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Semi-automated assembly of high-quality diploid human reference genomes.

ABSTRACT: The current human reference genome, GRCh38, represents over 20 years of effort to generate a high-quality assembly, which has benefitted society^1,2. However, it still has many gaps and errors, and does not represent a biological genome as it is a blend of multiple individuals^3,4. Recently, a high-quality telomere-to-telomere reference, CHM13, was generated with the latest long-read technologies, but it was derived from a hydatidiform mole cell line with a nearly homozygous genome⁵. To address these limitations, the Human Pangenome Reference Consortium formed with the goal of creating high-quality, cost-effective, diploid genome assemblies for a pangenome reference that represents human genetic diversity⁶. Here, in our first scientific report, we determined which combination of current genome sequencing and assembly approaches yield the most complete and accurate diploid genome assembly with minimal manual curation. Approaches that used highly accurate long reads and parent-child data with graph-based haplotype phasing during assembly outperformed those that did not. Developing a combination of the top-performing methods, we generated our first high-quality diploid reference assembly, containing only approximately four gaps per chromosome on average, with most chromosomes within ±1% of the length of CHM13. Nearly 48% of protein-coding genes have non-synonymous amino acid changes between haplotypes, and centromeric regions showed the highest diversity. Our findings serve as a foundation for assembling near-complete diploid human genomes at scale for a pangenome reference to capture global genetic variation from single nucleotides to structural rearrangements.

SUBMITTER: Jarvis ED

PROVIDER: S-EPMC9668749 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Semi-automated assembly of high-quality diploid human reference genomes.

Jarvis Erich D ED Formenti Giulio G Rhie Arang A Guarracino Andrea A Yang Chentao C Wood Jonathan J Tracey Alan A Thibaud-Nissen Francoise F Vollger Mitchell R MR Porubsky David D Cheng Haoyu H Asri Mobin M Logsdon Glennis A GA Carnevali Paolo P Chaisson Mark J P MJP Chin Chen-Shan CS Cody Sarah S Collins Joanna J Ebert Peter P Escalona Merly M Fedrigo Olivier O Fulton Robert S RS Fulton Lucinda L LL Garg Shilpa S Gerton Jennifer L JL Ghurye Jay J Granat Anastasiya A Green Richard E RE Harvey William W Hasenfeld Patrick P Hastie Alex A Haukness Marina M Jaeger Erich B EB Jain Miten M Kirsche Melanie M Kolmogorov Mikhail M Korbel Jan O JO Koren Sergey S Korlach Jonas J Lee Joyce J Li Daofeng D Lindsay Tina T Lucas Julian J Luo Feng F Marschall Tobias T Mitchell Matthew W MW McDaniel Jennifer J Nie Fan F Olsen Hugh E HE Olson Nathan D ND Pesout Trevor T Potapova Tamara T Puiu Daniela D Regier Allison A Ruan Jue J Salzberg Steven L SL Sanders Ashley D AD Schatz Michael C MC Schmitt Anthony A Schneider Valerie A VA Selvaraj Siddarth S Shafin Kishwar K Shumate Alaina A Stitziel Nathan O NO Stober Catherine C Torrance James J Wagner Justin J Wang Jianxin J Wenger Aaron A Xiao Chuanle C Zimin Aleksey V AV Zhang Guojie G Wang Ting T Li Heng H Garrison Erik E Haussler David D Hall Ira I Zook Justin M JM Eichler Evan E EE Phillippy Adam M AM Paten Benedict B Howe Kerstin K Miga Karen H KH

Nature 20221019 7936

The current human reference genome, GRCh38, represents over 20 years of effort to generate a high-quality assembly, which has benefitted society<sup>1,2</sup>. However, it still has many gaps and errors, and does not represent a biological genome as it is a blend of multiple individuals<sup>3,4</sup>. Recently, a high-quality telomere-to-telomere reference, CHM13, was generated with the latest long-read technologies, but it was derived from a hydatidiform mole cell line with a nearly homozygous ...[more]

PMID: 36261518

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Project description:BackgroundThe continued democratization of DNA sequencing has sparked a new wave of development of genome assembly and assembly validation methods. As individual research labs, rather than centralized centers, begin to sequence the majority of new genomes, it is important to establish best practices for genome assembly. However, recent evaluations such as GAGE and the Assemblathon have concluded that there is no single best approach to genome assembly. Instead, it is preferable to generate multiple assemblies and validate them to determine which is most useful for the desired analysis; this is a labor-intensive process that is often impossible or unfeasible.ResultsTo encourage best practices supported by the community, we present iMetAMOS, an automated ensemble assembly pipeline; iMetAMOS encapsulates the process of running, validating, and selecting a single assembly from multiple assemblies. iMetAMOS packages several leading open-source tools into a single binary that automates parameter selection and execution of multiple assemblers, scores the resulting assemblies based on multiple validation metrics, and annotates the assemblies for genes and contaminants. We demonstrate the utility of the ensemble process on 225 previously unassembled Mycobacterium tuberculosis genomes as well as a Rhodobacter sphaeroides benchmark dataset. On these real data, iMetAMOS reliably produces validated assemblies and identifies potential contamination without user intervention. In addition, intelligent parameter selection produces assemblies of R. sphaeroides comparable to or exceeding the quality of those from the GAGE-B evaluation, affecting the relative ranking of some assemblers.ConclusionsEnsemble assembly with iMetAMOS provides users with multiple, validated assemblies for each genome. Although computationally limited to small or mid-sized genomes, this approach is the most effective and reproducible means for generating high-quality assemblies and enables users to select an assembly best tailored to their specific needs.

Dataset Information

Semi-automated assembly of high-quality diploid human reference genomes.

Publications

Semi-automated assembly of high-quality diploid human reference genomes.

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