McGrath
authors.affiliation: McDonnell Genome Institute at Washington University, St. Louis, Missouri 63018, USA.
authors.forename: Karyn Meltz
authors.initials: KM
authors.lastname: Steinberg
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: Kate
authors.initials: K
authors.lastname: Auger
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Chow
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: Joanna
authors.initials: J
authors.lastname: Collins
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: Glenn
authors.initials: G
authors.lastname: Harden
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hubbard
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pelan
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: Jared T
authors.initials: JT
authors.lastname: Simpson
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: Glen
authors.initials: G
authors.lastname: Threadgold
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Torrance
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Wood
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Clarke
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Koren
authors.affiliation: Pacific Biosciences, Menlo Park, California 94025, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Boitano
authors.affiliation: Pacific Biosciences, Menlo Park, California 94025, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Peluso
authors.affiliation: Broad Institute, Cambridge, Massachusetts 02142, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Li
authors.affiliation: Pacific Biosciences, Menlo Park, California 94025, USA.
authors.forename: Chen-Shan
authors.initials: CS
authors.lastname: Chin
authors.affiliation: National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Phillippy
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Durbin
authors.affiliation: McDonnell Genome Institute at Washington University, St. Louis, Missouri 63018, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Flicek
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.|Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA.
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Church
mesh_terms: D020451:Contig Mapping / Q000379:methods* / Q000592:standards; D015894:Genome, Human; D023281:Genomics / Q000379:methods* / Q000592:standards; D006238:Haploidy; D006239:Haplotypes; D006801:Humans; D011110:Polymorphism, Genetic; D012015:Reference Standards; D017422:Sequence Analysis, DNA / Q000379:methods* / Q000592:standards; D012984:Software