Mammalian Genome最新文献

{"title":"Fine mapping and candidate gene analysis of Dravet syndrome modifier loci on mouse chromosomes 7 and 8.","authors":"Nicole A Hawkins, Nathan Speakes, Jennifer A Kearney","doi":"10.1007/s00335-024-10046-3","DOIUrl":"10.1007/s00335-024-10046-3","url":null,"abstract":"<p><p>Dravet syndrome is a developmental and epileptic encephalopathy (DEE) characterized by intractable seizures, comorbidities related to developmental, cognitive, and motor delays, and a high mortality burden due to sudden unexpected death in epilepsy (SUDEP). Most Dravet syndrome cases are attributed to SCN1A haploinsufficiency, with genetic modifiers and environmental factors influencing disease severity. Mouse models with heterozygous deletion of Scn1a recapitulate key features of Dravet syndrome, including seizures and premature mortality; however, severity varies depending on genetic background. Here, we refined two Dravet survival modifier (Dsm) loci, Dsm2 on chromosome 7 and Dsm3 on chromosome 8, using interval-specific congenic (ISC) mapping. Dsm2 was complex and encompassed at least two separate loci, while Dsm3 was refined to a single locus. Candidate modifier genes within these refined loci were prioritized based on brain expression, strain-dependent differences, and biological relevance to seizures or epilepsy. High priority candidate genes for Dsm2 include Nav2, Ptpn5, Ldha, Dbx1, Prmt3 and Slc6a5, while Dsm3 has a single high priority candidate, Psd3. This study underscores the complex genetic architecture underlying Dravet syndrome and provides insights into potential modifier genes that could influence disease severity and serve as novel therapeutic targets.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":"334-345"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11329421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting the potential deterioration of Barrett's esophagus based on gut microbiota: a Mendelian randomization analysis.","authors":"Conghan Li, Panyin Shu, Taiyu Shi, Yuerong Chen, Ping Mei, Yizhong Zhang, Yan Wang, Xinyan Du, Jianning Wang, Yixin Zhang, Bin Liu, Zhijin Sheng, Shixin Chan, Zhangyong Dan","doi":"10.1007/s00335-024-10042-7","DOIUrl":"10.1007/s00335-024-10042-7","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Esophageal adenocarcinoma (EAC) is one of the most malignant tumors in the digestive system. To make thing worse, the scarcity of treatment options is disheartening. However, if detected early, there is a possibility of reversing the condition. Unfortunately, there is still a lack of relevant early screening methods. Considering that Barrett's esophagus (BE), a precursor lesion of EAC, has been confirmed as the only known precursor of EAC. Analyzing which BE cases will progress to EAC and understanding the processes and mechanisms involved is of great significance for early screening of such patients. Considering the significant alterations in the gut microbiota of patients with BE and its potential role in the progression to EAC, this study aims to analyze the relationship between BE, EAC, and GM to identify potential diagnostic biomarkers and therapeutic targets. This study utilized comprehensive statistical data on gut microbiota from a large-scale genome-wide association meta-analysis conducted by the MiBioGen consortium (n = 18,340). Subsequently, we selected a set of single nucleotide polymorphisms (SNPs) that fell below the genome-wide significance threshold (1 × 10-5) as instrumental variables. To investigate the causal relationship between gut microbiota and BE and EAC, we employed various MR analysis methods, including Inverse Variance Weighting (IVW), MR-Egger regression, weighted median (WM), and weighted mean. Additionally, we assessed the level of pleiotropy, heterogeneity, and stability of genetic variations through MR-Egger intercept test, MR-PRESSO, Cochran's Q test, and \"leave-one-out\" sensitivity analysis. Furthermore, we conducted reverse MR analysis to identify the causal relationships between gut microbiota and BE and EAC. The results from the Inverse Variance-Weighted (IVW) analysis indicate that Alistipes (P = 4.86 × 10&lt;sup&gt;-2&lt;/sup&gt;), Lactobacillus (P = 2.11 × 10&lt;sup&gt;-2&lt;/sup&gt;), Prevotella 7 (P = 4.28 × 10&lt;sup&gt;-2&lt;/sup&gt;), and RuminococcaceaeUCG004 (P = 4.34 × 10&lt;sup&gt;-2&lt;/sup&gt;) are risk factors for Barrett's esophagus (BE), while Flavonifractor (P = 8.81 × 10&lt;sup&gt;-3&lt;/sup&gt;) and RuminococcaceaeUCG004 (P = 4.99 × 10&lt;sup&gt;-2&lt;/sup&gt;) are risk factors for esophageal adenocarcinoma (EAC). On the other hand, certain gut microbiota genera appear to have a protective effect against both BE and EAC. These include Eubacterium (nodatum group) (P = 4.51 × 10&lt;sup&gt;-2&lt;/sup&gt;), Holdemania (P = 1.22 × 10&lt;sup&gt;-2&lt;/sup&gt;), and Lactococcus (P = 3.39 × 10&lt;sup&gt;-2&lt;/sup&gt;) in the BE cohort, as well as Eubacterium (hallii group) (P = 4.07 × 10&lt;sup&gt;-2&lt;/sup&gt;) and Actinomyces (P = 3.62 × 10&lt;sup&gt;-3&lt;/sup&gt;) in the EAC cohort. According to the results of reverse MR analysis, no significant causal effects of BE and EAC on gut microbiota were observed. Furthermore, no significant heterogeneity or pleiotropy was detected in the instrumental variables. We have established a causal relationship between the gut microbiota and BE and EAC. This study holds profound si","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":"399-413"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the causal relationship between immune cells and prostatitis: evidence from bidirectional mendelian randomization analysis.","authors":"Genyi Qu, Weimin Jiang, Zhaohui Long, Xing Zhou, Yijie Wang, Guang Yang, Cheng Tang, Yong Xu","doi":"10.1007/s00335-024-10044-5","DOIUrl":"10.1007/s00335-024-10044-5","url":null,"abstract":"<p><p>Prostatitis represents a common disease of the male genitourinary system, significantly impacting the physical and mental health of male patients. While numerous studies have suggested a potential link between immune cell activity and prostatitis, the exact causal role of immune cells in prostatitis remains uncertain. This study aims to explore the causal relationship between immune cell characteristics and prostatitis using a bidirectional Mendelian randomization approach. This study utilizes data from the public GWAS database and employs bidirectional Mendelian randomization analysis to investigate the causal relationship between immune cells and prostatitis. The causal relationship between 731 immune cell features and prostatitis was primarily investigated through inverse variance weighting (IVW), complemented by MR-Egger regression, a simple model, the weighted median method, and a weighted model. Ultimately, the results underwent sensitivity analysis to assess the heterogeneity, horizontal pleiotropy, and stability of Single Nucleotide Polymorphisms (SNPs) in immune cells and prostatitis. MR analysis revealed 17 immune cells exhibiting significant causal effects on prostatitis. In contrast, findings from reverse MR indicated a significant causal relationship between prostatitis and 13 immune cells. Our study utilizes bidirectional Mendelian Randomization to establish causal relationships between specific immune cell phenotypes and prostatitis, highlighting the reciprocal influence between immune system behavior and the disease. Our findings suggest targeted therapeutic approaches and the importance of including diverse populations for broader validation and personalized treatment strategies.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":"474-483"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141179799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibroblasts as an in vitro model of circadian genetic and genomic studies.","authors":"Marcelo Francia, Merel Bot, Toni Boltz, Juan F De la Hoz, Marco Boks, René S Kahn, Roel A Ophoff","doi":"10.1007/s00335-024-10050-7","DOIUrl":"10.1007/s00335-024-10050-7","url":null,"abstract":"<p><p>Bipolar disorder (BD) is a heritable disorder characterized by shifts in mood that manifest in manic or depressive episodes. Clinical studies have identified abnormalities of the circadian system in BD patients as a hallmark of underlying pathophysiology. Fibroblasts are a well-established in vitro model for measuring circadian patterns. We set out to examine the underlying genetic architecture of circadian rhythm in fibroblasts, with the goal to assess its contribution to the polygenic nature of BD disease risk. We collected, from primary cell lines of 6 healthy individuals, temporal genomic features over a 48 h period from transcriptomic data (RNA-seq) and open chromatin data (ATAC-seq). The RNA-seq data showed that only a limited number of genes, primarily the known core clock genes such as ARNTL, CRY1, PER3, NR1D2 and TEF display circadian patterns of expression consistently across cell cultures. The ATAC-seq data identified that distinct transcription factor families, like those with the basic helix-loop-helix motif, were associated with regions that were increasing in accessibility over time. Whereas known glucocorticoid receptor target motifs were identified in those regions that were decreasing in accessibility. Further evaluation of these regions using stratified linkage disequilibrium score regression analysis failed to identify a significant presence of them in the known genetic architecture of BD, and other psychiatric disorders or neurobehavioral traits in which the circadian rhythm is affected. In this study, we characterize the biological pathways that are activated in this in vitro circadian model, evaluating the relevance of these processes in the context of the genetic architecture of BD and other disorders, highlighting its limitations and future applications for circadian genomic studies.