Home LiteratureArticle Details
PMID: 25597990 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Novel variation and de novo mutation rates in population-wide de novo assembled Danish trios.

Nature communications ·Vol. 6 ·2015-01-19 ·Pages 5969

Besenbacher S, Liu S, Izarzugaza JM, Grove J, Belling K, Bork-Jensen J, Huang S, Als TD, Li S, Yadav R, Rubio-García A, Lescai F, Demontis D, Rao J, Ye W, Mailund T, Friborg RM, Pedersen CN, Xu R, Sun J, Liu H, Wang O, Cheng X, Flores D, Rydza E, Rapacki K, Damm Sørensen J, Chmura P, Westergaard D, Dworzynski P, Sørensen TI, Lund O, Hansen T, Xu X, Li N, Bolund L, Pedersen O, Eiberg H, Krogh A, Børglum AD, Brunak S, Kristiansen K, Schierup MH, Wang J, Gupta R, Villesen P, Rasmussen S

Abstract

Building a population-specific catalogue of single nucleotide variants (SNVs), indels and structural variants (SVs) with frequencies, termed a national pan-genome, is critical for further advancing clinical and public health genetics in large cohorts. Here we report a Danish pan-genome obtained from sequencing 10 trios to high depth (50 × ). We report 536k novel SNVs and 283k novel short indels from mapping approaches and develop a population-wide de novo assembly approach to identify 132k novel indels larger than 10 nucleotides with low false discovery rates. We identify a higher proportion of indels and SVs than previous efforts showing the merits of high coverage and de novo assembly approaches. In addition, we use trio information to identify de novo mutations and use a probabilistic method to provide direct estimates of 1.27e-8 and 1.5e-9 per nucleotide per generation for SNVs and indels, respectively.

MeSH Terms
Algorithms Genome, Human/genetics Humans Mutation Rate Polymorphism, Single Nucleotide/genetics Sequence Analysis, DNA/methods
Authors & Affiliations
47 authors, click to expand affiliations / ORCID
Besenbacher Søren
Bioinformatics Research Center, Aarhus University, C. F. Møllers Allé 8, DK-8000 Aarhus, Denmark.
Liu Siyang
1] BGI Europe, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark [2] Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen, Denmark.
Izarzugaza José M G
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 208, DK-2800 Kgs Lyngby, Denmark.
Grove Jakob
1] Bioinformatics Research Center, Aarhus University, C. F. Møllers Allé 8, DK-8000 Aarhus, Denmark [2] Centre for Integrative Sequencing, iSEQ, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark [3] The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, DK-8000 Aarhus, Denmark [4] Department of Biomedicine, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark.
Belling Kirstine
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 208, DK-2800 Kgs Lyngby, Denmark.
Bork-Jensen Jette
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1-3, DK-2100 Copenhagen, Denmark.
Huang Shujia
1] BGI Europe, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark [2] School of Bioscience and Biotechnology, South China University of Technology, Guangzhou 510006, China.
Als Thomas D
1] Centre for Integrative Sequencing, iSEQ, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark [2] The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, DK-8000 Aarhus, Denmark [3] Department of Biomedicine, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark.
Li Shengting
1] BGI Europe, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark [2] Centre for Integrative Sequencing, iSEQ, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark [3] The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, DK-8000 Aarhus, Denmark [4] Department of Biomedicine, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark.
Yadav Rachita
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 208, DK-2800 Kgs Lyngby, Denmark.
Rubio-García Arcadio
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 208, DK-2800 Kgs Lyngby, Denmark.
Lescai Francesco
1] Centre for Integrative Sequencing, iSEQ, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark [2] The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, DK-8000 Aarhus, Denmark [3] Department of Biomedicine, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark.
Demontis Ditte
1] Centre for Integrative Sequencing, iSEQ, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark [2] The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, DK-8000 Aarhus, Denmark [3] Department of Biomedicine, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark.
Rao Junhua
BGI Europe, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark.
