Home LiteratureArticle Details
PMID: 26292667 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals.

Nature communications ·Vol. 6 ·2015-08-21 ·Pages 8018

Nagasaki M, Yasuda J, Katsuoka F, Nariai N, Kojima K, Kawai Y, Yamaguchi-Kabata Y, Yokozawa J, Danjoh I, Saito S, Sato Y, Mimori T, Tsuda K, Saito R, Pan X, Nishikawa S, Ito S, Kuroki Y, Tanabe O, Fuse N, Kuriyama S, Kiyomoto H, Hozawa A, Minegishi N, Douglas Engel J, Kinoshita K, Kure S, Yaegashi N, ToMMo Japanese Reference Panel Project, Yamamoto M

Abstract

The Tohoku Medical Megabank Organization reports the whole-genome sequences of 1,070 healthy Japanese individuals and construction of a Japanese population reference panel (1KJPN). Here we identify through this high-coverage sequencing (32.4 × on average), 21.2 million, including 12 million novel, single-nucleotide variants (SNVs) at an estimated false discovery rate of <1.0%. This detailed analysis detected signatures for purifying selection on regulatory elements as well as coding regions. We also catalogue structural variants, including 3.4 million insertions and deletions, and 25,923 genic copy-number variants. The 1KJPN was effective for imputing genotypes of the Japanese population genome wide. These data demonstrate the value of high-coverage sequencing for constructing population-specific variant panels, which covers 99.0% SNVs of minor allele frequency ≥0.1%, and its value for identifying causal rare variants of complex human disease phenotypes in genetic association studies.

