Korea4K: whole genome sequences of 4,157 Koreans with 107 phenotypes derived from extensive health check-ups.

BACKGROUND: Phenome-wide association studies (PheWASs) have been conducted on Asian populations, including Koreans, but many were based on chip or exome genotyping data. Such studies have limitations regarding whole genome-wide association analysis, making it crucial to have genome-to-phenome association information with the largest possible whole genome and matched phenome data to conduct further population-genome studies and develop health care services based on population genomics. RESULTS: Here, we present 4,157 whole genome sequences (Korea4K) coupled with 107 health check-up parameters as the largest genomic resource of the Korean Genome Project. It encompasses most of the variants with allele frequency >0.001 in Koreans, indicating that it sufficiently covered most of the common and rare genetic variants with commonly measured phenotypes for Koreans. Korea4K provides 45,537,252 variants, and half of them were not present in Korea1K (1,094 samples). We also identified 1,356 new genotype-phenotype associations that were not found by the Korea1K dataset. Phenomics analyses further revealed 24 significant genetic correlations, 14 pleiotropic associations, and 127 causal relationships based on Mendelian randomization among 37 traits. In addition, the Korea4K imputation reference panel, the largest Korean variants reference to date, showed a superior imputation performance to Korea1K across all allele frequency categories. CONCLUSIONS: Collectively, Korea4K provides not only the largest Korean genome data but also corresponding health check-up parameters and novel genome-phenome associations. The large-scale pathological whole genome-wide omics data will become a powerful set for genome-phenome level association studies to discover causal markers for the prediction and diagnosis of health conditions in future studies.

Northeastern Asian and Jomon-related genetic structure in the Three Kingdoms period of Gimhae, Korea.

The genetic history of prehistoric and protohistoric Korean populations is not well understood because only a small number of ancient genomes are available. Here, we report the first paleogenomic data from the Korean Three Kingdoms period, a crucial point in the cultural and historic formation of Korea. These data comprise eight shotgun-sequenced genomes from ancient Korea (0.7×-6.1× coverage). They were derived from two archeological sites in Gimhae: the Yuha-ri shell mound and the Daesung-dong tumuli, the latter being the most important funerary complex of the Gaya confederacy. All individuals are from between the 4th and 5th century CE and are best modeled as an admixture between a northern China Bronze Age genetic source and a source of Jomon-related ancestry that shares similarities with the present-day genomes from Japan. The observed substructure and proportion of Jomon-related ancestry suggest the presence of two genetic groups within the population and diversity among the Gaya population. We could not correlate the genomic differences between these two groups with either social status or sex. All the ancient individuals' genomic profiles, including phenotypically relevant SNPs associated with hair and eye color, facial morphology, and myopia, imply strong genetic and phenotypic continuity with modern Koreans for the last 1,700 years.

Multiple types of genomic variation contribute to adaptive traits in the mustelid subfamily Guloninae.

Species of the mustelid subfamily Guloninae inhabit diverse habitats on multiple continents, and occupy a variety of ecological niches. They differ in feeding ecologies, reproductive strategies and morphological adaptations. To identify candidate loci associated with adaptations to their respective environments, we generated a de novo assembly of the tayra (Eira barbara), the earliest diverging species in the subfamily, and compared this with the genomes available for the wolverine (Gulo gulo) and the sable (Martes zibellina). Our comparative genomic analyses included searching for signs of positive selection, examining changes in gene family sizes and searching for species-specific structural variants. Among candidate loci associated with phenotypic traits, we observed many related to diet, body condition and reproduction. For example, for the tayra, which has an atypical gulonine reproductive strategy of aseasonal breeding, we observed species-specific changes in many pregnancy-related genes. For the wolverine, a circumpolar hypercarnivore that must cope with seasonal food scarcity, we observed many changes in genes associated with diet and body condition. All types of genomic variation examined (single nucleotide polymorphisms, gene family expansions, structural variants) contributed substantially to the identification of candidate loci. This argues strongly for consideration of variation other than single nucleotide polymorphisms in comparative genomics studies aiming to identify loci of adaptive significance.

LT1, an ONT long-read-based assembly scaffolded with Hi-C data and polished with short reads.

