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1.
Virus Res ; 346: 199399, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38823688

RESUMO

Coronaviruses have caused three severe epidemics since the start of the 21st century: SARS, MERS and COVID-19. The severity of the ongoing COVID-19 pandemic and increasing likelihood of future coronavirus outbreaks motivates greater understanding of factors leading to severe coronavirus disease. We screened ten strains from the Collaborative Cross mouse genetic reference panel and identified strains CC006/TauUnc (CC006) and CC044/Unc (CC044) as coronavirus-susceptible and resistant, respectively, as indicated by variable weight loss and lung congestion scores four days post-infection. We generated a genetic mapping population of 755 CC006xCC044 F2 mice and exposed the mice to one of three genetically distinct mouse-adapted coronaviruses: clade 1a SARS-CoV MA15 (n=391), clade 1b SARS-CoV-2 MA10 (n=274), and clade 2 HKU3-CoV MA (n=90). Quantitative trait loci (QTL) mapping in SARS-CoV MA15- and SARS-CoV-2 MA10-infected F2 mice identified genetic loci associated with disease severity. Specifically, we identified seven loci associated with variation in outcome following infection with either virus, including one, HrS43, that is present in both groups. Three of these QTL, including HrS43, were also associated with HKU3-CoV MA outcome. HrS43 overlaps with a QTL previously reported by our lab that is associated with SARS-CoV MA15 outcome in CC011xCC074 F2 mice and is also syntenic with a human chromosomal region associated with severe COVID-19 outcomes in humans GWAS. The results reported here provide: (a) additional support for the involvement of this locus in SARS-CoV MA15 infection, (b) the first conclusive evidence that this locus is associated with susceptibility across the Sarbecovirus subgenus, and (c) demonstration of the relevance of mouse models in the study of coronavirus disease susceptibility in humans.


Assuntos
COVID-19 , Modelos Animais de Doenças , Locos de Características Quantitativas , SARS-CoV-2 , Animais , Camundongos , SARS-CoV-2/genética , COVID-19/virologia , Suscetibilidade a Doenças , Humanos , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/genética , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave/patogenicidade , Mapeamento Cromossômico , Infecções por Coronavirus/virologia , Feminino , Camundongos de Cruzamento Colaborativo/genética , Predisposição Genética para Doença , Masculino
2.
Front Endocrinol (Lausanne) ; 15: 1335855, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38800476

RESUMO

Introduction: Emerging data suggests liver disease may be initiated during development when there is high genome plasticity and the molecular pathways supporting liver function are being developed. Methods: Here, we leveraged our Collaborative Cross mouse model of developmental vitamin D deficiency (DVD) to investigate the role of DVD in dysregulating the molecular mechanisms underlying liver disease. We defined the effects on the adult liver transcriptome and metabolome and examined the role of epigenetic dysregulation. Given that the parental origin of the genome (POG) influences response to DVD, we used our established POG model [POG1-(CC011xCC001)F1 and POG2-(CC001xCC011)F1] to identify interindividual differences. Results: We found that DVD altered the adult liver transcriptome, primarily downregulating genes controlling liver development, response to injury/infection (detoxification & inflammation), cholesterol biosynthesis, and energy production. In concordance with these transcriptional changes, we found that DVD decreased liver cell membrane-associated lipids (including cholesterol) and pentose phosphate pathway metabolites. Each POG also exhibited distinct responses. POG1 exhibited almost 2X more differentially expressed genes (DEGs) with effects indicative of increased energy utilization. This included upregulation of lipid and amino acid metabolism genes and increased intermediate lipid and amino acid metabolites, increased energy cofactors, and decreased energy substrates. POG2 exhibited broader downregulation of cholesterol biosynthesis genes with a metabolomics profile indicative of decreased energy utilization. Although DVD primarily caused loss of liver DNA methylation for both POGs, only one epimutation was shared, and POG2 had 6.5X more differentially methylated genes. Differential methylation was detected at DEGs regulating developmental processes such as amino acid transport (POG1) and cell growth & differentiation (e.g., Wnt & cadherin signaling, POG2). Conclusions: These findings implicate a novel role for maternal vitamin D in programming essential offspring liver functions that are dysregulated in liver disease. Importantly, impairment of these processes was not rescued by vitamin D treatment at weaning, suggesting these effects require preventative measures. Substantial differences in POG response to DVD demonstrate that the parental genomic context of exposure determines offspring susceptibility.


