publication . Article . Preprint . Other literature type . 2019

Telomere-to-telomere assembly of a complete human X chromosome.

Jon Matthew Belton; Megan Y. Dennis; David Porubsky; Tamara A. Potapova; Anthony D. Schmitt; Kerstin Howe; Evan E. Eichler; Evan E. Eichler; Alice Young; Robert S. Fulton; ...
Open Access
  • Published: 16 Aug 2019 Journal: Nature, volume 585, pages 79-84 (issn: 0028-0836, eissn: 1476-4687, Copyright policy)
  • Publisher: Springer Science and Business Media LLC
Abstract
<jats:p>After nearly two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no one chromosome has been finished end to end, and hundreds of unresolved gaps persist <jats:sup>1,2</jats:sup>. The remaining gaps include ribosomal rDNA arrays, large near-identical segmental duplications, and satellite DNA arrays. These regions harbor largely unexplored variation of unknown consequence, and their absence from the current reference genome can lead to experimental artifacts and hide true variants when re-sequencing additional human genomes. Here we present a <jats:italic>de no...
Subjects
free text keywords: Multidisciplinary, Reference genome, Biology, Genome, Telomere assembly, Computational biology, Pseudoautosomal region, X chromosome, Tandem repeat, Human genome, Nanopore sequencing, Segmental duplication
Funded by
NIH| Unbiased analysis of genomic correlates of gene expression in health and disease
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1U01HL137183-01
  • Funding stream: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
,
WT| A New Durable Read EXtension Method for Very, Very Long Reads
Project
  • Funder: Wellcome Trust (WT)
  • Project Code: 212965
  • Funding stream: Genetics, Genomics and Population Research
,
NIH| Genomic Analysis of Centromere Assembly and Function
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01GM124041-02
  • Funding stream: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
,
NIH| Nanopore based profiling of epigenetic state
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1R01HG009190-01A1
  • Funding stream: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
,
NIH| Commercialization of HaploSeq as a Service (HaaS) for generating chromosome-span phased genome and exome sequence information
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 2R44HG008118-04A1
  • Funding stream: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
Download fromView all 4 versions
Nature
Article
Provider: UnpayWall
bioRxiv
Preprint . 2019
Provider: bioRxiv
http://dx.doi.org/10.1101/7359...
Other literature type . 2019
Provider: Datacite
18 references, page 1 of 2

1. Jain, M. ​et al.​ Nanopore sequencing and assembly of a human genome with ultra-long 2. Schneider, V. A. ​et al.​ Evaluation of GRCh38 and de novo haploid genome assemblies 3. Ross, M. T. ​et al.​ The DNA sequence of the human X chromosome. ​Nature​ ​434​, 325-337 4. Mefford, H. C. & Eichler, E. E. Duplication hotspots, rare genomic disorders, and common disease. ​Curr. Opin. Genet. Dev.​ ​19​, 196-204 (2009).

5. Langley, S. A., Miga, K. H., Karpen, G. H. & Langley, C. H. Haplotypes spanning 6. Eichler, E. E. Masquerading repeats: paralogous pitfalls of the human genome. ​Genome 7. Breitwieser, F. P., Pertea, M., Zimin, A. V. & Salzberg, S. L. Human contamination in 8. Schueler, M. G., Higgins, A. W., Rudd, M. K., Gustashaw, K. & Willard, H. F. Genomic and 10. Mortazavi, A., Williams, B. A., McCue, K., Schaeffer, L. & Wold, B. Mapping and quantifying assaying chromatin accessibility genome-wide. ​Curr. Protoc. Mol. Biol.​ ​109​, 21-29 (2015).

13. Staden, R. A strategy of DNA sequencing employing computer programs. ​Nucleic Acids 14. Nagarajan, N. & Pop, M. Sequence assembly demystified. ​Nat. Rev. Genet.​ ​14​, 157-167 15. Steinberg, K. M. ​et al.​ Single haplotype assembly of the human genome from a hydatidiform mole. ​Genome Res.​ ​24​, 2066-2076 (2014).

16. Li, H. ​et al.​ A synthetic-diploid benchmark for accurate variant-calling evaluation. ​Nat.

17. Vollger, M. R. ​et al.​ Long-read sequence and assembly of segmental duplications. ​Nat.

18. Huddleston, J. ​et al.​ Discovery and genotyping of structural variation from long-read haploid 24. Migeon, B. R. & Kennedy, J. F. Evidence for the inactivation of an X chromosome early in the development of the human female. ​Am. J. Hum. Genet.​ ​27​, 233-239 (1975).