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":"432-444"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11329553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141498399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"E3 ubiquitin ligase MARCH1 reduces inflammation and pyroptosis in cerebral ischemia-reperfusion injury via PCSK9 downregulation.","authors":"Hongmei Guo, Wanli Li, Zhigang Yang, Xiaobin Xing","doi":"10.1007/s00335-024-10055-2","DOIUrl":"10.1007/s00335-024-10055-2","url":null,"abstract":"<p><p>Pyroptosis has been regarded as caspase-1-mediated monocyte death that induces inflammation, showing a critical and detrimental role in the development of cerebral ischemia-reperfusion injury (IRI). MARCH1 is an E3 ubiquitin ligase that exerts potential anti-inflammatory functions. Therefore, the study probed into the significance of MARCH1 in inflammation and pyroptosis elicited by cerebral IRI. Middle cerebral artery occlusion/reperfusion (MCAO/R)-treated mice and oxygen glucose deprivation/reoxygenation (OGD/R)-treated hippocampal neurons were established to simulate cerebral IRI in vivo and in vitro. MARCH1 and PCSK9 expression was tested in MCAO/R-operated mice, and their interaction was identified by means of the cycloheximide assay and co-immunoprecipitation. The functional roles of MARCH1 and PCSK9 in cerebral IRI were subsequently determined by examining the neurological function, brain tissue changes, neuronal viability, inflammation, and pyroptosis through ectopic expression and knockdown experiments. PCSK9 expression was increased in the brain tissues of MCAO/R mice, while PCSK9 knockdown reduced brain damage and neurological deficits. Additionally, inflammation and pyroptosis were inhibited in OGD/R-exposed hippocampal neurons upon PCSK9 knockdown, accompanied by LDLR upregulation and NLRP3 inflammasome inactivation. Mechanistic experiments revealed that MARCH1 mediated ubiquitination and degradation of PCSK9, lowering PCSK9 protein expression. Furthermore, it was demonstrated that MARCH1 suppressed inflammation and pyroptosis after cerebral IRI by downregulating PCSK9 both in vivo and in vitro. Taken together, the present study demonstrate the protective effect of MARCH1 against cerebral IRI through PCSK9 downregulation, which might contribute to the discovery of new therapies for improving cerebral IRI.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":"346-361"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of genotype imputation using Glimpse tools on low coverage ancient DNA.","authors":"Hande Çubukcu, Gülşah Merve Kılınç","doi":"10.1007/s00335-024-10053-4","DOIUrl":"10.1007/s00335-024-10053-4","url":null,"abstract":"<p><p>Ancient DNA provides a unique frame for directly studying human population genetics in time and space. Still, since most of the ancient genomic data is low coverage, analysis is confronted with a low number of SNPs, genotype uncertainties, and reference-bias. Here, we for the first time benchmark the two distinct versions of Glimpse tools on 120 ancient human genomes from Eurasia including those largely from previously under-evaluated regions and compare the performance of genotype imputation with de facto analysis approaches for low coverage genomic data analysis. We further investigate the impact of two distinct reference panels on imputation accuracy for low coverage genomic data. We compute accuracy statistics and perform PCA and f₄-statistics to explore the behaviour of genotype imputation on low coverage data regarding (i)two versions of Glimpse, (ii)two reference panels, (iii)four post-imputation filters and coverages, as well as (iv)data type and geographical origin of the samples on the analyses. Our results reveal that even for 0.1X coverage ancient human genomes, genotype imputation using Glimpse-v2 is suitable. Additionally, using the 1000 Genomes merged with Human Genome Diversity Panel improves the accuracy of imputation for the rare variants with low MAF, which might be important not only for ancient genomics but also for modern human genomic studies based on low coverage data and for haplotype-based analysis. Most importantly, we reveal that genotype imputation of low coverage ancient human genomes reduces the genetic affinity of the samples towards human reference genome. Through solving one of the most challenging biases in data analysis, so-called reference bias, genotype imputation using Glimpse v2 is promising for low coverage ancient human genomic data analysis and for rare-variant-based and haplotype-based analysis.