Assuntos
Colesterol , Metabolismo Energético , Fígado , Deficiência de Vitamina D , Animais , Camundongos , Fígado/metabolismo , Deficiência de Vitamina D/metabolismo , Deficiência de Vitamina D/genética , Colesterol/metabolismo , Colesterol/biossíntese , Feminino , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Transcriptoma , Epigênese Genética
3.
Artigo em Inglês | MEDLINE | ID: mdl-38670234

RESUMO

BACKGROUND: The development of peanut allergy is due to a combination of genetic and environmental factors, although specific genes have proven difficult to identify. Previously, we reported that peanut-sensitized Collaborative Cross strain CC027/GeniUnc (CC027) mice develop anaphylaxis upon oral challenge to peanut, in contrast to C3H/HeJ (C3H) mice. OBJECTIVE: This study aimed to determine the genetic basis of orally induced anaphylaxis to peanut in CC027 mice. METHODS: A genetic mapping population between CC027 and C3H mice was designed to identify the genetic factors that drive oral anaphylaxis. A total of 356 CC027xC3H backcrossed mice were generated, sensitized to peanut, then challenged to peanut by oral gavage. Anaphylaxis and peanut-specific IgE were quantified for all mice. T-cell phenotyping was conducted on CC027 mice and 5 additional Collaborative Cross strains. RESULTS: Anaphylaxis to peanut was absent in 77% of backcrossed mice, with 19% showing moderate anaphylaxis and 4% having severe anaphylaxis. There were 8 genetic loci associated with variation in response to peanut challenge-6 associated with anaphylaxis (temperature decrease) and 2 associated with peanut-specific IgE levels. There were 2 major loci that impacted multiple aspects of the severity of acute anaphylaxis, at which the CC027 allele was associated with worse outcome. At one of these loci, CC027 has a private genetic variant in the Themis gene. Consistent with described functions of Themis, we found that CC027 mice have more immature T cells with fewer CD8+, CD4+, and CD4+CD25+CD127- regulatory T cells. CONCLUSIONS: Our results demonstrate a key role for Themis in the orally reactive CC027 mouse model of peanut allergy.

4.
Microbiome ; 11(1): 220, 2023 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-37784178

RESUMO

BACKGROUND: The gut microbiota is modulated by a combination of diet, host genetics, and sex effects. The magnitude of these effects and interactions among them is important to understanding inter-individual variability in gut microbiota. In a previous study, mouse strain-specific responses to American and ketogenic diets were observed along with several QTLs for metabolic traits. In the current study, we searched for genetic variants underlying differences in the gut microbiota in response to American and ketogenic diets, which are high in fat and vary in carbohydrate composition, between C57BL/6 J (B6) and FVB/NJ (FVB) mouse strains. RESULTS: Genetic mapping of microbial features revealed 18 loci under the QTL model (i.e., marginal effects that are not specific to diet or sex), 12 loci under the QTL by diet model, and 1 locus under the QTL by sex model. Multiple metabolic and microbial features map to the distal part of Chr 1 and Chr 16 along with eigenvectors extracted from principal coordinate analysis of measures of ß-diversity. Bilophila, Ruminiclostridium 9, and Rikenella (Chr 1) were identified as sex- and diet-independent QTL candidate keystone organisms, and Parabacteroides (Chr 16) was identified as a diet-specific, candidate keystone organism in confirmatory factor analyses of traits mapping to these regions. For many microbial features, irrespective of which QTL model was used, diet or the interaction between diet and a genotype were the strongest predictors of the abundance of each microbial trait. Sex, while important to the analyses, was not as strong of a predictor for microbial abundances. CONCLUSIONS: These results demonstrate that sex, diet, and genetic background have different magnitudes of effects on inter-individual differences in gut microbiota. Therefore, Precision Nutrition through the integration of genetic variation, microbiota, and sex affecting microbiota variation will be important to predict response to diets varying in carbohydrate composition. Video Abstract.


Assuntos
Dieta Cetogênica , Microbioma Gastrointestinal , Animais , Camundongos , Microbioma Gastrointestinal/genética , Camundongos Endogâmicos C57BL , Dieta , Bacteroidetes , Carboidratos
5.
bioRxiv ; 2023 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-37745496