MeSH Terms
Asians/genetics Genetic Variation Genome, Human Haplotypes Humans
Authors & Affiliations
30 authors, click to expand affiliations / ORCID
Nagasaki Masao
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. | Graduate School of Information Sciences, Tohoku University, 6-3-09, Aramaki Aza-Aoba, Aoba-ku, Sendai 980-8579, Japan.
Yasuda Jun
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Katsuoka Fumiki
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Nariai Naoki
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan.
Kojima Kaname
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Kawai Yosuke
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Yamaguchi-Kabata Yumi
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Yokozawa Junji
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Danjoh Inaho
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Saito Sakae
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Sato Yukuto
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Mimori Takahiro
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan.
Tsuda Kaoru
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan.
Saito Rumiko
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan.
Pan Xiaoqing
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan.
Nishikawa Satoshi
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan.
Ito Shin
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan.
Kuroki Yoko
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan.
Tanabe Osamu
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Fuse Nobuo
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Kuriyama Shinichi
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. | International Research Institute of Disaster Science, Tohoku University, 468-1, Aramaki Aza-Aoba, Aoba-ku, Sendai 980-0845, Japan.
Kiyomoto Hideyasu ORCID
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Hozawa Atsushi
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Minegishi Naoko
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Douglas Engel James
Department of Cell and Developmental Biology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109-2200, USA.
Kinoshita Kengo
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Information Sciences, Tohoku University, 6-3-09, Aramaki Aza-Aoba, Aoba-ku, Sendai 980-8579, Japan. | Institute of Development, Aging and Cancer, Tohoku University, 4-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Kure Shigeo
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Yaegashi Nobuo
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
ToMMo Japanese Reference Panel Project
Yamamoto Masayuki
Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8573, Japan. | Graduate School of Medicine, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Investigators
18 investigators, click to expand
Tsuboi Akito
Nagami Fuji
Kawame Hiroshi
Tomita Hiroaki
Tsuji Ichiro
Nakaya Jun
Sugawara Junichi
Suzuki Kichiya
Kikuya Masahiro
Abe Michiaki
Nakaya Naoki
Osumi Noriko
Yamashita Riu
Ogishima Soichi
Takai Takako
Tominaga Teiji
Taki Yasuyuki
Suzuki Yoichi
References (68)
68 references, click to expand
  1. Immunobiological determinants in organ transplantation.
    Ann R Coll Surg Engl. 1983 May;65(3):139-44 PMID: 6344730
  2. Large recurrent microdeletions associated with schizophrenia.
    Nature. 2008 Sep 11;455(7210):232-6 PMID: 18668039
  3. dbNSFP v2.0: a database of human non-synonymous SNVs and their functional predictions and annotations.
    Hum Mutat. 2013 Sep;34(9):E2393-402 PMID: 23843252
  4. The human alpha-amylase multigene family consists of haplotypes with variable numbers of genes.
    Genomics. 1989 Jul;5(1):29-42 PMID: 2788608
  5. Genome sequencing identifies major causes of severe intellectual disability.
    Nature. 2014 Jul 17;511(7509):344-7 PMID: 24896178
  6. Genome-wide association study identifies HLA-DP as a susceptibility gene for pediatric asthma in Asian populations.
    PLoS Genet. 2011 Jul;7(7):e1002170 PMID: 21814517
  7. Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants.
    Nature. 2013 Jan 10;493(7431):216-20 PMID: 23201682
  8. A genome wide association study of genetic loci that influence tumour biomarkers cancer antigen 19-9, carcinoembryonic antigen and α fetoprotein and their associations with cancer risk.
    Gut. 2014 Jan;63(1):143-51 PMID: 23300138
  9. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project.
    Nature. 2007 Jun 14;447(7146):799-816 PMID: 17571346
  10. Diet and the evolution of human amylase gene copy number variation.
    Nat Genet. 2007 Oct;39(10):1256-60 PMID: 17828263
  11. An integrated map of genetic variation from 1,092 human genomes.
    Nature. 2012 Nov 1;491(7422):56-65 PMID: 23128226
  12. Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses.
    Genes Dev. 2011 Sep 15;25(18):1915-27 PMID: 21890647
  13. Whole-genome sequence variation, population structure and demographic history of the Dutch population.
    Nat Genet. 2014 Aug;46(8):818-25 PMID: 24974849
  14. Large-scale whole-genome sequencing of the Icelandic population.
    Nat Genet. 2015 May;47(5):435-44 PMID: 25807286
  15. The Growing Importance of CNVs: New Insights for Detection and Clinical Interpretation.
    Front Genet. 2013 May 30;4:92 PMID: 23750167
  16. A haplotype map of the human genome.
    Nature. 2005 Oct 27;437(7063):1299-320 PMID: 16255080
  17. Heritability and familiality of type 2 diabetes and related quantitative traits in the Botnia Study.
    Diabetologia. 2011 Nov;54(11):2811-9 PMID: 21826484
  18. Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction.
    Nat Genet. 2002 Dec;32(4):650-4 PMID: 12426569
  19. An efficient quantitation method of next-generation sequencing libraries by using MiSeq sequencer.
    Anal Biochem. 2014 Dec 1;466:27-9 PMID: 25173513
  20. Newborn screening in Japan: restructuring for the new era.
    Ann Acad Med Singapore. 2008 Dec;37(12 Suppl):13-5 PMID: 19904475
  21. Distribution and medical impact of loss-of-function variants in the Finnish founder population.
    PLoS Genet. 2014 Jul;10(7):e1004494 PMID: 25078778
  22. Toward better understanding of artifacts in variant calling from high-coverage samples.
    Bioinformatics. 2014 Oct 15;30(20):2843-51 PMID: 24974202
  23. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease.
    Nat Genet. 2008 Sep;40(9):1107-12 PMID: 19165925
  24. miRBase: annotating high confidence microRNAs using deep sequencing data.
