Genome Research Foundation

Background Large-scale genome projects have advanced the characterization of human genetic diversity; however, the lack of deeply sequenced, multiomic resources representing the Korean population has limited systematic evaluation of population-specific variation and its functional and translational impact. Results We present Korea10K, a population-scale genomic and multiomic resource comprising 10,239 high-depth whole genomes (mean coverage 30×) with integrated molecular and phenotypic data. Analysis of 9,000 unrelated individuals enabled near-complete discovery of rare and ultra-rare variants and supported the construction of a high-resolution, population-specific imputation panel. Koreans exhibit pronounced autosomal genetic homogeneity despite substantial diversity in Y-chromosomal, mitochondrial, and HLA lineages, reflecting long-term demographic continuity. We further identified 16.4 million variants that alter CpG dinucleotide context, revealing widespread sequence-driven modulation of the genomic CG landscape. Notably, population-specific CG-eliminating variants disrupt CpG probe targets in widely used methylation arrays, introducing a systematic source of bias in epigenome-wide association studies and epigenetic clock estimation. Conclusion Korea10K establishes a high-resolution genomic and multiomic reference for the Korean population and reveals a previously unrecognized interaction between genetic variation and epigenomic measurement. This resource provides a foundation for precision medicine and highlights the need for ancestry-aware interpretation of molecular data.

The Dokdo sea lion (Zalophus japonicus), commonly referred to as Gangchi in Korea and the Japanese sea lion internationally, was endemic to the Northwest Pacific before its extinction in the 1950s. However, its origins, speciation, and genetic diversity remain poorly understood. To address this, we sequenced DNA from 16 Z. japonicus bone fragments, obtained from Dokdo and Ulleungdo islands in Korea. Our genome-wide SNP analyses reveal Z. japonicus as the earliest diverged species within its genus, redefining its evolutionary relationship with the California (Z. californianus) and Galapagos (Z. wollebaeki) sea lions. Our research further elucidates the phylogeny of Z. japonicus, shedding light on the complexity of the genetic isolation process within its genus that was prompted by the geographic isolation of the three populations of Zalophus ancestral stock. Conversely, the genetic signature of the Dokdo sea lion genome can be modeled as an evolutionary pathway involving gene flow from Otariidae species with shared range. In addition, we discovered that the population decline of Z. japonicus started already over 100,000 years ago; however, Z. japonicus genome maintained a relatively high heterozygosity despite nearing extinction. Our genome-scale analysis sheds light on the phylogeny of Z. japonicus, the evolutionary pathways underlying its speciation, and its genetic diversity before extinction. Broadly, we elucidate Zalophus gene flow complexity and genetic diversities among extant species. Furthermore, this study offers retrospective genomic insights into the extinction process of a carnivorous marine mammal, information that could aid conservation efforts for extant Otariidae species.

Chronic inflammatory atopic dermatitis (AD) is a skin disorder characterized by cutaneous inflammation and a dysfunctional skin barrier. Although perilla seed oil (PO) is known to exhibit various biological activities, including anti-cancer, anti-inflammatory, and anti-oxidant effects, its inhibitory effects together with the ethanol extract of PO (PE) on atopic and inflammatory responses in the dermal skin has not yet been investigated. In the present study, PE significantly reduced mRNA expressions of inflammation-associated cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, IL-6, IL-8, and IL-33. Furthermore, PE decreased the levels of the chemokine, thymus- and activation-regulated chemokine (TARC/CCL17) in TNF-α and interferon (IFN)-γ-stimulated human HaCaT keratinocytes. In addition, PE effectively suppressed activation of MAPK/NF-κB and JAK/STAT signaling pathways in HaCaT keratinocytes co-stimulated with TNF-α and IFN-γ. These findings indicate that PE possesses anti-inflammatory and anti-atopic properties, suggesting its potential benefits in treating inflammatory skin diseases including AD.

We present KOREF1-G-TTAGGA, a Telomere-to-Telomere Accurate and Gapless Genome Assembly of KOREF1, representing a Korean standard reference genome. It was constructed utilizing 89 x PacBio HiFi, 298 x Oxford Nanopore Technology ultra-long reads (104 x > 100 kb), and parental short reads (Paternal: 37 x, Maternal: 40 x). The paternal and maternal haplotypes span 2.91 Gb and 3.03 Gb, respectively, successfully closing all unresolved gaps from the previous KOREF1 releases in 2016 and 2022. Notably, both phased haploid assemblies exhibit high base-level accuracy (Quality Value, QV: 81.19 and 79.03 corresponding to one error per 132 and 80 Mb) with minimal phasing errors (Switch error: 0.1%, 0.33%, respectively). Evaluations of read-to-assembly concordance revealed remarkably few structural errors (Assembly Quality Index, AQI: 99.77, 99.69, respectively, far surpassing the reference quality threshold of 90) with superior assembly continuity (Genome Continuity Inspector score: 84.92, 80.78 each), establishing KOREF1 as one of the most complete Asian reference genomes. Thus, it can serve as a foundational resource for constructing the future Korean Pangenome Reference. As a national multiomics reference initiative launched in 2006, KOREF1-G-TTAGGA is also accompanied by multiomic data of transcriptome, epigenome, proteome, and ATAC-seq from blood and cell lines. ### Competing Interest Statement J. Bhak is the founder of AgingLab. S. Jeon is the CEO of AgingLab. Y. Cho is an employee of CG Invites Co., LTD and Invites Genomics Co., LTD. B. H. L. and J. S. L. are the employees of nSAGE Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. Ministry of SMEs and Startups, 1425157253 Ulsan National Institute of Science and Technology, 1425157301 Ulsan National Institute of Science and Technology, 1.200108.01 Ulsan National Institute of Science and Technology, 1.200047.01 Ministry of Trade, Industry and Energy, https://ror.org/008nkqk13, 10046043, 10050164, 10063239, 10040231 Ulsan National Institute of Science and Technology, 1.160003.01 Ministry of Trade, Industry and Energy, https://ror.org/008nkqk13, RS-2024-00435468 BioBigData.Korea, RS-2024-00438566

