The genome is the human blueprint. Our goal is to decipher the blueprint 23and elucidate its hidden biology. An individual’s genetic background has substantial impact on their risk of diseases. Systems Genetics evaluates the cau-sality of human genetic variations on human phenotypes, using statistical and bioinformatic approaches. While recent developments in sequencing technolo-gies have provided ample resources, little is known regarding how to develop the methodology to integrate large-scale human genomics data with diverse biological and clinical information. We focus on large-scale human genome, omics and phenome data, and the underlying high-dimensional network. By developing novel bioinformatics methodologies, we redefine human biology as systems genetics. Our team aims to elucidate disease biology and contribute to novel drug discovery and implementation of genomic personalized medicine.We analyzed single-cell transcriptomes of COVID-19 patients and controls. A series of single cell analysis deciphered critical roles of innate immune cells in severe COVID-19. Integration with human genomes identified cell type and context-specific eQTL effects of the COVID-19 risk variants. Regarding gut microbe data, we developed a novel genomic approach to reconstruct personal information from the metagenome sequencing data. Using this metagenome-based genotype-calling approach, the genotypes of both common and rare variants could be reconstructed from microbiome samples, some of which were clinically relevant. Towards implementation of personalized medicine, we de-veloped novel frameworks to utilize the polygenic risk score (PRS), estimated based on genome-wide association studies (GWAS). Assortative mating (AM) is a pattern characterized by phenotypic similarities between mating partners. Gametic phase disequilibrium (e.g., comparisons between PRS from odd and even chromosomes) is a signature of parental AM. Through cross- biobank analysis, we found shared but heterogeneous impacts of AM between popula-tions. The achievements of our team cover diverse scientific fields towards true understanding of the blueprint.Figure: Integration of single cell RNA-seq and human genomes of severe COVID-19We constructed an integrative analysis of single cell RNA-seq and human genomes of the 148 COVID-19 cases and controls of Japanese ancestry. Critical roles of innate immune cells in severe COVID-19 biology were identified (Edahiro R et al. Nat Genet 2023).Recent Major PublicationsYamamoto K, Sonehara K, Namba S, Konuma T, Masuko H, Miyawaki S, BioBank Japan Project, Kamatani Y, Hizawa N, Ozono K, Yengo L, Okada Y. Genetic footprints of assortative mating in the Japanese population. Nat Hum Behav 7, 65-73 (2023)Edahiro R, Shirai Y, Takeshima Y, Sakakibara S, Yamaguchi Y, Murakami T, Morita T, Kato Y, Liu YC, Motooka D, Naito Y, Takuwa A, Sugihara F, Tanaka K, Wing JB, Sonehara K, Tomofuji Y, Japan COVID-19 Task Force, Namkoong H, Tanaka H, Lee H, Fukunaga K, Hirata H, Takeda Y, Okuzaki D, Kumanogoh A, Okada Y. Single-cell analyses and host genetics highlight the role of innate immune cells in COVID-19 severity. Nat Genet 55, 753-767 (2023)Tomofuji Y, Sonehara K, Kishikawa T, Maeda Y, Ogawa K, Kawabata S, Nii T, Okuno T, Oguro-Igashira E, Kinoshita M, Takagaki M, Yamamoto K, Kurakawa T, Yagita-Sakamaki M, Hosokawa A, Motooka D, Matsumoto Y, Matsuoka H, Yoshimura M, Ohshima S, Nakamura S, Inohara H, Kishima H, Mochizuki H, Takeda K, Kumano-goh A, Okada Y. Reconstruction of the personal informa-tion from human genome reads in gut metagenome sequencing data. Nat Microbiol 8, 1079-1094 (2023)Invited presentationsOkada Y. “Statistical genetics elucidates biology of infec-tious diseases” Human Cell Atlas Asia 2023 Meeting (Kolkata, India) November 2023Okada Y. “Statistical Genetics Elucidates Biology and Personalized Medicine of Rheumatology” American Col-lege of Rheumatology Annual Meeting 2023 (San Diego, USA) November 2023Okada Y. “Statistical Genetics Elucidates Disease Biology and Drug Discovery” G-CAN 2023 Ninth Annual Research Symposium and Workshops (La Jolla, USA) November 2023Okada Y. “Statistical genetics elucidates host genetics of COVID-19” The XXIII International Congress of Genetics (Melbourne, Austria) July 2023Okada Y. “BioBank Japan and what we have learnt so far” European Society of Human Genetics Annual Meet-ing 2023 (Glasgow, UK) June 2023Laboratory for Systems GeneticsTeam Leader: Yukinori Okada
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