Ye Weijian
BGI Europe, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark.
Mailund Thomas
1] Bioinformatics Research Center, Aarhus University, C. F. Møllers Allé 8, DK-8000 Aarhus, Denmark [2] Centre for Integrative Sequencing, iSEQ, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark.
Friborg Rune M
1] Bioinformatics Research Center, Aarhus University, C. F. Møllers Allé 8, DK-8000 Aarhus, Denmark [2] Centre for Integrative Sequencing, iSEQ, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark.
Pedersen Christian N S
Bioinformatics Research Center, Aarhus University, C. F. Møllers Allé 8, DK-8000 Aarhus, Denmark.
Xu Ruiqi
BGI Europe, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark.
Sun Jihua
BGI Europe, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark.
Liu Hao
BGI Europe, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark.
Wang Ou
BGI Europe, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark.
Cheng Xiaofang
BGI Europe, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark.
Flores David
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 208, DK-2800 Kgs Lyngby, Denmark.
Rydza Emil
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 208, DK-2800 Kgs Lyngby, Denmark.
Rapacki Kristoffer
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 208, DK-2800 Kgs Lyngby, Denmark.
Damm Sørensen John
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 208, DK-2800 Kgs Lyngby, Denmark.
Chmura Piotr
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 208, DK-2800 Kgs Lyngby, Denmark.
Westergaard David
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 208, DK-2800 Kgs Lyngby, Denmark.
Dworzynski Piotr
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 208, DK-2800 Kgs Lyngby, Denmark.
Sørensen Thorkild I A
1] The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1-3, DK-2100 Copenhagen, Denmark [2] Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Nordre Fasanvej 57, Hovedvejen 5, DK2000 Copenhagen, Denmark.
Lund Ole
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 208, DK-2800 Kgs Lyngby, Denmark.
Hansen Torben
1] The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1-3, DK-2100 Copenhagen, Denmark [2] Faculty of Health Sciences, University of Southern Denmark, DK-5000 Odense, Denmark.
Xu Xun
BGI Europe, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark.
Li Ning
BGI Europe, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark.
Bolund Lars
1] Centre for Integrative Sequencing, iSEQ, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark [2] Department of Biomedicine, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark.
Pedersen Oluf
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 1-3, DK-2100 Copenhagen, Denmark.
Eiberg Hans
Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
Krogh Anders
1] Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen, Denmark [2] Centre for GeoGenetics, Natural History Museum of Denmark, University of Copenhagen, Øster Voldgade 5-7, DK-1350 Copenhagen, Denmark.
Børglum Anders D
1] Centre for Integrative Sequencing, iSEQ, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark [2] The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, DK-8000 Aarhus, Denmark [3] Department of Biomedicine, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark.
Brunak Søren
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 208, DK-2800 Kgs Lyngby, Denmark.
Kristiansen Karsten
Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen, Denmark.
Schierup Mikkel H
1] Bioinformatics Research Center, Aarhus University, C. F. Møllers Allé 8, DK-8000 Aarhus, Denmark [2] Centre for Integrative Sequencing, iSEQ, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark.
Wang Jun
1] BGI Europe, Ole Maaløes Vej 3, DK-2200 Copenhagen, Denmark [2] Department of Biology, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen, Denmark [3] Centre for Integrative Sequencing, iSEQ, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark.
Gupta Ramneek
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 208, DK-2800 Kgs Lyngby, Denmark.
Villesen Palle
1] Bioinformatics Research Center, Aarhus University, C. F. Møllers Allé 8, DK-8000 Aarhus, Denmark [2] Centre for Integrative Sequencing, iSEQ, Aarhus University, Bartholins Allé 6, building 1242, DK-8000 Aarhus, Denmark.
Rasmussen Simon
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Kemitorvet 208, DK-2800 Kgs Lyngby, Denmark.
