The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

<Original Papers>Structure analysis of BasS and BasR in rice seedling blight pathogen Burkholderia plantarii

Burkholderia plantani is a plant pathogen causing rice seedling blight. It produces tropolone, the disease causing substance. To elucidate and understand molecular mechanisms of the pathogenesis, we analyzed the genome of B. plantarii. In this study, we focused on two component system, in prokaryotic signal transduction. This system is basically composed of a histidine kinase (HK, sensor) residing in the inner membrane and a cognate response regulator (RR) in the cytoplasm. Here, BasS, a histidine kinase (HK, sensor) and BasR, a response regulator (RR) in this strain, were structurally analysed, showing these are tandemely ordered. Phylogenetic analysis of these prodcuts were also analysed. Construction of plasmids for gene disruption of these genes, basS and basR was also carried out, in terms of future study approach in reverse genetics. Obtaining mutants by transformation will be useful for understanding the relationships between pathogenesis and function of these genes

제주/쓰시마 조초성 산호의 수온 기록자로서의 가능성 평가

In an effort to develop high-resolution sea surface temperature (SST) proxies for mid-latitude regions, two massive reef-building coral species, Alveopora and Favia, were collected from Jeju and Tsushima Islands, respectively. Their skeletons were subsequently analyzed for annual growth banding, Sr/Ca and Mg/Ca ratios. Hermatypic corals are thinly distributed in the waters of Jeju Island, where Alveopora japonica was the only dominant coral species. A higher diversity of hermatypic corals were observed in the waters of Tsushima Island, where Favia sp. was the most common coral species and even forming an about 6-m-high reef structure. Both Alveopora and Favia showed annual growth layers consisting of couplets of high- and low-density bands. Sr/Ca ratio of both species and Mg/Ca ratio of Alveopora also showed seasonal variation, likely reflecting SST variation. These results suggest the possibility that Alveopora and Favia species can be used as potential SST proxies. However, this study also highlights the potential growth disturbance of middle latitude corals due to high rainfall during monsoon and low SST during winter. This possibility should be taken into account in the investigation of Sr/Ca(Mg/Ca)-SST relationships