Haplotype-aware variant calling with PEPPER-Margin-DeepVariant enables high accuracy in nanopore long-reads

Long-read sequencing has the potential to transform variant detection by reaching currently difficult-to-map regions and routinely linking together adjacent variations to enable read-based phasing. Third-generation nanopore sequence data have demonstrated a long read length, but current interpretati...

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Published inNature methods Vol. 18; no. 11; pp. 1322 - 1332
Main Authors Shafin, Kishwar, Pesout, Trevor, Chang, Pi-Chuan, Nattestad, Maria, Kolesnikov, Alexey, Goel, Sidharth, Baid, Gunjan, Kolmogorov, Mikhail, Eizenga, Jordan M., Miga, Karen H., Carnevali, Paolo, Jain, Miten, Carroll, Andrew, Paten, Benedict
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.11.2021
Nature Publishing Group
Subjects
631/114/1305
631/114/2785
631/1647/794
631/208/726/649
631/61/212
Bioinformatics
Biological Microscopy
Biological Techniques
Biomedical and Life Sciences
Biomedical Engineering/Biotechnology
Diploids
DNA sequencing
Genes
Genetic research
Genetic variation
Genome, Human
Genomes
Genomics
Genotyping
Haplotypes
High-Throughput Nucleotide Sequencing - methods
Humans
Identification methods
Life Sciences
Methods
Molecular Sequence Annotation
Nanopores
Nanotechnology
Nucleotide sequencing
Nucleotides
Pipelines
Polymorphism, Single Nucleotide
Proteomics
Sequence Analysis, DNA - methods
Software
Vegetables
United States
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Abstract Long-read sequencing has the potential to transform variant detection by reaching currently difficult-to-map regions and routinely linking together adjacent variations to enable read-based phasing. Third-generation nanopore sequence data have demonstrated a long read length, but current interpretation methods for their novel pore-based signal have unique error profiles, making accurate analysis challenging. Here, we introduce a haplotype-aware variant calling pipeline, PEPPER-Margin-DeepVariant, that produces state-of-the-art variant calling results with nanopore data. We show that our nanopore-based method outperforms the short-read-based single-nucleotide-variant identification method at the whole-genome scale and produces high-quality single-nucleotide variants in segmental duplications and low-mappability regions where short-read-based genotyping fails. We show that our pipeline can provide highly contiguous phase blocks across the genome with nanopore reads, contiguously spanning between 85% and 92% of annotated genes across six samples. We also extend PEPPER-Margin-DeepVariant to PacBio HiFi data, providing an efficient solution with superior performance over the current WhatsHap-DeepVariant standard. Finally, we demonstrate de novo assembly polishing methods that use nanopore and PacBio HiFi reads to produce diploid assemblies with high accuracy (Q35+ nanopore-polished and Q40+ PacBio HiFi-polished). The PEPPER-Margin-DeepVariant pipeline achieves highly accurate variant calling using nanopore and other long-read sequencing data.
AbstractList Long-read sequencing has the potential to transform variant detection by reaching currently difficult-to-map regions and routinely linking together adjacent variations to enable read-based phasing. Third-generation nanopore sequence data have demonstrated a long read length, but current interpretation methods for their novel pore-based signal have unique error profiles, making accurate analysis challenging. Here, we introduce a haplotype-aware variant calling pipeline, PEPPER-Margin-DeepVariant, that produces state-of-the-art variant calling results with nanopore data. We show that our nanopore-based method outperforms the short-read-based single-nucleotide-variant identification method at the whole-genome scale and produces high-quality single-nucleotide variants in segmental duplications and low-mappability regions where short-read-based genotyping fails. We show that our pipeline can provide highly contiguous phase blocks across the genome with nanopore reads, contiguously spanning between 85% and 92% of annotated genes across six samples. We also extend PEPPER-Margin-DeepVariant to PacBio HiFi data, providing an efficient solution with superior performance over the current WhatsHap-DeepVariant standard. Finally, we demonstrate de novo assembly polishing methods that use nanopore and PacBio HiFi reads to produce diploid assemblies with high accuracy (Q35+ nanopore-polished and Q40+ PacBio HiFi-polished).