    Nucleic Acids Res. 2014 Jan;42(Database issue):D68-73 PMID: 24275495
  25. Unsupervised pattern discovery in human chromatin structure through genomic segmentation.
    Nat Methods. 2012 May;9(5):473-6 PMID: 22426492
  26. An integrated encyclopedia of DNA elements in the human genome.
    Nature. 2012 Sep 6;489(7414):57-74 PMID: 22955616
  27. The IMGT/HLA database.
    Nucleic Acids Res. 2013 Jan;41(Database issue):D1222-7 PMID: 23080122
  28. Inferring the joint demographic history of multiple populations from multidimensional SNP frequency data.
    PLoS Genet. 2009 Oct;5(10):e1000695 PMID: 19851460
  29. The HLA genomic loci map: expression, interaction, diversity and disease.
    J Hum Genet. 2009 Jan;54(1):15-39 PMID: 19158813
  30. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development.
    PLoS One. 2011;6(7):e22542 PMID: 21799892
  31. Integrating common and rare genetic variation in diverse human populations.
    Nature. 2010 Sep 2;467(7311):52-8 PMID: 20811451
  32. An abundance of rare functional variants in 202 drug target genes sequenced in 14,002 people.
    Science. 2012 Jul 6;337(6090):100-4 PMID: 22604722
  33. A framework for variation discovery and genotyping using next-generation DNA sequencing data.
    Nat Genet. 2011 May;43(5):491-8 PMID: 21478889
  34. ChromHMM: automating chromatin-state discovery and characterization.
    Nat Methods. 2012 Mar;9(3):215-6 PMID: 22373907
  35. Estimation of linkage between the Lutheran and the Lewis blood groups.
    Acta Pathol Microbiol Scand. 1951;29(3):339-44 PMID: 14933035
  36. High-throughput DNA typing of HLA-A, -B, -C, and -DRB1 loci by a PCR-SSOP-Luminex method in the Japanese population.
    Immunogenetics. 2005 Nov;57(10):717-29 PMID: 16215732
  37. 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
  38. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC.
    Nat Genet. 2006 Oct;38(10):1166-72 PMID: 16998491
  39. Reconstituting the frequency spectrum of ascertained single-nucleotide polymorphism data.
    Genetics. 2004 Dec;168(4):2373-82 PMID: 15371362
  40. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.
    Nature. 2007 Jun 7;447(7145):661-78 PMID: 17554300
  41. Finding the missing heritability of complex diseases.
    Nature. 2009 Oct 8;461(7265):747-53 PMID: 19812666
  42. Genome-wide association study identifies novel loci associated with serum level of vitamin B12 in Chinese men.
    Hum Mol Genet. 2012 Jun 1;21(11):2610-7 PMID: 22367966
  43. HLA-VBSeq: accurate HLA typing at full resolution from whole-genome sequencing data.
    BMC Genomics. 2015;16 Suppl 2:S7 PMID: 25708870
  44. A genome-wide association study identifies RNF213 as the first Moyamoya disease gene.
    J Hum Genet. 2011 Jan;56(1):34-40 PMID: 21048783
  45. A general framework for estimating the relative pathogenicity of human genetic variants.
    Nat Genet. 2014 Mar;46(3):310-5 PMID: 24487276
  46. Analyzing and minimizing PCR amplification bias in Illumina sequencing libraries.
    Genome Biol. 2011;12(2):R18 PMID: 21338519
  47. Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins.
    Nat Commun. 2014;5:4835 PMID: 25203624
  48. Sequencing depth and coverage: key considerations in genomic analyses.
    Nat Rev Genet. 2014 Feb;15(2):121-32 PMID: 24434847
  49. Donor-recipient allele-level HLA matching of unrelated cord blood units reveals high degrees of mismatch and alters graft selection.
    Bone Marrow Transplant. 2014 Sep;49(9):1184-6 PMID: 25000459
  50. iSVP: an integrated structural variant calling pipeline from high-throughput sequencing data.
    BMC Syst Biol. 2013;7 Suppl 6:S8 PMID: 24564972
  51. Improved whole-chromosome phasing for disease and population genetic studies.
    Nat Methods. 2013 Jan;10(1):5-6 PMID: 23269371
  52. Simultaneous inference of selection and population growth from patterns of variation in the human genome.
    Proc Natl Acad Sci U S A. 2005 May 31;102(22):7882-7 PMID: 15905331
  53. Long insert whole genome sequencing for copy number variant and translocation detection.
    Nucleic Acids Res. 2014 Jan;42(2):e8 PMID: 24071583
  54. Fast and accurate short read alignment with Burrows-Wheeler transform.
    Bioinformatics. 2009 Jul 15;25(14):1754-60 PMID: 19451168
  55. BreakDancer: an algorithm for high-resolution mapping of genomic structural variation.
    Nat Methods. 2009 Sep;6(9):677-81 PMID: 19668202
  56. Challenges and standards in integrating surveys of structural variation.
    Nat Genet. 2007 Jul;39(7 Suppl):S7-15 PMID: 17597783
  57. SUGAR: graphical user interface-based data refiner for high-throughput DNA sequencing.
    BMC Genomics. 2014;15:664 PMID: 25103311
  58. Molecular genetic analysis of the human Lewis histo-blood group system. II. Secretor gene inactivation by a novel single missense mutation A385T in Japanese nonsecretor individuals.
    J Biol Chem. 1996 Apr 19;271(16):9830-7 PMID: 8621666
  59. Japonica array: improved genotype imputation by designing a population-specific SNP array with 1070 Japanese individuals.
    J Hum Genet. 2015 Oct;60(10):581-7 PMID: 26108142
  60. 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
  61. On the allelic spectrum of human disease.
    Trends Genet. 2001 Sep;17(9):502-10 PMID: 11525833
  62. Deep whole-genome sequencing of 100 southeast Asian Malays.
    Am J Hum Genet. 2013 Jan 10;92(1):52-66 PMID: 23290073
  63. The human gene mutation database.
    Nucleic Acids Res. 1998 Jan 1;26(1):285-7 PMID: 9399854
  64. Functional impact of global rare copy number variation in autism spectrum disorders.
    Nature. 2010 Jul 15;466(7304):368-72 PMID: 20531469
  65. Estimating the heritability of colorectal cancer.
    Hum Mol Genet. 2014 Jul 15;23(14):3898-905 PMID: 24562164
  66. Birth prevalence of disorders detectable through newborn screening by race/ethnicity.
    Genet Med. 2012 Nov;14(11):937-45 PMID: 22766612
  67. CNVs conferring risk of autism or schizophrenia affect cognition in controls.
    Nature. 2014 Jan 16;505(7483):361-6 PMID: 24352232
  68. Initial sequencing and analysis of the human genome.
    Nature. 2001 Feb 15;409(6822):860-921 PMID: 11237011
Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms9018
Published
2015-08-21
Epub
2015-00-21
Pages
8018
Language
English
Region
England
NLM ID
101528555
PMCID
PMC4560751
Subset
IM
External Links
PubMed source DOI: 10.1038/ncomms9018 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