We present LT1, the first high-quality human reference genome from the Baltic States. LT1 is a female de novo human reference genome assembly, constructed using 57× nanopore long reads and polished using 47× short paired-end reads. We utilized 72 GB of Hi-C chromosomal mapping data for scaffolding, to maximize assembly contiguity and accuracy. The contig assembly of LT1 was 2.73 Gbp in length, comprising 4490 contigs with an NG50 value of 12.0 Mbp. After scaffolding with Hi-C data and manual curation, the final assembly has an NG50 value of 137 Mbp and 4699 scaffolds. Assessment of gene prediction quality using Benchmarking Universal Single-Copy Orthologs (BUSCO) identified 89.3% of the single-copy orthologous genes included in the benchmark. Detailed characterization of LT1 suggests it has 73,744 predicted transcripts, 4.2 million autosomal SNPs, 974,616 short indels, and 12,079 large structural variants. These data may be used as a benchmark for further in-depth genomic analyses of Baltic populations.

Regional TMPRSS2 V197M Allele Frequencies Are Correlated with COVID-19 Case Fatality Rates.

Coronavirus disease, COVID-19 (coronavirus disease 2019), caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has a higher case fatality rate in European countries than in others, especially East Asian ones. One potential explanation for this regional difference is the diversity of the viral infection efficiency. Here, we analyzed the allele frequencies of a nonsynonymous variant rs12329760 (V197M) in the TMPRSS2 gene, a key enzyme essential for viral infection and found a significant association between the COVID-19 case fatality rate and the V197M allele frequencies, using over 200,000 present-day and ancient genomic samples. East Asian countries have higher V197M allele frequencies than other regions, including European countries which correlates to their lower case fatality rates. Structural and energy calculation analysis of the V197M amino acid change showed that it destabilizes the TMPRSS2 protein, possibly negatively affecting its ACE2 and viral spike protein processing.

Comparative analysis of 7 short-read sequencing platforms using the Korean Reference Genome: MGI and Illumina sequencing benchmark for whole-genome sequencing.

BACKGROUND: DNBSEQ-T7 is a new whole-genome sequencer developed by Complete Genomics and MGI using DNA nanoball and combinatorial probe anchor synthesis technologies to generate short reads at a very large scale-up to 60 human genomes per day. However, it has not been objectively and systematically compared against Illumina short-read sequencers. FINDINGS: By using the same KOREF sample, the Korean Reference Genome, we have compared 7 sequencing platforms including BGISEQ-500, DNBSEQ-T7, HiSeq2000, HiSeq2500, HiSeq4000, HiSeqX10, and NovaSeq6000. We measured sequencing quality by comparing sequencing statistics (base quality, duplication rate, and random error rate), mapping statistics (mapping rate, depth distribution, and percent GC coverage), and variant statistics (transition/transversion ratio, dbSNP annotation rate, and concordance rate with single-nucleotide polymorphism [SNP] genotyping chip) across the 7 sequencing platforms. We found that MGI platforms showed a higher concordance rate for SNP genotyping than HiSeq2000 and HiSeq4000. The similarity matrix of variant calls confirmed that the 2 MGI platforms have the most similar characteristics to the HiSeq2500 platform. CONCLUSIONS: Overall, MGI and Illumina sequencing platforms showed comparable levels of sequencing quality, uniformity of coverage, percent GC coverage, and variant accuracy; thus we conclude that the MGI platforms can be used for a wide range of genomics research fields at a lower cost than the Illumina platforms.

Polygenic risk score validation using Korean genomes of 265 early-onset acute myocardial infarction patients and 636 healthy controls.