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":"461-473"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic diversity of North African populations in the 17q21 genomic region.","authors":"Mohsen Messaoudi, Andrew J Pakstis, Takwa Ezzaher, Sami Boussetta, Amel Ben Ammar Elgaaied, Kenneth K Kidd, Lotfi Cherni","doi":"10.1007/s00335-024-10051-6","DOIUrl":"10.1007/s00335-024-10051-6","url":null,"abstract":"<p><p>The demographic history of human populations in North Africa has been characterized by complex migration processes that have determined the current genetic structure of these populations. We examined the autosomal markers of eight sampled populations in northern Africa (Tunisia and Libya) to explore their genetic structure and to place them in a global context. We genotyped a set of 30 autosomal single-nucleotide polymorphisms (SNPs) extending 9.5 Mb and encompassing the 17q21 inversion region. Our data include 403 individuals from Tunisia and Libya. To put our populations in the global context, we analyzed our data in comparison with other populations, including those of the 1000 Genomes Project. To evaluate the data, we conducted genetic diversity, principal component, STRUCTURE, and haplotype analyses. The analysis of genetic composition revealed the genetic heterogeneity of North African populations. The principal component and STRUCTURE analyses converged and revealed the intermediate position of North Africans between Europeans and Asians. Haplotypic analysis demonstrated that the normal (H1) and inverted (H2) polymorphisms in the chromosome 17q21 region occur in North Africa at frequencies similar to those found in European and Southwest Asian populations. The results highlight the complex demographic history of North Africa, reflecting the influence of genetic flow from Europe and the Near East that dates to the prehistoric period. These gene flows added to demographic factors (inbreeding, endogamy), natural factors (topography, Sahara), and cultural factors that play a role in the emergence of the diverse and heterogeneous genetic structures of North African populations. This study contributes to a better understanding of the complex structure of North African populations.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":"445-460"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revealing the key role of cuproptosis in osteoporosis via the bioinformatic analysis and experimental validation of cuproptosis-related genes.","authors":"Jianxing Chen, Qifeng Sun, Yi Wang, Wenzhe Yin","doi":"10.1007/s00335-024-10049-0","DOIUrl":"10.1007/s00335-024-10049-0","url":null,"abstract":"<p><p>The incidence of osteoporosis has rapidly increased owing to the ageing population. Cuproptosis, a novel mechanism that regulates cell death, may be a new therapeutic approach. However, the relevance of cuproptosis in the immune microenvironment and osteoporosis immunotherapy is still unknown. We intersected the differentially expressed genes from osteoporotic samples with 75 cuproptosis-related genes to identify 16 significantly expressed cuproptosis genes. We further explored the connection between the cuproptosis pattern, immune microenvironment, and immunotherapy. The weighted gene co-expression network analysis algorithm was used to identify cuproptosis phenotype-associated genes, and we used quantitative real-time PCR and immunohistochemistry in mouse femur tissues to verify hub gene (MAP2K2, FDX1, COX19, VEGFA, CDKN2A, and NFE2L2) expression. Six hub genes and 59 cuproptosis phenotype-associated genes involved in immunisation were identified among the osteoporosis and control groups, and the majority of these 59 genes were enriched in the inflammatory response, as well as in signal transducers, Janus kinase, and transcription pathway activators. In addition, two different clusters of cuproptosis were found, and immune infiltration analysis showed that gene Cluster 1 had a greater immune score and immune infiltration level. Further analysis revealed that three key genes (COX19, MAP2K2, and FDX1) were highly correlated with immune cell infiltration, and external experiments validated the association of these three genes with the prognosis of osteoporosis. We used the three key mRNAs COX19, MAP2K2, and FDX1 as a classification model that may systematically elucidate the complex connection between cuproptosis and the immune microenvironment of osteoporosis. New insights into osteoporosis pathogenesis and immunotherapy prospects may be gained from this study.