RESUMO

Background: The development of peanut allergy is due to a combination of genetic and environmental factors, although specific genes have proven difficult to identify. Previously, we reported that peanut-sensitized CC027/GeniUnc (CC027) mice develop anaphylaxis upon oral challenge to peanut, unlike C3H/HeJ (C3H) mice. Objective: To determine the genetic basis of orally-induced anaphylaxis to peanut in CC027 mice. Methods: A genetic mapping population between CC027 and C3H mice was designed to identify the genetic factors that drive oral anaphylaxis. A total of 356 CC027xC3H backcrossed mice were generated, sensitized to peanut, then challenged to peanut by oral gavage. Anaphylaxis and peanut-specific IgE were quantified for all mice. T-cell phenotyping was conducted on CC027 and five additional CC strains. Results: Anaphylaxis to peanut was absent in 77% of backcrossed mice, with 19% showing moderate anaphylaxis, and 4% having severe anaphylaxis. A total of eight genetic loci were associated with variation in response to peanut challenge, six associated with anaphylaxis (temperature decrease) and two associated with peanut-specific IgE levels. There were two major loci that impacted multiple aspects of the severity of acute anaphylaxis, at which the CC027 allele was associated with worse outcome. At one of these loci, CC027 has a private genetic variant in the Themis (thymocyte-expressed molecule involved in selection) gene. Consistent with Themis' described functions, we found that CC027 have more immature T cells with fewer CD8+, CD4+, and CD4+CD25+CD127- regulatory T cells. Conclusion: Our results demonstrate a key role for Themis in the orally-reactive CC027 mouse model of peanut allergy.

6.
Front Toxicol ; 5: 1171175, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37304253

RESUMO

Toxicology research has rapidly evolved, leveraging increasingly advanced technologies in high-throughput approaches to yield important information on toxicological mechanisms and health outcomes. Data produced through toxicology studies are consequently becoming larger, often producing high-dimensional data. These types of data hold promise for imparting new knowledge, yet inherently have complexities causing them to be a rate-limiting element for researchers, particularly those that are housed in "wet lab" settings (i.e., researchers that use liquids to analyze various chemicals and biomarkers as opposed to more computationally focused, "dry lab" researchers). These types of challenges represent topics of ongoing conversation amongst our team and researchers in the field. The aim of this perspective is to i) summarize hurdles in analyzing high-dimensional data in toxicology that require improved training and translation for wet lab researchers, ii) highlight example methods that have aided in translating data analysis techniques to wet lab researchers; and iii) describe challenges that remain to be effectively addressed, to date, in toxicology research. Specific aspects include methodologies that could be introduced to wet lab researchers, including data pre-processing, machine learning, and data reduction. Current challenges discussed include model interpretability, study biases, and data analysis training. Example efforts implemented to translate these data analysis techniques are also mentioned, including online data analysis resources and hands-on workshops. Questions are also posed to continue conversation in the toxicology community. Contents of this perspective represent timely issues broadly occurring in the fields of bioinformatics and toxicology that require ongoing dialogue between wet and dry lab researchers.

7.
Res Sq ; 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36778219

RESUMO

Background The gut microbiota is modulated by a combination of diet, host genetics, and sex effects. The magnitude of these effects and interactions among them is important to understanding inter-individual variability in gut microbiota. In a previous study, mouse strain-specific responses to American and ketogenic diets were observed along with several QTL for metabolic traits. In the current study, we searched for genetic variants underlying differences in the gut microbiota in response to American and ketogenic diets, which are high in fat and vary in carbohydrate composition, between C57BL/6J (B6) and FVB/NJ (FVB) mouse strains. Results Genetic mapping of microbial features revealed 18 loci under the QTL model (i.e., marginal effects that are not specific to diet or sex), 12 loci under the QTL by diet model, and 1 locus under the QTL by sex model. Multiple metabolic and microbial features map to the distal part of Chr 1 and Chr 16 along with eigenvectors extracted from principal coordinate analysis of measures of ß-diversity. Bilophila , Ruminiclostridium 9 , and Rikenella (Chr 1) were identified as sex and diet independent QTL candidate keystone organisms and Rikenelleceae RC9 Gut Group (Chr 16) was identified as a diet-specific, candidate keystone organism in confirmatory factor analyses of traits mapping to these regions. For many microbial features, irrespective of which QTL model was used, diet or the interaction between diet and a genotype were the strongest predictors of the abundance of each microbial trait. Sex, while important to the analyses, was not as strong of a predictor for microbial abundances. Conclusions These results demonstrate that sex, diet, and genetic background have different magnitudes of effects on inter-individual differences in gut microbiota. Therefore, Precision Nutrition through the integration of genetic variation, microbiota, and sex affecting microbiota variation will be important to predict response to diets varying in carbohydrate composition.