References (48)
48 references, click to expand
  1. SOAPdenovo2: an empirically improved memory-efficient short-read de novo assembler.
    Gigascience. 2012 Dec 27;1(1):18 PMID: 23587118
  2. AdapterRemoval: easy cleaning of next-generation sequencing reads.
    BMC Res Notes. 2012;5:337 PMID: 22748135
  3. Current status and new features of the Consensus Coding Sequence database.
    Nucleic Acids Res. 2014 Jan;42(Database issue):D865-72 PMID: 24217909
  4. Comprehensive characterization of human genome variation by high coverage whole-genome sequencing of forty four Caucasians.
    PLoS One. 2013;8(4):e59494 PMID: 23577066
  5. A systematic survey of loss-of-function variants in human protein-coding genes.
    Science. 2012 Feb 17;335(6070):823-8 PMID: 22344438
  6. An integrated map of genetic variation from 1,092 human genomes.
    Nature. 2012 Nov 1;491(7422):56-65 PMID: 23128226
  7. Automating resequencing-based detection of insertion-deletion polymorphisms.
    Nat Genet. 2006 Dec;38(12):1457-62 PMID: 17115056
  8. The diploid genome sequence of an individual human.
    PLoS Biol. 2007 Sep 4;5(10):e254 PMID: 17803354
  9. Evolution and functional impact of rare coding variation from deep sequencing of human exomes.
    Science. 2012 Jul 6;337(6090):64-9 PMID: 22604720
  10. Determinants of mutation rate variation in the human germline.
    Annu Rev Genomics Hum Genet. 2014;15:47-70 PMID: 25000986
  11. The consensus coding sequence (CCDS) project: Identifying a common protein-coding gene set for the human and mouse genomes.
    Genome Res. 2009 Jul;19(7):1316-23 PMID: 19498102
  12. Whole-genome sequence variation, population structure and demographic history of the Dutch population.
    Nat Genet. 2014 Aug;46(8):818-25 PMID: 24974849
  13. Revising the human mutation rate: implications for understanding human evolution.
    Nat Rev Genet. 2012 Oct;13(10):745-53 PMID: 22965354
  14. AGE: defining breakpoints of genomic structural variants at single-nucleotide resolution, through optimal alignments with gap excision.
    Bioinformatics. 2011 Mar 1;27(5):595-603 PMID: 21233167
  15. Rate of de novo mutations and the importance of father's age to disease risk.
    Nature. 2012 Aug 23;488(7412):471-5 PMID: 22914163
  16. Structural variation in two human genomes mapped at single-nucleotide resolution by whole genome de novo assembly.
    Nat Biotechnol. 2011 Aug;29(8):723-30 PMID: 21785424
  17. Toward better understanding of artifacts in variant calling from high-coverage samples.
    Bioinformatics. 2014 Oct 15;30(20):2843-51 PMID: 24974202
  18. Rate, molecular spectrum, and consequences of human mutation.
    Proc Natl Acad Sci U S A. 2010 Jan 19;107(3):961-8 PMID: 20080596
  19. Tandem repeats finder: a program to analyze DNA sequences.
    Nucleic Acids Res. 1999 Jan 15;27(2):573-80 PMID: 9862982
  20. From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline.
    Curr Protoc Bioinformatics. 2013;43:11.10.1-33 PMID: 25431634
  21. The origin, evolution, and functional impact of short insertion-deletion variants identified in 179 human genomes.
    Genome Res. 2013 May;23(5):749-61 PMID: 23478400
  22. The Sequence Alignment/Map format and SAMtools.
    Bioinformatics. 2009 Aug 15;25(16):2078-9 PMID: 19505943
  23. De novo mutations in human genetic disease.
    Nat Rev Genet. 2012 Aug;13(8):565-75 PMID: 22805709
  24. Ensembl 2013.
    Nucleic Acids Res. 2013 Jan;41(Database issue):D48-55 PMID: 23203987
  25. Linkage studies of cholestasis familiaris groenlandica/Byler-like disease with polymorphic protein and blood group markers.
