A complete reference genome improves analysis of human genetic variation
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Abstract
Compared to its predecessors, the Telomere-to-Telomere CHM13 genome adds nearly 200 million base pairs of sequence, corrects thousands of structural errors, and unlocks the most complex regions of the human genome for clinical and functional study. We show how this reference universally improves read mapping and variant calling for 3202 and 17 globally diverse samples sequenced with short and long reads, respectively. We identify hundreds of thousands of variants per sample in previously unresolved regions, showcasing the promise of the T2T-CHM13 reference for evolutionary and biomedical discovery. Simultaneously, this reference eliminates tens of thousands of spurious variants per sample, including reduction of false positives in 269 medically relevant genes by up to a factor of 12. Because of these improvements in variant discovery coupled with population and functional genomic resources, T2T-CHM13 is positioned to replace GRCh38 as the prevailing reference for human genetics.
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Using T2T-CHM13 directly improves genomic analyses, for example discovering 3.7 million additional SNPs in regions non-syntenic to GRCh38 and better representing true CNVs of 1KG samples compared with GRCh38.
“Using T2T-CHM13 directly improves genomic analyses; for example, discovering 3.7 million additional single-nucleotide polymorphisms (SNPs) in regions non-syntenic to GRCh38 and better representing the true copy number variants (CNVs) of samples from the 1000 Genomes Project (1KG) compared with GRCh38 (refs. 1,4).”
From A draft human pangenome reference. (2023) · cites this paper as [4]
In ‘T2T-CHM13 enables variant calling in previously unresolved and corrected regions of the genome’ (page unavailable), the paper reports 3,692,439 PASS variants in nonsyntenic regions across 1KGP samples, but does not identify all of them as SNPs. Its copy-number comparisons with GRCh38 use SGDP individuals, not a demonstration that T2T-CHM13 better represents true CNVs in 1KGP samples. (LLM, conf=0.86)
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Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- [87]Wagner J, Olson ND, McDaniel J, Zook JM, Challenging medically-relevant genes benchmark set (NIST Public Data Repository, 2021) doi: 10.18434/MDS2-2475 · DOI
Cited by
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“7 million additional single-nucleotide polymorphisms (SNPs) in regions non-syntenic to GRCh38 and better representing the true copy-number variants (CNVs) of 1000 Genomes Project (1KG) samples when compared to GRCh38 (1000 Genomes Project Consortium et al., 2015; Aganezov et al., 2022).”
BackgroundInfluentialSelf-citationComplete genomic and epigenetic maps of human centromeres
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Self-citation
- Authors
- Aganezov, S., Yan, S. M., Soto, D. C., Kirsche, M., Zarate, S., Avdeyev, P., Taylor, D. J., Shafin, K., Shumate, A., Xiao, C., Wagner, J., McDaniel, J., Olson, N. D., Sauria, M. E. G., Vollger, M. R., Rhie, A., Meredith, M., Martin, S., Lee, J., Koren, S., Rosenfeld, J. A., Paten, B., Layer, R., Chin, C.-S., Sedlazeck, F. J., Hansen, N. F., Miller, D. E., Phillippy, A. M., Miga, K. H., McCoy, R. C., Dennis, M. Y., Zook, J. M., & Schatz, M. C.
- Affiliations
- Johns Hopkins University (US)
- University of California, Davis (US)
- National Institutes of Health (US)
- University of California, Santa Cruz (US)
- National Institute of Standards and Technology (US)
- University of Washington (US)
- University of Colorado Boulder (US)
- BioNano Genomics (United States) (US)
- Rutgers Cancer Institute (US)
- DNAnexus (United States) (US)
- Baylor College of Medicine (US)
- National Human Genome Research Institute (US)
- Seattle Children's Hospital (US)
- Corresponding author
- McCoy, Rajiv C.
- Dennis, Megan Y.
- Zook, Justin M.
- Schatz, Michael C.
- ORCID
- Aganezov, Sergey
- Yan, Stephanie M.
- Soto, Daniela C.
- Kirsche, Melanie
- Zarate, Samantha
- Avdeyev, Pavel
- Taylor, Dylan J.
- Shafin, Kishwar
- Shumate, Alaina
- Xiao, Chunlin
- Wagner, Justin
- McDaniel, Jennifer
- Olson, Nathan D.
- Sauria, Michael E. G.
- Vollger, Mitchell R.
- Rhie, Arang
- Meredith, Melissa
- Lee, Joyce
- Koren, Sergey
- Rosenfeld, Jeffrey A.
- Paten, Benedict
- Layer, Ryan
- Chin, Chen-Shan
- Sedlazeck, Fritz J.
- Hansen, Nancy F.
- Miller, Danny E.
- Phillippy, Adam M.
- Miga, Karen H.
- McCoy, Rajiv C.
- Dennis, Megan Y.
- Zook, Justin M.
- Schatz, Michael C.
- Venue
- Science
- Published
- 2022-04
- Volume
- 376
- Issue
- 6588
- Pages
- eabl3533-eabl3533
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC9336181
- OpenAlex
- W4225399233
- Cited by
- 441
- References
- 113
- Citations by year
- 2026: 66 · 2025: 91 · 2024: 122 · 2023: 75 · 2022: 82 · 2021: 1 · 2019: 1 · 2012: 2
- FWCI
- 31.84
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by
- Locations
- Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (OT2OD026682)
- National Institute of Mental Health (DP2MH119424)
- National Human Genome Research Institute (UM1HG008898, R01HG010485, R21HG010548, U01HG010971, R00HG009532, R01HG011274, U01HG010961, U24HG010263, U24HG011853, U24HG007234, U24HG006620, U41HG010972, R01HG006677)
- National Cancer Institute (U01CA253481)
- National Institute of General Medical Sciences (R35GM133747)
- National Institute of Diabetes and Digestive and Kidney Diseases (R24DK106766)
- 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 › Genomics and Rare Diseases
- Keywords
- T2T-CHM13, human reference genome, telomere-to-telomere genome assembly, structural variants, variant calling, read mapping, false positive variants, long-read sequencing, human genetic variation
- MeSH terms
- Humans, Reference Standards, Genetic Variation, Genome, Human, Sequence Analysis, DNA, Genomics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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