Haplotype-aware Diplotyping from Noisy Long Reads

Overview

Journal Genome Biol

Specialties Biology
Genetics

Date 2019 Jun 5

PMID 31159868

Citations 34

Authors

Jana Ebler

Marina Haukness

Trevor Pesout

Tobias Marschall

Benedict Paten

Affiliations

Soon will be listed here.

Abstract

Current genotyping approaches for single-nucleotide variations rely on short, accurate reads from second-generation sequencing devices. Presently, third-generation sequencing platforms are rapidly becoming more widespread, yet approaches for leveraging their long but error-prone reads for genotyping are lacking. Here, we introduce a novel statistical framework for the joint inference of haplotypes and genotypes from noisy long reads, which we term diplotyping. Our technique takes full advantage of linkage information provided by long reads. We validate hundreds of thousands of candidate variants that have not yet been included in the high-confidence reference set of the Genome-in-a-Bottle effort.

Citing Articles

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References

Browning S, Browning B . Haplotype phasing: existing methods and new developments. Nat Rev Genet. 2011; 12(10):703-14. PMC: 3217888. DOI: 10.1038/nrg3054. View

Arndt P, Hwa T, Petrov D . Substantial regional variation in substitution rates in the human genome: importance of GC content, gene density, and telomere-specific effects. J Mol Evol. 2005; 60(6):748-63. DOI: 10.1007/s00239-004-0222-5. View

Ebler J, Haukness M, Pesout T, Marschall T, Paten B . Haplotype-aware diplotyping from noisy long reads. Genome Biol. 2019; 20(1):116. PMC: 6547545. DOI: 10.1186/s13059-019-1709-0. View

Altemose N, Miga K, Maggioni M, Willard H . Genomic characterization of large heterochromatic gaps in the human genome assembly. PLoS Comput Biol. 2014; 10(5):e1003628. PMC: 4022460. DOI: 10.1371/journal.pcbi.1003628. View

Guo F, Wang D, Wang L . Progressive approach for SNP calling and haplotype assembly using single molecular sequencing data. Bioinformatics. 2018; 34(12):2012-2018. DOI: 10.1093/bioinformatics/bty059. View

Patterson M, Marschall T, Pisanti N, van Iersel L, Stougie L, Klau G . WhatsHap: Weighted Haplotype Assembly for Future-Generation Sequencing Reads. J Comput Biol. 2015; 22(6):498-509. DOI: 10.1089/cmb.2014.0157. View

Li N, Stephens M . Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data. Genetics. 2004; 165(4):2213-33. PMC: 1462870. DOI: 10.1093/genetics/165.4.2213. View

Garg S, Rautiainen M, Novak A, Garrison E, Durbin R, Marschall T . A graph-based approach to diploid genome assembly. Bioinformatics. 2018; 34(13):i105-i114. PMC: 6022571. DOI: 10.1093/bioinformatics/bty279. View

Harrow J, Frankish A, Gonzalez J, Tapanari E, Diekhans M, Kokocinski F . GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res. 2012; 22(9):1760-74. PMC: 3431492. DOI: 10.1101/gr.135350.111. View

10.

Auton A, Brooks L, Durbin R, Garrison E, Kang H, Korbel J . A global reference for human genetic variation. Nature. 2015; 526(7571):68-74. PMC: 4750478. DOI: 10.1038/nature15393. View

11.

Weisenfeld N, Yin S, Sharpe T, Lau B, Hegarty R, Holmes L . Comprehensive variation discovery in single human genomes. Nat Genet. 2014; 46(12):1350-5. PMC: 4244235. DOI: 10.1038/ng.3121. View

12.

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N . The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25(16):2078-9. PMC: 2723002. DOI: 10.1093/bioinformatics/btp352. View

13.

Rosenbloom K, Sloan C, Malladi V, Dreszer T, Learned K, Kirkup V . ENCODE data in the UCSC Genome Browser: year 5 update. Nucleic Acids Res. 2012; 41(Database issue):D56-63. PMC: 3531152. DOI: 10.1093/nar/gks1172. View

14.

Kuleshov V . Probabilistic single-individual haplotyping. Bioinformatics. 2014; 30(17):i379-85. PMC: 4147930. DOI: 10.1093/bioinformatics/btu484. View

15.

Wang J, Raskin L, Samuels D, Shyr Y, Guo Y . Genome measures used for quality control are dependent on gene function and ancestry. Bioinformatics. 2014; 31(3):318-23. PMC: 4308666. DOI: 10.1093/bioinformatics/btu668. View

16.

Luo R, Sedlazeck F, Lam T, Schatz M . A multi-task convolutional deep neural network for variant calling in single molecule sequencing. Nat Commun. 2019; 10(1):998. PMC: 6397153. DOI: 10.1038/s41467-019-09025-z. View

17.

Glusman G, Cox H, Roach J . Whole-genome haplotyping approaches and genomic medicine. Genome Med. 2014; 6(9):73. PMC: 4254418. DOI: 10.1186/s13073-014-0073-7. View

18.

Poplin R, Chang P, Alexander D, Schwartz S, Colthurst T, Ku A . A universal SNP and small-indel variant caller using deep neural networks. Nat Biotechnol. 2018; 36(10):983-987. DOI: 10.1038/nbt.4235. View

19.

Rand A, Jain M, Eizenga J, Musselman-Brown A, Olsen H, Akeson M . Mapping DNA methylation with high-throughput nanopore sequencing. Nat Methods. 2017; 14(4):411-413. PMC: 5704956. DOI: 10.1038/nmeth.4189. View

20.

Jain M, Fiddes I, Miga K, Olsen H, Paten B, Akeson M . Improved data analysis for the MinION nanopore sequencer. Nat Methods. 2015; 12(4):351-6. PMC: 4907500. DOI: 10.1038/nmeth.3290. View