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A diploid assembly-based benchmark for variants in the major histocompatibility complex
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Abstract
Most human genomes are characterized by aligning individual reads to the reference genome, but accurate long reads and linked reads now enable us to construct accurate, phased de novo assemblies. We focus on a medically important, highly variable, 5 million base-pair (bp) region where diploid assembly is particularly useful - the Major Histocompatibility Complex (MHC). Here, we develop a human genome benchmark derived from a diploid assembly for the openly-consented Genome in a Bottle sample HG002. We assemble a single contig for each haplotype, align them to the reference, call phased small and structural variants, and define a small variant benchmark for the MHC, covering 94% of the MHC and 22368 variants smaller than 50 bp, 49% more variants than a mapping-based benchmark. This benchmark reliably identifies errors in mapping-based callsets, and enables performance assessment in regions with much denser, complex variation than regions covered by previous benchmarks.
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The -z200000,10000 parameter was used to improve alignment contiguity, as it was previously shown to improve variant recall in regions with dense variation.
“We used -z200000,10000 parameter to improve alignment contiguity, as it was previously shown to improve variant recall in regions with dense variation, such as the major histocompatibility complex81.”
From A draft human pangenome reference. (2023) · cites this paper as [81]
The Methods section, “Making variant calls from the assembly” (page unavailable), says the authors added -z200000,10000 to increase Minimap2 mapping sensitivity and calling of complex variants in the MHC. It does not state that the parameter improved alignment contiguity or demonstrate improved variant recall in regions with dense variation. (LLM, conf=0.88)
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Metadata
- Authors
- Chin, C.-S., Wagner, J., Zeng, Q., Garrison, E., Garg, S., Fungtammasan, A., Rautiainen, M., Aganezov, S., Kirsche, M., Zarate, S., Schatz, M. C., Xiao, C., Rowell, W. J., Markello, C., Farek, J., Sedlazeck, F. J., Bansal, V., Yoo, B., Miller, N., Zhou, X., Carroll, A., Barrio, A. M., Salit, M., Marschall, T., Dilthey, A. T., & Zook, J. M.
- Affiliations
- DNAnexus (United States) (US)
- National Institute of Standards and Technology (US)
- LabCorp (United States) (US)
- University of California, Santa Cruz (US)
- Harvard University (US)
- Max Planck Institute for Informatics (DE)
- Johns Hopkins University (US)
- National Institutes of Health (US)
- Pacific Biosciences (United States) (US)
- Baylor College of Medicine (US)
- University of California San Diego (US)
- Children's Mercy Hospital (US)
- Stanford University (US)
- Google (United States) (US)
- Heinrich Heine University Düsseldorf (DE)
- Corresponding author
- Zook, Justin M.
- ORCID
- Chin, Chen-Shan
- Wagner, Justin
- Zeng, Qiandong
- Garrison, Erik
- Garg, Shilpa
- Fungtammasan, Arkarachai
- Rautiainen, Mikko
- Aganezov, Sergey
- Kirsche, Melanie
- Zarate, Samantha
- Schatz, Michael C.
- Xiao, Chunlin
- Rowell, William J.
- Markello, Charles
- Farek, Jesse
- Sedlazeck, Fritz J.
- Bansal, Vikas
- Yoo, Byunggil
- Miller, Neil
- Zhou, Xin
- Carroll, Andrew
- Barrio, Alvaro Martinez
- Salit, Marc
- Marschall, Tobias
- Dilthey, Alexander T.
- Zook, Justin M.
- Venue
- Nature Communications
- Published
- 2020-09-22
- Volume
- 11
- Issue
- 1
- Pages
- 4794-4794
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7508831
- OpenAlex
- W3089079506
- Cited by
- 82
- References
- 39
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 17 · 2023: 16 · 2022: 14 · 2021: 15 · 2020: 3
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- United States Department of Commerce | National Institute of Standards and Technology (Intramural)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- major histocompatibility complex, haplotype phasing, structural variants, small variants, Genome in a Bottle, HG002, long-read sequencing, human genetic variation
- MeSH terms
- Cell Line, Diploidy, Haplotypes, Humans, Major Histocompatibility Complex, Genetic Variation, Genome, Human, Benchmarking
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