Long-read sequencing has the potential to transform variant detection by reaching currently difficult-to-map regions and routinely linking together adjacent variations to enable read-based phasing. Third-generation nanopore sequence data have demonstrated a long read length, but current interpretation methods for their novel pore-based signal have unique error profiles, making accurate analysis challenging. Here, we introduce a haplotype-aware variant calling pipeline, PEPPER-Margin-DeepVariant, that produces state-of-the-art variant calling results with nanopore data. We show that our nanopore-based method outperforms the short-read-based single-nucleotide-variant identification method at the whole-genome scale and produces high-quality single-nucleotide variants in segmental duplications and low-mappability regions where short-read-based genotyping fails. We show that our pipeline can provide highly contiguous phase blocks across the genome with nanopore reads, contiguously spanning between 85% and 92% of annotated genes across six samples. We also extend PEPPER-Margin-DeepVariant to PacBio HiFi data, providing an efficient solution with superior performance over the current WhatsHap-DeepVariant standard. Finally, we demonstrate de novo assembly polishing methods that use nanopore and PacBio HiFi reads to produce diploid assemblies with high accuracy (Q35+ nanopore-polished and Q40+ PacBio HiFi-polished).The PEPPER-Margin-DeepVariant pipeline achieves highly accurate variant calling using nanopore and other long-read sequencing data.
Long-read sequencing has the potential to transform variant detection by reaching currently difficult-to-map regions and routinely linking together adjacent variations to enable read-based phasing. Third-generation nanopore sequence data have demonstrated a long read length, but current interpretation methods for their novel pore-based signal have unique error profiles, making accurate analysis challenging. Here, we introduce a haplotype-aware variant calling pipeline, PEPPER-Margin-DeepVariant, that produces state-of-the-art variant calling results with nanopore data. We show that our nanopore-based method outperforms the short-read-based single-nucleotide-variant identification method at the whole-genome scale and produces high-quality single-nucleotide variants in segmental duplications and low-mappability regions where short-read-based genotyping fails. We show that our pipeline can provide highly contiguous phase blocks across the genome with nanopore reads, contiguously spanning between 85% and 92% of annotated genes across six samples. We also extend PEPPER-Margin-DeepVariant to PacBio HiFi data, providing an efficient solution with superior performance over the current WhatsHap-DeepVariant standard. Finally, we demonstrate de novo assembly polishing methods that use nanopore and PacBio HiFi reads to produce diploid assemblies with high accuracy (Q35+ nanopore-polished and Q40+ PacBio HiFi-polished).Long-read sequencing has the potential to transform variant detection by reaching currently difficult-to-map regions and routinely linking together adjacent variations to enable read-based phasing. Third-generation nanopore sequence data have demonstrated a long read length, but current interpretation methods for their novel pore-based signal have unique error profiles, making accurate analysis challenging. Here, we introduce a haplotype-aware variant calling pipeline, PEPPER-Margin-DeepVariant, that produces state-of-the-art variant calling results with nanopore data. We show that our nanopore-based method outperforms the short-read-based single-nucleotide-variant identification method at the whole-genome scale and produces high-quality single-nucleotide variants in segmental duplications and low-mappability regions where short-read-based genotyping fails. We show that our pipeline can provide highly contiguous phase blocks across the genome with nanopore reads, contiguously spanning between 85% and 92% of annotated genes across six samples. We also extend PEPPER-Margin-DeepVariant to PacBio HiFi data, providing an efficient solution with superior performance over the current WhatsHap-DeepVariant standard. Finally, we demonstrate de novo assembly polishing methods that use nanopore and PacBio HiFi reads to produce diploid assemblies with high accuracy (Q35+ nanopore-polished and Q40+ PacBio HiFi-polished).
Long-read sequencing has the potential to transform variant detection by reaching currently difficult-to-map regions and routinely linking together adjacent variations to enable read based phasing. Third-generation nanopore sequence data has demonstrated a long read length, but current interpretation methods for its novel pore-based signal have unique error profiles, making accurate analysis challenging. Here, we introduce a haplotype-aware variant calling pipeline PEPPER-Margin-DeepVariant that produces state-of-the-art variant calling results with nanopore data. We show that our nanopore-based method outperforms the short-read-based single nucleotide variant identification method at the whole genome-scale and produces high quality single nucleotide variants in segmental duplications and low-mappability regions where short-read based genotyping fails. We show that our pipeline can provide highly-contiguous phase blocks across the genome with nanopore reads, contiguously spanning between 85% to 92% of annotated genes across six samples. We also extend PEPPER-Margin-DeepVariant to PacBio HiFi data, providing an efficient solution with superior performance than the current WhatsHap-DeepVariant standard. Finally, we demonstrate de novo assembly polishing methods that use nanopore and PacBio HiFi reads to produce diploid assemblies with high accuracy (Q35+ nanopore-polished and Q40+ PacBio-HiFi-polished). Further information on research design is available in the Nature Research Reporting Summary linked to this article.