8.
Diabetes ; 72(1): 135-148, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36219827

RESUMO

Despite the successes of human genome-wide association studies, the causal genes underlying most metabolic traits remain unclear. We used outbred heterogeneous stock (HS) rats, coupled with expression data and mediation analysis, to identify quantitative trait loci (QTLs) and candidate gene mediators for adiposity, glucose tolerance, serum lipids, and other metabolic traits. Physiological traits were measured in 1,519 male HS rats, with liver and adipose transcriptomes measured in >410 rats. Genotypes were imputed from low-coverage whole-genome sequencing. Linear mixed models were used to detect physiological and expression QTLs (pQTLs and eQTLs, respectively), using both single nucleotide polymorphism (SNP)- and haplotype-based models for pQTL mapping. Genes with cis-eQTLs that overlapped pQTLs were assessed as causal candidates through mediation analysis. We identified 14 SNP-based pQTLs and 19 haplotype-based pQTLs, of which 10 were in common. Using mediation, we identified the following genes as candidate mediators of pQTLs: Grk5 for fat pad weight and serum triglyceride pQTLs on Chr1, Krtcap3 for fat pad weight and serum triglyceride pQTLs on Chr6, Ilrun for a fat pad weight pQTL on Chr20, and Rfx6 for a whole pancreatic insulin content pQTL on Chr20. Furthermore, we verified Grk5 and Ktrcap3 using gene knockdown/out models, thereby shedding light on novel regulators of obesity.


Assuntos
Adiposidade , Insulinas , Ratos , Masculino , Humanos , Animais , Adiposidade/genética , Estudo de Associação Genômica Ampla , Obesidade/genética , Triglicerídeos , Insulinas/genética , Lipídeos , Polimorfismo de Nucleotídeo Único
9.
PLoS Genet ; 18(5): e1010184, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35533209

RESUMO

Genetic studies often seek to establish a causal chain of events originating from genetic variation through to molecular and clinical phenotypes. When multiple phenotypes share a common genetic association, one phenotype may act as an intermediate for the genetic effects on the other. Alternatively, the phenotypes may be causally unrelated but share genetic loci. Mediation analysis represents a class of causal inference approaches used to determine which of these scenarios is most plausible. We have developed a general approach to mediation analysis based on Bayesian model selection and have implemented it in an R package, bmediatR. Bayesian model selection provides a flexible framework that can be tailored to different analyses. Our approach can incorporate prior information about the likelihood of models and the strength of causal effects. It can also accommodate multiple genetic variants or multi-state haplotypes. Our approach reports posterior probabilities that can be useful in interpreting uncertainty among competing models. We compared bmediatR with other popular methods, including the Sobel test, Mendelian randomization, and Bayesian network analysis using simulated data. We found that bmediatR performed as well or better than these alternatives in most scenarios. We applied bmediatR to proteome data from Diversity Outbred (DO) mice, a multi-parent population, and demonstrate the power of mediation with multi-state haplotypes. We also applied bmediatR to data from human cell lines to identify transcripts that are mediated through or are expressed independently from local chromatin accessibility. We demonstrate that Bayesian model selection provides a powerful and versatile approach to identify causal relationships in genetic studies using model organism or human data.


Assuntos
Análise de Mediação , Análise da Randomização Mendeliana , Animais , Teorema de Bayes , Causalidade , Análise da Randomização Mendeliana/métodos , Camundongos , Fenótipo
10.
Physiol Genomics ; 54(6): 206-219, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35467982

RESUMO

Transcriptomic analysis in metabolically active tissues allows a systems genetics approach to identify causal genes and networks involved in metabolic disease. Outbred heterogeneous stock (HS) rats are used for genetic mapping of complex traits, but to-date, a systems genetics analysis of metabolic tissues has not been done. We investigated whether adiposity-associated genes and gene coexpression networks in outbred heterogeneous stock (HS) rats overlap those found in humans. We analyzed RNAseq data from adipose tissue of 415 male HS rats, correlated these transcripts with body weight (BW) and compared transcriptome signatures to two human cohorts: the "African American Genetics of Metabolism and Expression" and "Metabolic Syndrome in Men." We used weighted gene coexpression network analysis to identify adiposity-associated gene networks and mediation analysis to identify genes under genetic control whose expression drives adiposity. We identified 554 orthologous "consensus genes" whose expression correlates with BW in the rat and with body mass index (BMI) in both human cohorts. Consensus genes fell within eight coexpressed networks and were enriched for genes involved in immune system function, cell growth, extracellular matrix organization, and lipid metabolic processes. We identified 19 consensus genes for which genetic variation may influence BW via their expression, including those involved in lipolysis (e.g., Hcar1), inflammation (e.g., Rgs1), adipogenesis (e.g., Tmem120b), or no previously known role in obesity (e.g., St14 and Ms4a6a). Strong concordance between HS rat and human BW/BMI associated transcripts demonstrates translational utility of the rat model, while identification of novel genes expands our knowledge of the genetics underlying obesity.