25. Vollger, M. R. ​et al.​ Improved assembly and variant detection of a haploid human genome using single-molecule, high-fidelity long reads. ​bioRxiv​ 635037 (2019). doi:​10.1101/635037 26. Willard, H. F., Smith, K. D. & Sutherland, J. Isolation and characterization of a major tandem repeat family from the human X chromosome. ​Nucleic Acids Res.​ ​11​, 2017-2033 27. Waye, J. S. & Willard, H. F. Nucleotide sequence heterogeneity of alpha satellite repetitive 30. Loman, N. J., Quick, J. & Simpson, J. T. A complete bacterial genome assembled de novo 31. Koren, S., Phillippy, A. M., Simpson, J. T., Loman, N. J. & Loose, M. Reply to 'Errors in 34. Schmutz, J. ​et al.​ Quality assessment of the human genome sequence. ​Nature​ ​429​, 35. Falconer, E. ​et al.​ DNA template strand sequencing of single-cells maps genomic rearrangements at high resolution. ​Nat. Methods​ ​9​, 1107-1112 (2012).

36. Sanders, A. D. ​et al.​ Characterizing polymorphic inversions in human genomes by single-cell sequencing. ​Genome Res.​ ​26​, 1575-1587 (2016). in Human Populations. ​Genetics​ ​209​, 907-920 (2018).

37. Lucotte, E. A. ​et al.​ Dynamic Copy Number Evolution of X- and Y-Linked Ampliconic Genes 38. Killen, M. W. ​et al.​ Configuration and rearrangement of the human GAGE gene clusters. Am. J. Transl. Res.​ ​3​, 234-242 (2011).

39. Rand, A. C. ​et al.​ Mapping DNA methylation with high-throughput nanopore sequencing.

40. Carrel, L., Cottle, A. A., Goglin, K. C. & Willard, H. F. A first-generation X-inactivation profile of the human X chromosome. ​Proc. Natl. Acad. Sci. U. S. A.​ ​96​, 14440-14444 (1999). [OpenAIRE]

41. Giorgetti, L. ​et al.​ Structural organization of the inactive X chromosome in the mouse.

44. Donlon, T. A., Bruns, G. A., Latt, S. A., Mulholland, J. & Wyman, A. R. A chromosome 45. Ge, Y., Wagner, M. J., Siciliano, M. & Wells, D. E. Sequence, higher order repeat structure, 46. Dutra, A. S., Mignot, E. & Puck, J. M. Gene localization and syntenic mapping by FISH in the dog. ​Cytogenet. Cell Genet.​ ​74​, 113-117 (1996).

47. Willatt, L. & Morgan, S. M. Shaffer LG, Slovak ML, Campbell LJ (2009): ISCN 2009 an international system for human cytogenetic nomenclature. ​Hum. Genet.​ ​126​, 603 (2009). [OpenAIRE]

48. Quick, J. Ultra-long read sequencing protocol for RAD004 v3 (protocols.io.mrxc57n).

18 references, page 1 of 2
Abstract
<jats:p>After nearly two decades of improvements, the current human reference genome (GRCh38) is the most accurate and complete vertebrate genome ever produced. However, no one chromosome has been finished end to end, and hundreds of unresolved gaps persist <jats:sup>1,2</jats:sup>. The remaining gaps include ribosomal rDNA arrays, large near-identical segmental duplications, and satellite DNA arrays. These regions harbor largely unexplored variation of unknown consequence, and their absence from the current reference genome can lead to experimental artifacts and hide true variants when re-sequencing additional human genomes. Here we present a <jats:italic>de no...
Subjects
free text keywords: Multidisciplinary, Reference genome, Biology, Genome, Telomere assembly, Computational biology, Pseudoautosomal region, X chromosome, Tandem repeat, Human genome, Nanopore sequencing, Segmental duplication
Funded by
NIH| Unbiased analysis of genomic correlates of gene expression in health and disease
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1U01HL137183-01
  • Funding stream: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
,
WT| A New Durable Read EXtension Method for Very, Very Long Reads
Project
  • Funder: Wellcome Trust (WT)
  • Project Code: 212965
  • Funding stream: Genetics, Genomics and Population Research
,
NIH| Genomic Analysis of Centromere Assembly and Function
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 5R01GM124041-02
  • Funding stream: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
,
NIH| Nanopore based profiling of epigenetic state
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 1R01HG009190-01A1
  • Funding stream: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
,
NIH| Commercialization of HaploSeq as a Service (HaaS) for generating chromosome-span phased genome and exome sequence information
Project
  • Funder: National Institutes of Health (NIH)
  • Project Code: 2R44HG008118-04A1
  • Funding stream: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
Download fromView all 4 versions
Nature
Article
Provider: UnpayWall
bioRxiv
Preprint . 2019
Provider: bioRxiv
http://dx.doi.org/10.1101/7359...
Other literature type . 2019
Provider: Datacite
18 references, page 1 of 2

1. Jain, M. ​et al.​ Nanopore sequencing and assembly of a human genome with ultra-long 2. Schneider, V. A. ​et al.​ Evaluation of GRCh38 and de novo haploid genome assemblies 3. Ross, M. T. ​et al.​ The DNA sequence of the human X chromosome. ​Nature​ ​434​, 325-337 4. Mefford, H. C. & Eichler, E. E. Duplication hotspots, rare genomic disorders, and common disease. ​Curr. Opin. Genet. Dev.​ ​19​, 196-204 (2009).