Long-read sequencing has the potential to transform variant detection by reaching currently difficult-to-map regions and routinely linking together adjacent variations to enable read-based phasing. Third-generation nanopore sequence data have demonstrated a long read length, but current interpretation methods for their novel pore-based signal have unique error profiles, making accurate analysis challenging. Here, we introduce a haplotype-aware variant calling pipeline, PEPPER-Margin-DeepVariant, that produces state-of-the-art variant calling results with nanopore data. We show that our nanopore-based method outperforms the short-read-based single-nucleotide-variant identification method at the whole-genome scale and produces high-quality single-nucleotide variants in segmental duplications and low-mappability regions where short-read-based genotyping fails. We show that our pipeline can provide highly contiguous phase blocks across the genome with nanopore reads, contiguously spanning between 85% and 92% of annotated genes across six samples. We also extend PEPPER-Margin-DeepVariant to PacBio HiFi data, providing an efficient solution with superior performance over the current WhatsHap-DeepVariant standard. Finally, we demonstrate de novo assembly polishing methods that use nanopore and PacBio HiFi reads to produce diploid assemblies with high accuracy (Q35+ nanopore-polished and Q40+ PacBio HiFi-polished). The PEPPER-Margin-DeepVariant pipeline achieves highly accurate variant calling using nanopore and other long-read sequencing data.
Audience Academic
Author Carroll, Andrew
Pesout, Trevor
Nattestad, Maria
Carnevali, Paolo
Paten, Benedict
Miga, Karen H.
Kolesnikov, Alexey
Goel, Sidharth
Jain, Miten
Eizenga, Jordan M.
Baid, Gunjan
Shafin, Kishwar
Chang, Pi-Chuan
Kolmogorov, Mikhail
AuthorAffiliation 3 Chan Zuckerberg Initiative, Redwood City, CA, USA
1 UC Santa Cruz Genomics Institute, Santa Cruz, CA, USA
2 Google Inc, 1600 Amphitheatre Pkwy, Mountain View, CA
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/34725481$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
Copyright The Author(s), under exclusive licence to Springer Nature America, Inc. 2021
2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
COPYRIGHT 2021 Nature Publishing Group
The Author(s), under exclusive licence to Springer Nature America, Inc. 2021.
Copyright_xml – notice: The Author(s), under exclusive licence to Springer Nature America, Inc. 2021
– notice: 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
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These authors contributed equally.
B.P. and A.C. designed and executed the study. K.S. developed PEPPER. T.P. developed Margin. P.C. designed candidate import functionality in DeepVariant. K.S., T.P. P.C. contributed equally to the methods development and core analysis presented. M.N. designed alt-event alignment in DeepVariant, A.K. contributed to haplotype sorting and improvements on DeepVariant runtime, S.G. contributed to candidate import module of DeepVariant, G.B. designed and executed the post-processing model to improve multiallelic variant accuracy. M.K. designed and evaluated assembly polishing. J.M.E. designed local phasing metric and contributed to phasing evaluation. K.H.M. provided experimental design guidance, P.C. generated assemblies and provided guidance on assembly polishing. M.J. performed nanopore sequencing, quality control and helped to design and execute analysis. All authors approve of the final manuscript.
Author Contributions
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Snippet Long-read sequencing has the potential to transform variant detection by reaching currently difficult-to-map regions and routinely linking together adjacent...
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SubjectTerms 631/114/1305
631/114/2785
631/1647/794
631/208/726/649
631/61/212
Bioinformatics
Biological Microscopy
Biological Techniques
Biomedical and Life Sciences
Biomedical Engineering/Biotechnology
Diploids
DNA sequencing
Genes
Genetic research
Genetic variation
Genome, Human
Genomes
Genomics
Genotyping
Haplotypes
High-Throughput Nucleotide Sequencing - methods
Humans
Identification methods
Life Sciences
Methods
Molecular Sequence Annotation
Nanopores
Nanotechnology
Nucleotide sequencing
Nucleotides
Pipelines
Polymorphism, Single Nucleotide
Proteomics
Sequence Analysis, DNA - methods
Software
Vegetables
Title Haplotype-aware variant calling with PEPPER-Margin-DeepVariant enables high accuracy in nanopore long-reads
URI https://link.springer.com/article/10.1038/s41592-021-01299-w
https://www.ncbi.nlm.nih.gov/pubmed/34725481
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https://pubmed.ncbi.nlm.nih.gov/PMC8571015
Volume 18
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