Assuntos
Redes Reguladoras de Genes , Obesidade , Transcriptoma , Tecido Adiposo/metabolismo , Adiposidade/genética , Animais , Perfilação da Expressão Gênica , Humanos , Masculino , Obesidade/genética , Ratos
11.
Toxicology ; 461: 152902, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34418498

RESUMO

Development of TAK-875 was discontinued when a small number of serious drug-induced liver injury (DILI) cases were observed in Phase 3 clinical trials. Subsequent studies have identified hepatocellular oxidative stress, mitochondrial dysfunction, altered bile acid homeostasis, and immune response as mechanisms of TAK-875 DILI and the contribution of genetic risk factors in oxidative response and mitochondrial pathways to the toxicity susceptibility observed in patients. We tested the hypothesis that a novel preclinical approach based on gene pathway analysis in the livers of Collaborative Cross mice could be used to identify human-relevant mechanisms of toxicity and genetic risk factors at the level of the hepatocyte as reported in a human genome-wide association study. Eight (8) male mice (4 matched pairs) from each of 45 Collaborative Cross lines were treated with a single oral (gavage) dose of either vehicle or 600 mg/kg TAK-875. As expected, liver injury was not detected histologically and few changes in plasma biomarkers of hepatotoxicity were observed. However, gene expression profiling in the liver identified hundreds of transcripts responsive to TAK-875 treatment across all strains reflecting alterations in immune response and bile acid homeostasis and the interaction of treatment and strain reflecting oxidative stress and mitochondrial dysfunction. Fold-change expression values were then used to develop pathway-based phenotypes for genetic mapping which identified candidate risk factor genes for TAK-875 toxicity susceptibility at the level of the hepatocyte. Taken together, these findings support our hypothesis that a gene pathway-based approach using Collaborative Cross mice could inform sensitive strains, human-relevant mechanisms of toxicity, and genetic risk factors for TAK-875 DILI. This novel preclinical approach may be helpful in understanding, predicting, and ultimately preventing clinical DILI for other drugs.


Assuntos
Benzofuranos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Hepatócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Sulfonas/toxicidade , Animais , Ácidos e Sais Biliares/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Camundongos de Cruzamento Colaborativo , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hepatócitos/patologia , Humanos , Masculino , Camundongos , Fatores de Risco
12.
Genetics ; 218(1)2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-33693696

RESUMO

Female mammals are functional mosaics of their parental X-linked gene expression due to X chromosome inactivation (XCI). This process inactivates one copy of the X chromosome in each cell during embryogenesis and that state is maintained clonally through mitosis. In mice, the choice of which parental X chromosome remains active is determined by the X chromosome controlling element (Xce), which has been mapped to a 176-kb candidate interval. A series of functional Xce alleles has been characterized or inferred for classical inbred strains based on biased, or skewed, inactivation of the parental X chromosomes in crosses between strains. To further explore the function structure basis and location of the Xce, we measured allele-specific expression of X-linked genes in a large population of F1 females generated from Collaborative Cross (CC) strains. Using published sequence data and applying a Bayesian "Pólya urn" model of XCI skew, we report two major findings. First, inter-individual variability in XCI suggests mouse epiblasts contain on average 20-30 cells contributing to brain. Second, CC founder strain NOD/ShiLtJ has a novel and unique functional allele, Xceg, that is the weakest in the Xce allelic series. Despite phylogenetic analysis confirming that NOD/ShiLtJ carries a haplotype almost identical to the well-characterized C57BL/6J (Xceb), we observed unexpected patterns of XCI skewing in females carrying the NOD/ShiLtJ haplotype within the Xce. Copy number variation is common at the Xce locus and we conclude that the observed allelic series is a product of independent and recurring duplications shared between weak Xce alleles.


