title: De novo assembly and phasing of a Korean human genome.
abstract: Advances in genome assembly and phasing provide an opportunity to investigate the diploid architecture of the human genome and reveal the full range of structural variation across population groups. Here we report the de novo assembly and haplotype phasing of the Korean individual AK1 (ref. 1) using single-molecule real-time sequencing, next-generation mapping, microfluidics-based linked reads, and bacterial artificial chromosome (BAC) sequencing approaches. Single-molecule sequencing coupled with next-generation mapping generated a highly contiguous assembly, with a contig N50 size of 17.9 Mb and a scaffold N50 size of 44.8 Mb, resolving 8 chromosomal arms into single scaffolds. The de novo assembly, along with local assemblies and spanning long reads, closes 105 and extends into 72 out of 190 euchromatic gaps in the reference genome, adding 1.03 Mb of previously intractable sequence. High concordance between the assembly and paired-end sequences from 62,758 BAC clones provides strong support for the robustness of the assembly. We identify 18,210 structural variants by direct comparison of the assembly with the human reference, identifying thousands of breakpoints that, to our knowledge, have not been reported before. Many of the insertions are reflected in the transcriptome and are shared across the Asian population. We performed haplotype phasing of the assembly with short reads, long reads and linked reads from whole-genome sequencing and with short reads from 31,719 BAC clones, thereby achieving phased blocks with an N50 size of 11.6 Mb. Haplotigs assembled from single-molecule real-time reads assigned to haplotypes on phased blocks covered 89% of genes. The haplotigs accurately characterized the hypervariable major histocompatability complex region as well as demonstrating allele configuration in clinically relevant genes such as CYP2D6. This work presents the most contiguous diploid human genome assembly so far, with extensive investigation of unreported and Asian-specific structural variants, and high-quality haplotyping of clinically relevant alleles for precision medicine.
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, South Korea.|Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, South Korea.|Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 110-799, South Korea.|Bioinformatics Institute, Macrogen Inc., Seoul 153-023, South Korea.|Genome Institute, Macrogen Inc., Seoul 153-023, South Korea.
authors.forename: Jeong-Sun
authors.initials: JS
authors.lastname: Seo
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, South Korea.|Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, South Korea.|Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 110-799, South Korea.
authors.forename: Arang
authors.initials: A
authors.lastname: Rhie
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, South Korea.|Bioinformatics Institute, Macrogen Inc., Seoul 153-023, South Korea.
authors.forename: Junsoo
authors.initials: J
authors.lastname: Kim
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, South Korea.|Genome Institute, Macrogen Inc., Seoul 153-023, South Korea.
authors.forename: Sangjin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, South Korea.|Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, South Korea.|Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 110-799, South Korea.
authors.forename: Min-Hwan
authors.initials: MH
authors.lastname: Sohn
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, South Korea.|Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul 110-799, South Korea.|Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 110-799, South Korea.
authors.forename: Chang-Uk
authors.initials: CU
authors.lastname: Kim
authors.affiliation: BioNano Genomics, San Diego, California 92121, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Hastie
authors.affiliation: BioNano Genomics, San Diego, California 92121, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Cao
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, South Korea.|Genome Institute, Macrogen Inc., Seoul 153-023, South Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Yun
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, South Korea.|Genome Institute, Macrogen Inc., Seoul 153-023, South Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, South Korea.|Genome Institute, Macrogen Inc., Seoul 153-023, South Korea.
authors.forename: Junho
authors.initials: J
authors.lastname: Kuk
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, South Korea.|Genome Institute, Macrogen Inc., Seoul 153-023, South Korea.
authors.forename: Gun Hwa
authors.initials: GH
authors.lastname: Park
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, South Korea.|Genome Institute, Macrogen Inc., Seoul 153-023, South Korea.
authors.forename: Juhyeok
authors.initials: J
authors.lastname: Kim
authors.affiliation: Bioinformatics Institute, Macrogen Inc., Seoul 153-023, South Korea.
authors.forename: Hanna
authors.initials: H
authors.lastname: Ryu
authors.affiliation: Bioinformatics Institute, Macrogen Inc., Seoul 153-023, South Korea.
authors.forename: Jongbum
authors.initials: J
authors.lastname: Kim
authors.affiliation: Bioinformatics Institute, Macrogen Inc., Seoul 153-023, South Korea.
authors.forename: Mira
authors.initials: M
authors.lastname: Roh
authors.affiliation: Bioinformatics Institute, Macrogen Inc., Seoul 153-023, South Korea.
authors.forename: Jeonghun
authors.initials: J
authors.lastname: Baek
authors.affiliation: Pacific Biosciences of California, Inc., Menlo Park, California 94025, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Hunkapiller
authors.affiliation: Pacific Biosciences of California, Inc., Menlo Park, California 94025, USA.
authors.forename: Jonas
authors.initials: J
authors.lastname: Korlach
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, South Korea.|Genome Institute, Macrogen Inc., Seoul 153-023, South Korea.
authors.forename: Jong-Yeon
authors.initials: JY
authors.lastname: Shin
authors.affiliation: Bioinformatics Institute, Macrogen Inc., Seoul 153-023, South Korea.
authors.forename: Changhoon
authors.initials: C
authors.lastname: Kim
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics*; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D020451:Contig Mapping; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004171:Diploidy; D014644:Genetic Variation / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006239:Haplotypes / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000235:genetics; D006801:Humans; D057285:Precision Medicine; D012015:Reference Standards; D056910:Republic of Korea; D017422:Sequence Analysis, DNA
chemical_list: D000949:Histocompatibility Antigens Class II; D019389:Cytochrome P-450 CYP2D6