Genome Wide Identification of SARS-CoV Susceptibility Loci Using the Collaborative Cross
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE64660 | GEO | 2015/01/06
SECONDARY ACCESSION(S): PRJNA271585
REPOSITORIES: GEO
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Project description:New systems genetics approaches are needed to rapidly identify host genes and genetic networks that regulate complex disease outcomes. Using genetically diverse animals from incipient lines of the Collaborative Cross mouse panel, we demonstrate a greatly expanded range of phenotypes relative to classical mouse models of SARS-CoV infection including lung pathology, weight loss and viral titer. Genetic mapping revealed several loci contributing to differential disease responses, including an 8.5Mb locus associated with vascular cuffing on chromosome 3 that contained 23 genes and 13 noncoding RNAs. Integrating phenotypic and genetic data narrowed this region to a single gene, Trim55, an E3 ubiquitin ligase with a role in muscle fiber maintenance. Lung pathology and transcriptomic data from mice genetically deficient in Trim55 were used to validate its role in SARS-CoV-induced vascular cuffing and inflammation. These data establish the Collaborative Cross platform as a powerful genetic resource for uncovering genetic contributions of complex traits in microbial disease severity, inflammation and virus replication in models of outbred populations.
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Project description:ObjectiveAnimal studies remain essential for understanding mechanisms of epilepsy and identifying new therapeutic targets. However, existing animal models of epilepsy do not reflect the high level of genetic diversity found in the human population. The Collaborative Cross (CC) population is a genetically diverse recombinant inbred panel of mice. The CC offers large genotypic and phenotypic diversity, inbred strains with stable genomes that allow for repeated phenotypic measurements, and genomic tools including whole genome sequence to identify candidate genes and candidate variants.MethodsWe evaluated multiple complex epileptic traits in a sampling of 35 CC inbred strains using the flurothyl-induced seizure and kindling paradigm. We created an F2 population of 297 mice with extreme seizure susceptibility and performed quantitative trait loci (QTL) mapping to identify genomic regions associated with seizure sensitivity. We used quantitative RNA sequencing from CC hippocampal tissue to identify candidate genes and whole genome sequence to identify genetic variants likely affecting gene expression.ResultsWe identified new mouse models with extreme seizure susceptibility, seizure propagation, epileptogenesis, and SUDEP (sudden unexpected death in epilepsy). We performed QTL mapping and identified one known and seven novel loci associated with seizure sensitivity. We combined whole genome sequencing and hippocampal gene expression to pinpoint biologically plausible candidate genes (eg, Gabra2) and variants associated with seizure sensitivity.SignificanceNew mouse models of epilepsy are needed to better understand the complex genetic architecture of seizures and to identify therapeutics. We performed a phenotypic screen utilizing a novel genetic reference population of CC mice. The data we provide enable the identification of protective/risk genes and novel molecular mechanisms linked to complex seizure traits that are currently challenging to study and treat.
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2012-02-22 | E-GEOD-36016 | biostudies-arrayexpress
Project description:We performed transcriptomic profiling of cells derived from human pluripotent stem cells (PSCs) using our previously described distal lung directed differentiation protocol to generate alveolar type II epithelial-like cells (iAT2s). We used the SPC2 human iPSC line containing a SFTPC-tdTomato knock-in reporter. SFTPC-tdTomato+ iAT2s were sorted on day 41 and again on day 69 of differentiation. iAT2s were single-cell passaged in self-renewing 3D alveolosphere culture approximately every 2 weeks through day 194 of differentiation. On day 208, iAT2s were single-cell passaged onto Transwell inserts. Apical media was removed on day 210 to initiate air-liquid interface culture. On day 218, 6 replicate wells of iAT2s were exposed to SARS-CoV-2 in an apical inoculum and 3 replicate wells were exposed to mock. On day 219, three mock and three post-infection samples (1 dpi) were collected. Three additional post-infection samples (4 dpi) were collected on day 222. We find that SARS-CoV-2 infected iAT2s express a rapid global transcriptomic change characterized by a shift to an inflammatory phenotype, time-dependent epithelial interferon responses, and rapid loss of the mature lung alveolar epithelial program.
2020-09-21 | GSE153277 | GEO
Project description:BackgroundSalmonella is a Gram-negative bacterium causing a wide range of clinical syndromes ranging from typhoid fever to diarrheic disease. Non-typhoidal Salmonella (NTS) serovars infect humans and animals, causing important health burden in the world. Susceptibility to salmonellosis varies between individuals under the control of host genes, as demonstrated by the identification of over 20 genetic loci in various mouse crosses. We have investigated the host response to S. Typhimurium infection in 35 Collaborative Cross (CC) strains, a genetic population which involves wild-derived strains that had not been previously assessed.ResultsOne hundred and forty-eight mice from 35 CC strains were challenged intravenously with 1000 colony-forming units (CFUs) of S. Typhimurium. Bacterial load was measured in spleen and liver at day 4 post-infection. CC strains differed significantly (P?<?0.0001) in spleen and liver bacterial loads, while sex and age had no effect. Two significant quantitative trait loci (QTLs) on chromosomes 8 and 10 and one suggestive QTL on chromosome 1 were found for spleen bacterial load, while two suggestive QTLs on chromosomes 6 and 17 were found for liver bacterial load. These QTLs are caused by distinct allelic patterns, principally involving alleles originating from the wild-derived founders. Using sequence variations between the eight CC founder strains combined with database mining for expression in target organs and known immune phenotypes, we were able to refine the QTLs intervals and establish a list of the most promising candidate genes. Furthermore, we identified one strain, CC042/GeniUnc (CC042), as highly susceptible to S. Typhimurium infection.ConclusionsBy exploring a broader genetic variation, the Collaborative Cross population has revealed novel loci of resistance to Salmonella Typhimurium. It also led to the identification of CC042 as an extremely susceptible strain.
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