    Hum Hered. 1993 Jul-Aug;43(4):250-6 PMID: 8344670
  26. Basic local alignment search tool.
    J Mol Biol. 1990 Oct 5;215(3):403-10 PMID: 2231712
  27. A framework for variation discovery and genotyping using next-generation DNA sequencing data.
    Nat Genet. 2011 May;43(5):491-8 PMID: 21478889
  28. Patterns and rates of exonic de novo mutations in autism spectrum disorders.
    Nature. 2012 May 10;485(7397):242-5 PMID: 22495311
  29. Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads.
    Bioinformatics. 2009 Nov 1;25(21):2865-71 PMID: 19561018
  30. Building the sequence map of the human pan-genome.
    Nat Biotechnol. 2010 Jan;28(1):57-63 PMID: 19997067
  31. Whole-genome sequencing in autism identifies hot spots for de novo germline mutation.
    Cell. 2012 Dec 21;151(7):1431-42 PMID: 23260136
  32. Linkage between serum cholinesterase 2 (CHE2) and gamma-crystallin gene cluster (CRYG): assignment to chromosome 2.
    Clin Genet. 1989 May;35(5):313-21 PMID: 2758686
  33. Tracking and coordinating an international curation effort for the CCDS Project.
    Database (Oxford). 2012;2012:bas008 PMID: 22434842
  34. DeNovoGear: de novo indel and point mutation discovery and phasing.
    Nat Methods. 2013 Oct;10(10):985-7 PMID: 23975140
  35. PLINK: a tool set for whole-genome association and population-based linkage analyses.
    Am J Hum Genet. 2007 Sep;81(3):559-75 PMID: 17701901
  36. Discovery and genotyping of genome structural polymorphism by sequencing on a population scale.
    Nat Genet. 2011 Mar;43(3):269-76 PMID: 21317889
  37. Probabilistic whole-genome alignments reveal high indel rates in the human and mouse genomes.
    Bioinformatics. 2007 Jul 1;23(13):i289-96 PMID: 17646308
  38. A map of human genome variation from population-scale sequencing.
    Nature. 2010 Oct 28;467(7319):1061-73 PMID: 20981092
  39. Fast and accurate short read alignment with Burrows-Wheeler transform.
    Bioinformatics. 2009 Jul 15;25(14):1754-60 PMID: 19451168
  40. BreakDancer: an algorithm for high-resolution mapping of genomic structural variation.
    Nat Methods. 2009 Sep;6(9):677-81 PMID: 19668202
  41. The Genome of the Netherlands: design, and project goals.
    Eur J Hum Genet. 2014 Feb;22(2):221-7 PMID: 23714750
  42. Nucleotide-resolution analysis of structural variants using BreakSeq and a breakpoint library.
    Nat Biotechnol. 2010 Jan;28(1):47-55 PMID: 20037582
  43. CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing.
    Genome Res. 2011 Jun;21(6):974-84 PMID: 21324876
  44. The Database of Genomic Variants: a curated collection of structural variation in the human genome.
    Nucleic Acids Res. 2014 Jan;42(Database issue):D986-92 PMID: 24174537
  45. Deep whole-genome sequencing of 100 southeast Asian Malays.
    Am J Hum Genet. 2013 Jan 10;92(1):52-66 PMID: 23290073
  46. Mapping copy number variation by population-scale genome sequencing.
    Nature. 2011 Feb 3;470(7332):59-65 PMID: 21293372
  47. Adaptive seeds tame genomic sequence comparison.
    Genome Res. 2011 Mar;21(3):487-93 PMID: 21209072
  48. De novo assembly of human genomes with massively parallel short read sequencing.
    Genome Res. 2010 Feb;20(2):265-72 PMID: 20019144
Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms6969
Published
2015-01-19
Epub
2015-00-19
Pages
5969
Language
English
Region
England
NLM ID
101528555
PMCID
PMC4309431
Subset
IM
External Links
PubMed source DOI: 10.1038/ncomms6969 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2