Assuntos
Mecanismo Genético de Compensação de Dose , Inativação do Cromossomo X/genética , Cromossomo X/genética , Alelos , Animais , Teorema de Bayes , Mapeamento Cromossômico/métodos , Variações do Número de Cópias de DNA/genética , Genes Ligados ao Cromossomo X/genética , Haplótipos , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Filogenia , RNA Longo não Codificante/genética
13.
Sci Rep ; 11(1): 2071, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33483609

RESUMO

Chronic kidney disease (CKD), which can ultimately progress to kidney failure, is influenced by genetics and the environment. Genes identified in human genome wide association studies (GWAS) explain only a small proportion of the heritable variation and lack functional validation, indicating the need for additional model systems. Outbred heterogeneous stock (HS) rats have been used for genetic fine-mapping of complex traits, but have not previously been used for CKD traits. We performed GWAS for urinary protein excretion (UPE) and CKD related serum biochemistries in 245 male HS rats. Quantitative trait loci (QTL) were identified using a linear mixed effect model that tested for association with imputed genotypes. Candidate genes were identified using bioinformatics tools and targeted RNAseq followed by testing in a novel in vitro model of human tubule, hypoxia-induced damage. We identified two QTL for UPE and five for serum biochemistries. Protein modeling identified a missense variant within Septin 8 (Sept8) as a candidate for UPE. Sept8/SEPTIN8 expression increased in HS rats with elevated UPE and tubulointerstitial injury and in the in vitro hypoxia model. SEPTIN8 is detected within proximal tubule cells in human kidney samples and localizes with acetyl-alpha tubulin in the culture system. After hypoxia, SEPTIN8 staining becomes diffuse and appears to relocalize with actin. These data suggest a role of SEPTIN8 in cellular organization and structure in response to environmental stress. This study demonstrates that integration of a rat genetic model with an environmentally induced tubule damage system identifies Sept8/SEPTIN8 and informs novel aspects of the complex gene by environmental interactions contributing to CKD risk.


Assuntos
Túbulos Renais/patologia , Rim/patologia , Septinas/genética , Animais , Hipóxia Celular , Efeito Fundador , Haplótipos , Humanos , Masculino , Ratos
14.
Genetics ; 216(4): 957-983, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33082282

RESUMO

Multiparental populations (MPPs) are experimental populations in which the genome of every individual is a mosaic of known founder haplotypes. These populations are useful for detecting quantitative trait loci (QTL) because tests of association can leverage inferred founder haplotype descent. It is difficult, however, to determine how haplotypes at a locus group into distinct functional alleles, termed the allelic series. The allelic series is important because it provides information about the number of causal variants at a QTL and their combined effects. In this study, we introduce a fully Bayesian model selection framework for inferring the allelic series. This framework accounts for sources of uncertainty found in typical MPPs, including the number and composition of functional alleles. Our prior distribution for the allelic series is based on the Chinese restaurant process, a relative of the Dirichlet process, and we leverage its connection to the coalescent to introduce additional prior information about haplotype relatedness via a phylogenetic tree. We evaluate our approach via simulation and apply it to QTL from two MPPs: the Collaborative Cross (CC) and the Drosophila Synthetic Population Resource (DSPR). We find that, although posterior inference of the exact allelic series is often uncertain, we are able to distinguish biallelic QTL from more complex multiallelic cases. Additionally, our allele-based approach improves haplotype effect estimation when the true number of functional alleles is small. Our method, Tree-Based Inference of Multiallelism via Bayesian Regression (TIMBR), provides new insight into the genetic architecture of QTL in MPPs.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Haplótipos , Locos de Características Quantitativas , Animais , Teorema de Bayes , Drosophila , Efeito Fundador , Frequência do Gene , Padrões de Herança , Modelos Genéticos
15.
Curr Dev Nutr ; 4(8): nzaa106, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32851199

RESUMO

BACKGROUND: Liver metabolite concentrations have the potential to be key biomarkers of systemic metabolic dysfunction and overall health. However, for most conditions we do not know the extent to which genetic differences regulate susceptibility to metabolic responses. This limits our ability to detect and diagnose effects in heterogeneous populations. OBJECTIVES: Here, we investigated the extent to which naturally occurring genetic differences regulate maternal liver metabolic response to vitamin D deficiency (VDD), particularly during perinatal periods when such changes can adversely affect maternal and fetal health. METHODS: We used a panel of 8 inbred Collaborative Cross (CC) mouse strains, each with a different genetic background (72 dams, 3-6/treatment group, per strain). We identified robust maternal liver metabolic responses to vitamin D depletion before and during gestation and lactation using a vitamin-D-deficient (VDD; 0 IU vitamin D3/kg) or -sufficient diet (1000 IU vitamin D3/kg). We then identified VDD-induced metabolite changes influenced by strain genetic background. RESULTS: We detected a significant VDD effect by orthogonal partial least squares discriminant analysis (Q2 = 0.266, pQ2 = 0.002): primarily, altered concentrations of 78 metabolites involved in lipid, amino acid, and nucleotide metabolism (variable importance to projection score ≥1.5). Metabolites in unsaturated fatty acid and glycerophospholipid metabolism pathways were significantly enriched [False Discovery Rate (FDR) <0.05]. VDD also significantly altered concentrations of putative markers of uremic toxemia, acylglycerols, and dipeptides. The extent of the metabolic response to VDD was strongly dependent on genetic strain, ranging from robustly responsive to nonresponsive. Two strains (CC017/Unc and CC032/GeniUnc) were particularly sensitive to VDD; however, each strain altered different pathways. CONCLUSIONS: These novel findings demonstrate that maternal VDD induces different liver metabolic effects in different genetic backgrounds. Strains with differing susceptibility and metabolic response to VDD represent unique tools to identify causal susceptibility factors and further elucidate the role of VDD-induced metabolic changes in maternal and/or fetal health for ultimately translating findings to human populations.