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":"414-431"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The expression profile of brain-derived exosomal miRNAs reveals the key molecules responsible for spontaneous motor function recovery in a rat model with permanent middle cerebral artery occlusion.","authors":"Liuyu Liu, Shengri Chen, Shuolin Liang, Zhijian Liang","doi":"10.1007/s00335-024-10052-5","DOIUrl":"10.1007/s00335-024-10052-5","url":null,"abstract":"<p><p>The analysis of alterations in the expression and functionality of brain-derived exosomal miRNAs within ischemic stroke lesions provides significant insights into the mechanisms that contribute to disease recovery. We assessed spontaneous motor function in a rat model of permanent middle cerebral artery occlusion (pMCAO) using motor function scores and magnetic resonance imaging (MRI). Brain-derived exosomes from the infarcted brain tissue of the animal model were extracted and high-throughput sequencing of them was performed followed by bioinformatics analysis for differentially expressed miRNAs target genes. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to measure expression levels of differentially expressed miRNAs at various time points. The oxygen-glucose deprivation (OGD) model was established to investigate gene function through the assessment of cell proliferation and apoptosis using EdU proliferation and JC-1 apoptosis assay. The rat model demonstrated a spontaneous recovery of motor function and a reduction in cerebral infarction area from day 1 to day 14 post-operation. Over the course of the recovery period, miR-24-3p, miR-129-1-3p, and miR-212-5p maintained consistent expression levels, reaching their peak on the initial day following surgery. In the cell model, EdU detection indicated that miR-129-1-3p promoted cellular proliferation, while JC-1 detection revealed its suppressive impact on cellular apoptosis. The current research findings indicated the presence of spontaneous motor function restoration in a rat model of ischemic stroke. MiR-24-3p, miR-129-1-3p, and miR-212-5p were identified as pivotal genes in this recovery process, with miR-129-1-3p potentially influencing the restoration of spontaneous motor function in ischemic stroke through the regulation of neuronal proliferation and apoptosis.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":"362-376"},"PeriodicalIF":2.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141600333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generation of a humanized mAce2 and a conditional hACE2 mouse models permissive to SARS-COV-2 infection.","authors":"I-Wen Song, Megan Washington, Carolina Leynes, Jason Hsu, Kempaiah Rayavara, Yangjin Bae, Nele Haelterman, Yuqing Chen, Ming-Ming Jiang, Aleksandra Drelich, Vivian Tat, Denise G Lanza, Isabel Lorenzo, Jason D Heaney, Chien-Te Kent Tseng, Brendan Lee, Ronit Marom","doi":"10.1007/s00335-024-10033-8","DOIUrl":"10.1007/s00335-024-10033-8","url":null,"abstract":"<p><p>The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) remains a public health concern and a subject of active research effort. Development of pre-clinical animal models is critical to study viral-host interaction, tissue tropism, disease mechanisms, therapeutic approaches, and long-term sequelae of infection. Here, we report two mouse models for studying SARS-CoV-2: A knock-in mAce2^F83Y,H353K mouse that expresses a mouse-human hybrid form of the angiotensin-converting enzyme 2 (ACE2) receptor under the endogenous mouse Ace2 promoter, and a Rosa26 conditional knock-in mouse carrying the human ACE2 allele (Rosa26^hACE2). Although the mAce2^F83Y,H353K mice were susceptible to intranasal inoculation with SARS-CoV-2, they did not show gross phenotypic abnormalities. Next, we generated a Rosa26^hACE2;CMV-Cre mouse line that ubiquitously expresses the human ACE2 receptor. By day 3 post infection with SARS-CoV-2, Rosa26^hACE2;CMV-Cre mice showed significant weight loss, a variable degree of alveolar wall thickening and reduced survival rates. Viral load measurements confirmed inoculation in lung and brain tissues of infected Rosa26^hACE2;CMV-Cre mice. The phenotypic spectrum displayed by our different mouse models translates to the broad range of clinical symptoms seen in the human patients and can serve as a resource for the community to model and explore both treatment strategies and long-term consequences of SARS-CoV-2 infection.</p>","PeriodicalId":18259,"journal":{"name":"Mammalian Genome","volume":" ","pages":"113-121"},"PeriodicalIF":2.7,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140136963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}