BACKGROUND: The polygenic risk score (PRS) developed for coronary artery disease (CAD) is known to be effective for classifying patients with CAD and predicting subsequent events. However, the PRS was developed mainly based on the analysis of Caucasian genomes and has not been validated for East Asians. We aimed to evaluate the PRS in the genomes of Korean early-onset AMI patients (n = 265, age ≤50 years) following PCI and controls (n = 636) to examine whether the PRS improves risk prediction beyond conventional risk factors. RESULTS: The odds ratio of the PRS was 1.83 (95% confidence interval [CI]: 1.69-1.99) for early-onset AMI patients compared with the controls. For the classification of patients, the area under the curve (AUC) for the combined model with the six conventional risk factors (diabetes mellitus, family history of CAD, hypertension, body mass index, hypercholesterolemia, and current smoking) and PRS was 0.92 (95% CI: 0.90-0.94) while that for the six conventional risk factors was 0.91 (95% CI: 0.85-0.93). Although the AUC for PRS alone was 0.65 (95% CI: 0.61-0.69), adding the PRS to the six conventional risk factors significantly improved the accuracy of the prediction model (P = 0.015). Patients with the upper 50% of PRS showed a higher frequency of repeat revascularization (hazard ratio = 2.19, 95% CI: 1.47-3.26) than the others. CONCLUSIONS: The PRS using 265 early-onset AMI genomes showed improvement in the identification of patients in the Korean population and showed potential for genomic screening in early life to complement conventional risk prediction.

Welfare Genome Project: A Participatory Korean Personal Genome Project With Free Health Check-Up and Genetic Report Followed by Counseling.

The Welfare Genome Project (WGP) provided 1,000 healthy Korean volunteers with detailed genetic and health reports to test the social perception of integrating personal genetic and healthcare data at a large-scale. WGP was launched in 2016 in the Ulsan Metropolitan City as the first large-scale genome project with public participation in Korea. The project produced a set of genetic materials, genotype information, clinical data, and lifestyle survey answers from participants aged 20-96. As compensation, the participants received a free general health check-up on 110 clinical traits, accompanied by a genetic report of their genotypes followed by genetic counseling. In a follow-up survey, 91.0% of the participants indicated that their genetic reports motivated them to improve their health. Overall, WGP expanded not only the general awareness of genomics, DNA sequencing technologies, bioinformatics, and bioethics regulations among all the parties involved, but also the general public's understanding of how genome projects can indirectly benefit their health and lifestyle management. WGP established a data construction framework for not only scientific research but also the welfare of participants. In the future, the WGP framework can help lay the groundwork for a new personalized healthcare system that is seamlessly integrated with existing public medical infrastructure.

Complete genome sequence and bioinformatics analysis of nine Egyptian females with clinical information from different geographic regions in Egypt.

Egyptians are at a crossroad between Africa and Eurasia, providing useful genomic resources for analyzing both genetic and environmental factors for future personalized medicine. Two personal Egyptian whole genomes have been published previously by us and here nine female whole genome sequences with clinical information have been added to expand the genomic resource of Egyptian personal genomes. Here we report the analysis of whole genomes of nine Egyptian females from different regions using Illumina short-read sequencers. At 30x sequencing coverage, we identified 12 SNPs that were shared in most of the subjects associated with obesity which are concordant with their clinical diagnosis. Also, we found mtDNA mutation A4282G is common in all the samples and this is associated with chronic progressive external ophthalmoplegia (CPEO). Haplogroup and Admixture analyses revealed that most Egyptian samples are close to the other north Mediterranean, Middle Eastern, and European, respectively, possibly reflecting the into-Africa influx of human migration. In conclusion, we present whole-genome sequences of nine Egyptian females with personal clinical information that cover the diverse regions of Egypt. Although limited in sample size, the whole genomes data provides possible geno-phenotype candidate markers that are relevant to the region's diseases.

Korean Genome Project: 1094 Korean personal genomes with clinical information.

We present the initial phase of the Korean Genome Project (Korea1K), including 1094 whole genomes (sequenced at an average depth of 31×), along with data of 79 quantitative clinical traits. We identified 39 million single-nucleotide variants and indels of which half were singleton or doubleton and detected Korean-specific patterns based on several types of genomic variations. A genome-wide association study illustrated the power of whole-genome sequences for analyzing clinical traits, identifying nine more significant candidate alleles than previously reported from the same linkage disequilibrium blocks. Also, Korea1K, as a reference, showed better imputation accuracy for Koreans than the 1KGP panel. As proof of utility, germline variants in cancer samples could be filtered out more effectively when the Korea1K variome was used as a panel of normals compared to non-Korean variome sets. Overall, this study shows that Korea1K can be a useful genotypic and phenotypic resource for clinical and ethnogenetic studies.