16.
PLoS Genet ; 16(1): e1008537, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961859

RESUMO

Gene transcription profiles across tissues are largely defined by the activity of regulatory elements, most of which correspond to regions of accessible chromatin. Regulatory element activity is in turn modulated by genetic variation, resulting in variable transcription rates across individuals. The interplay of these factors, however, is poorly understood. Here we characterize expression and chromatin state dynamics across three tissues-liver, lung, and kidney-in 47 strains of the Collaborative Cross (CC) mouse population, examining the regulation of these dynamics by expression quantitative trait loci (eQTL) and chromatin QTL (cQTL). QTL whose allelic effects were consistent across tissues were detected for 1,101 genes and 133 chromatin regions. Also detected were eQTL and cQTL whose allelic effects differed across tissues, including local-eQTL for Pik3c2g detected in all three tissues but with distinct allelic effects. Leveraging overlapping measurements of gene expression and chromatin accessibility on the same mice from multiple tissues, we used mediation analysis to identify chromatin and gene expression intermediates of eQTL effects. Based on QTL and mediation analyses over multiple tissues, we propose a causal model for the distal genetic regulation of Akr1e1, a gene involved in glycogen metabolism, through the zinc finger transcription factor Zfp985 and chromatin intermediates. This analysis demonstrates the complexity of transcriptional and chromatin dynamics and their regulation over multiple tissues, as well as the value of the CC and related genetic resource populations for identifying specific regulatory mechanisms within cells and tissues.


Assuntos
Montagem e Desmontagem da Cromatina , Cromatina/química , Locos de Características Quantitativas , Animais , Cromatina/genética , Cromatina/metabolismo , Rim/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Fígado/metabolismo , Pulmão/metabolismo , Masculino , Camundongos , Especificidade de Órgãos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo
17.
Psychopharmacology (Berl) ; 237(4): 979-996, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31897574

RESUMO

RATIONALE: Few effective treatments exist for cocaine use disorders due to gaps in knowledge about its complex etiology. Genetically defined animal models provide a useful tool for advancing our understanding of the biological and genetic underpinnings of addiction-related behavior and evaluating potential treatments. However, many attempts at developing mouse models of behavioral disorders were based on overly simplified single gene perturbations, often leading to inconsistent and misleading results in pre-clinical pharmacology studies. A genetically complex mouse model may better reflect disease-related behaviors. OBJECTIVES: Screening defined, yet genetically complex, intercrosses of the Collaborative Cross (CC) mice revealed two lines, RIX04/17 and RIX41/51, with extreme high and low behavioral responses to cocaine. We characterized these lines as well as their CC parents, CC004/TauUnc and CC041/TauUnc, to evaluate their utility as novel model systems for studying the biological and genetic mechanisms underlying behavioral responses to cocaine. METHODS: Behavioral responses to acute (initial locomotor sensitivity) and repeated (behavioral sensitization, conditioned place preference, intravenous self-administration) exposures to cocaine were assessed. We also examined the monoaminergic system (striatal tissue content and in vivo fast scan cyclic voltammetry), HPA axis reactivity, and circadian rhythms as potential mechanisms for the divergent phenotypic behaviors observed in the two strains, as these systems have a previously known role in mediating addiction-related behaviors. RESULTS: RIX04/17 and 41/51 show strikingly divergent initial locomotor sensitivity to cocaine with RIX04/17 exhibiting very high and RIX41/51 almost no response. The lines also differ in the emergence of behavioral sensitization with RIX41/51 requiring more exposures to exhibit a sensitized response. Both lines show conditioned place preference for cocaine. We determined that the cocaine sensitivity phenotype in each RIX line was largely driven by the genetic influence of one CC parental strain, CC004/TauUnc and CC041/TauUnc. CC004 demonstrates active operant cocaine self-administration and CC041 is unable to acquire under the same testing conditions, a deficit which is specific to cocaine as both strains show operant response for a natural food reward. Examination of potential mechanisms driving differential responses to cocaine show strain differences in molecular and behavioral circadian rhythms. Additionally, while there is no difference in striatal dopamine tissue content or dynamics, there are selective differences in striatal norepinephrine and serotonergic tissue content. CONCLUSIONS: These CC strains offer a complex polygenic model system to study underlying mechanisms of cocaine response. We propose that CC041/TauUnc and CC004/TauUnc will be useful for studying genetic and biological mechanisms underlying resistance or vulnerability to the stimulatory and reinforcing effects of cocaine.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/genética , Cocaína/administração & dosagem , Camundongos de Cruzamento Colaborativo/genética , Locomoção/genética , Reforço Psicológico , Recompensa , Animais , Comportamento Aditivo/genética , Comportamento Aditivo/metabolismo , Comportamento Aditivo/psicologia , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Transtornos Relacionados ao Uso de Cocaína/psicologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Inibidores da Captação de Dopamina/administração & dosagem , Feminino , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Autoadministração , Especificidade da Espécie
18.
Toxicol Sci ; 172(2): 265-278, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31501888