5. Langley, S. A., Miga, K. H., Karpen, G. H. & Langley, C. H. Haplotypes spanning 6. Eichler, E. E. Masquerading repeats: paralogous pitfalls of the human genome. ​Genome 7. Breitwieser, F. P., Pertea, M., Zimin, A. V. & Salzberg, S. L. Human contamination in 8. Schueler, M. G., Higgins, A. W., Rudd, M. K., Gustashaw, K. & Willard, H. F. Genomic and 10. Mortazavi, A., Williams, B. A., McCue, K., Schaeffer, L. & Wold, B. Mapping and quantifying assaying chromatin accessibility genome-wide. ​Curr. Protoc. Mol. Biol.​ ​109​, 21-29 (2015).

13. Staden, R. A strategy of DNA sequencing employing computer programs. ​Nucleic Acids 14. Nagarajan, N. & Pop, M. Sequence assembly demystified. ​Nat. Rev. Genet.​ ​14​, 157-167 15. Steinberg, K. M. ​et al.​ Single haplotype assembly of the human genome from a hydatidiform mole. ​Genome Res.​ ​24​, 2066-2076 (2014).

16. Li, H. ​et al.​ A synthetic-diploid benchmark for accurate variant-calling evaluation. ​Nat.

17. Vollger, M. R. ​et al.​ Long-read sequence and assembly of segmental duplications. ​Nat.

18. Huddleston, J. ​et al.​ Discovery and genotyping of structural variation from long-read haploid 24. Migeon, B. R. & Kennedy, J. F. Evidence for the inactivation of an X chromosome early in the development of the human female. ​Am. J. Hum. Genet.​ ​27​, 233-239 (1975).

25. Vollger, M. R. ​et al.​ Improved assembly and variant detection of a haploid human genome using single-molecule, high-fidelity long reads. ​bioRxiv​ 635037 (2019). doi:​10.1101/635037 26. Willard, H. F., Smith, K. D. & Sutherland, J. Isolation and characterization of a major tandem repeat family from the human X chromosome. ​Nucleic Acids Res.​ ​11​, 2017-2033 27. Waye, J. S. & Willard, H. F. Nucleotide sequence heterogeneity of alpha satellite repetitive 30. Loman, N. J., Quick, J. & Simpson, J. T. A complete bacterial genome assembled de novo 31. Koren, S., Phillippy, A. M., Simpson, J. T., Loman, N. J. & Loose, M. Reply to 'Errors in 34. Schmutz, J. ​et al.​ Quality assessment of the human genome sequence. ​Nature​ ​429​, 35. Falconer, E. ​et al.​ DNA template strand sequencing of single-cells maps genomic rearrangements at high resolution. ​Nat. Methods​ ​9​, 1107-1112 (2012).

36. Sanders, A. D. ​et al.​ Characterizing polymorphic inversions in human genomes by single-cell sequencing. ​Genome Res.​ ​26​, 1575-1587 (2016). in Human Populations. ​Genetics​ ​209​, 907-920 (2018).

37. Lucotte, E. A. ​et al.​ Dynamic Copy Number Evolution of X- and Y-Linked Ampliconic Genes 38. Killen, M. W. ​et al.​ Configuration and rearrangement of the human GAGE gene clusters. Am. J. Transl. Res.​ ​3​, 234-242 (2011).

39. Rand, A. C. ​et al.​ Mapping DNA methylation with high-throughput nanopore sequencing.

40. Carrel, L., Cottle, A. A., Goglin, K. C. & Willard, H. F. A first-generation X-inactivation profile of the human X chromosome. ​Proc. Natl. Acad. Sci. U. S. A.​ ​96​, 14440-14444 (1999). [OpenAIRE]

41. Giorgetti, L. ​et al.​ Structural organization of the inactive X chromosome in the mouse.

44. Donlon, T. A., Bruns, G. A., Latt, S. A., Mulholland, J. & Wyman, A. R. A chromosome 45. Ge, Y., Wagner, M. J., Siciliano, M. & Wells, D. E. Sequence, higher order repeat structure, 46. Dutra, A. S., Mignot, E. & Puck, J. M. Gene localization and syntenic mapping by FISH in the dog. ​Cytogenet. Cell Genet.​ ​74​, 113-117 (1996).

47. Willatt, L. & Morgan, S. M. Shaffer LG, Slovak ML, Campbell LJ (2009): ISCN 2009 an international system for human cytogenetic nomenclature. ​Hum. Genet.​ ​126​, 603 (2009). [OpenAIRE]

48. Quick, J. Ultra-long read sequencing protocol for RAD004 v3 (protocols.io.mrxc57n).

18 references, page 1 of 2
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