We present Korea10K, the largest genomic dataset of the Korean population, comprising 10,239 high-coverage whole genomes (mean depth 30×) with matched multi-omic profiles and phenotype data. Korea10K achieves complete and near-complete discovery of very rare and ultra-rare alleles, respectively, at 9,000 Korean genomes. This dataset provides the high-quality population-specific imputation panel, enabling accurate inference of low-frequency variants. Admixture analyses confirm the overall genetic homogeneity of the Korean population, despite its diverse Y-chromosomal, mitochondrial, and HLA repertoires. This pattern reflects a long and continuous lineage history characterized by persistent internal admixture and genomic homogenization over thousands of years on the Korean peninsula. We also identified 16.8 million genomic variants that directly modify CG sites by creating or abolishing CG dinucleotides, providing the population-scale evidence of coordinated genomic-epigenomic regulatory mechanism in Koreans. ### Competing Interest Statement S. Jeon is CEO and H.R. is an employee of AgingLab Inc. Y. Cho is an employee of CG Invites Co., LTD and Invites Genomics Co., LTD. B.L. is CEO and J.L. is an employee of nSAGE. G.C. is co-founder of Nebula Genomics and Glottatech.com. The remaining authors declare no competing interests. * ABHet : Heterozygotic Allele Balance AC : Allele Count AF : Allele Frequency AFR : African AI : Artificial Intelligence Alt : Alternative allele AMR : Ad Mixed American BEB : Bengali in Bangladesh CDX : Chinese Dai in Xishuangbanna, China CGV : CG context-associated Variant CHB : Han Chinese in Beijing, China CHS : Han Chinese South, China CLM : Colombian in Medellin, Colombia COVID-19 : Coronavirus Disease 2019 EAS : East Asian EBI : The European Bioinformatics Institute EUR : European ESN : Esan in Nigeria FDR : False Discovery Rate FIN : Finnish in Finland GATK : Genome Analysis Tool Kit GBR : British from England and Scotland GeDiPNet : Genes, Diseases and Pathway Networks GIH : Gujarati Indians in Houston, Texas, USA gnomAD : Genome Aggregation Database GO : Gene Ontology GVCF : Genomic Variant Call Format GWAS : Genome-Wide Association Study GWD : Gambian in Western Division – Mandinka HC : Health Check-up HLA : Histocompatibility Leukocyte Antigen HWE : Hardy-Weinburg Equilibrium IBS : Iberian populations in Spain ISOGG : International Society of Genetic Genealogy ITU : Indian Telugu in the UK JPT : Japanese in Tokyo, Japan KGP : Korean Genome Project KHV : Kinh in Ho Chi Minh City, Vietnam KOR : Korean in Korea10K KOREF : Korean Reference KPGP : Korean Personal Genome Project KEGG : Kyoto Encyclopedia of Gene and Genome LD : Linkage Disequilibrium LEPR : Leptin Receptor LQ : Lifestyle Questionnaire LWK : Luhya in Webuye, Kenya MAF : Minor Allele Frequency MFP : ModelFinder MHC : Major Histocompatibility Complex MSL : Mende in Sierra Leone MTA : Material Transfer Agreement MXL : Mexican Ancestry in Los Angeles CA USA PBMC : Peripheral Blood Mononuclear Cells PCA : Principal Component Analysis PEL : Peruvian in Lima, Peru PUR : Punjabi in Lahore, Pakistan\ QC : Quality Control QTL : Quantitative Trait Loci R² : Squared Correlation Coefficients rCRS : revised Cambridge Reference Sequence RSRS : Reconstructed Sapiens Reference Sequence SAS : South Asian SD : Standard Deviation SLC15A5 : Solute Carrier Family 15 Member 5 SNV : Single Nucleotide Variant TOPMed : Trans-Omics for Precision Medicine TSI : Toscani in Italia TWAS : Transcriptome-Wide Association Study VEP : Variants Effect Predictor VQSR : Variant Quality Score Recalibration WGS : Whole-Genome Sequencing YRI : Yoruba in Ibadan, Nigeria 1KGP : The 1000 Genome Project Ulsan National Institute of Science and Technology, https://ror.org/017cjz748, 1.200108.01, 1.200047.01 Ministry of SMEs and Startups, 1425157301, 1425156792, 1425157253 Ministry of Trade, Industry and Energy, 20016225, RS-2024-00435468