Genomic structure and evolution of multigene families: “Flowers” on the human genome

We report the results of an extensive investigation of genomic structures in the human genome, with a particular focus on relatively large repeats (>50 kb) in adjacent chromosomal regions. We named such structures “Flowers” because the pattern observed on dot plots resembles a flower. We detected a total of 291 Flowers in the human genome. They were predominantly located in euchromatic regions. Flowers are gene-rich compared to the average gene density of the genome. Genes involved in systems receiving environmental information, such as immunity and detoxification, were overrepresented in Flowers. Within a Flower, the mean number of duplication units was approximately four. The maximum and minimum identities between homologs in a Flower showed different distributions; the maximum identity was often concentrated to 100% identity, while the minimum identity was evenly distributed in the range of 78% to 100%. Using a gene conversion detection test, we found frequent and/or recent gene conversion events within the tested Flowers. Interestingly, many of those converted regions contained protein-coding genes. Computer simulation studies suggest that one role of such frequent gene conversions is the elongation of the life span of gene families in a Flower by the resurrection of pseudogenes

The hepatic circadian clock is preserved in a lipid-induced mouse model of non-alcoholic steatohepatitis

金沢大学医薬保健研究域医学系Recent studies have correlated metabolic diseases, such as metabolic syndrome and non-alcoholic fatty liver disease, with the circadian clock. However, whether such metabolic changes per se affect the circadian clock remains controversial. To address this, we investigated the daily mRNA expression profiles of clock genes in the liver of a dietary mouse model of non-alcoholic steatohepatitis (NASH) using a custom-made, high-precision DNA chip. C57BL/6J mice fed an atherogenic diet for 5 weeks developed hypercholesterolemia, oxidative stress, and NASH. DNA chip analyses revealed that the atherogenic diet had a great influence on the mRNA expression of a wide range of genes linked to mitochondrial energy production, redox regulation, and carbohydrate and lipid metabolism. However, the rhythmic mRNA expression of the clock genes in the liver remained intact. Most of the circadianly expressed genes also showed 24-h rhythmicity. These findings suggest that the biological clock is protected against such a metabolic derangement as NASH. © 2009 Elsevier Inc. All rights reserved

Recent Results from LHD Experiment with Emphasis on Relation to Theory from Experimentalist’s View

he Large Helical Device (LHD) has been extending an operational regime of net-current free plasmas towardsthe fusion relevant condition with taking advantage of a net current-free heliotron concept and employing a superconducting coil system. Heating capability has exceeded 10 MW and the central ion and electron temperatureshave reached 7 and 10 keV, respectively. The maximum value of β and pulse length have been extended to 3.2% and 150 s, respectively. Many encouraging physical findings have been obtained. Topics from recent experiments, which should be emphasized from the aspect of theoretical approaches, are reviewed. Those are (1) Prominent features in the inward shifted configuration, i.e., mitigation of an ideal interchange mode in the configuration with magnetic hill, and confinement improvement due to suppression of both anomalous and neoclassical transport, (2) Demonstration ofbifurcation of radial electric field and associated formation of an internal transport barrier, and (3) Dynamics of magnetic islands and clarification of the role of separatrix

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

ラット ニオケル カルシウム フカカ ノ ノルエピネフリン ニヨル キュウセイ サシツ カクチョウ ショウガイ : サシツ ケッコウ ドウタイ ナラビニ シンゾウ チョウオンパホウ ニヨル ケントウ

拡張不全は左室収縮の低下を伴わない心不全で,左室収縮の低下による収縮不全とは病態,基礎疾患,予後が異なることが明らかにされつつある.しかし,その発生メカニズムについては十分に解明されていない.本研究では雄性ラット42匹を用い,対照群,塩化カルシウム投与群,ノルエピネフリン投与群,塩化カルシウム投与後,塩化カルシウム+ノルエピネフリン投与群において,左室血行動態,左室拡張障害について検討をおこなった.4群でチップ付き圧カテーテルを左室内へ挿入し,また別の4群で心臓超音波法により左室駆出率を測定した.さらに別に拡張早期急速流人期血流速波形(E波),拡張後期流人速波形(A波),E波減速時間(DCT),組織ドプラ法で拡張早期僧帽弁輪速度(Ea波)を測定した.その結果,塩化カルシウム群,ノルエピネフリン群では左室拡張末期圧は変化を認めなかったが,塩化カルシウム+ノルエピネフリン投与群で左室拡張末期圧は著しい上昇を認めた.また,塩化カルシウム+ノルエピネフリン群では左室駆出率は対照群と有意差を認めなかったが,E波,DCT,Ea波は対照群に比し有意な減少を認めた.以上より,塩化カルシウム負荷下でのノルエピネフリン投与で急激な心臓拡張障害が惹起され,心臓の拡張障害の発生にノルエピネフリンが関与している可能性が示唆された.In diastolic dysfunction, cardiac cells in the diastolic phase do not rapidly or completely return to the normal state of relaxation. However, the detailed mechanism remains unknown. To develop an acute diastolic dysfunction model in the rat, norepinephrine (30μg/kg/min) with calcium (12mg/kg/min) was administered for 20 minutes, following 20-minute administration of calcium, compared with the control group. A cardiovascular mikro-tip pressure transducer catheter was inserted into the left ventricle, and the intraventricular pressure and left ventricular end-diastolic pressure were determined. Early diastolic mitral annular velocity (Ea), E and A waves, deceleration time (DCT) and left ventricular ejection fraction were estimated using tissue Doppler imaging and echocardiography. In the norepinephrine with calcium group, no significant change in left ventricular pressure was found, but left ventricular end-diastolic pressure was markedly increased. On echocardiography, no change was found in left ventricular ejection fraction, but the E wave, DCT and Ea wave were decreased, in comparison with the control, calcium alone and norepinephrine alone groups. The results of this study could indicate that norepinephrine administration with calcium causes acute diastolic dysfunction in the rat