RESUMO

Idelalisib is a phosphatidylinositol 3-kinase inhibitor highly selective for the delta isoform that has shown good efficacy in treating chronic lymphocytic leukemia and follicular lymphoma. In clinical trials, however, idelalisib was associated with rare, but potentially serious liver and lung toxicities. In this study, we used the Collaborative Cross (CC) mouse population to identify genetic factors associated with the drug response that may inform risk management strategies for idelalisib in humans. Eight male mice (4 matched pairs) from 50 CC lines were treated once daily for 14 days by oral gavage with either vehicle or idelalisib at a dose selected to achieve clinically relevant peak plasma concentrations (150 mg/kg/day). The drug was well tolerated across all CC lines, and there were no observations of overt liver injury. Differences across CC lines were seen in drug concentration in plasma samples collected at the approximate Tmax on study Days 1, 7, and 14. There were also small but statistically significant treatment-induced alterations in plasma total bile acids and microRNA-122, and these may indicate early hepatocellular stress required for immune-mediated hepatotoxicity in humans. Idelalisib treatment further induced significant elevations in the total cell count of terminal bronchoalveolar lavage fluid, which may be analogous to pneumonitis observed in the clinic. Genetic mapping identified loci associated with interim plasma idelalisib concentration and the other 3 treatment-related endpoints. Thirteen priority candidate quantitative trait genes identified in CC mice may now guide interrogation of risk factors for adverse drug responses associated with idelalisib in humans.


Assuntos
Antineoplásicos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/genética , Lesão Pulmonar/genética , Fosfatidilinositol 3-Quinase/toxicidade , Inibidores de Proteínas Quinases/toxicidade , Locos de Características Quantitativas/efeitos dos fármacos , Animais , Antineoplásicos/sangue , Biomarcadores/sangue , Líquido da Lavagem Broncoalveolar/citologia , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Mapeamento Cromossômico , Relação Dose-Resposta a Droga , Testes de Função Hepática , Lesão Pulmonar/sangue , Lesão Pulmonar/induzido quimicamente , Camundongos Endogâmicos , MicroRNAs/sangue , Estresse Oxidativo , Fosfatidilinositol 3-Quinase/sangue , Polimorfismo de Nucleotídeo Único , Inibidores de Proteínas Quinases/sangue , Purinas , Quinazolinonas , Fatores de Risco , Especificidade da Espécie , Toxicogenética
19.
G3 (Bethesda) ; 9(5): 1613-1622, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-30877080

RESUMO

Reproductive success in the eight founder strains of the Collaborative Cross (CC) was measured using a diallel-mating scheme. Over a 48-month period we generated 4,448 litters, and provided 24,782 weaned pups for use in 16 different published experiments. We identified factors that affect the average litter size in a cross by estimating the overall contribution of parent-of-origin, heterosis, inbred, and epistatic effects using a Bayesian zero-truncated overdispersed Poisson mixed model. The phenotypic variance of litter size has a substantial contribution (82%) from unexplained and environmental sources, but no detectable effect of seasonality. Most of the explained variance was due to additive effects (9.2%) and parental sex (maternal vs. paternal strain; 5.8%), with epistasis accounting for 3.4%. Within the parental effects, the effect of the dam's strain explained more than the sire's strain (13.2% vs. 1.8%), and the dam's strain effects account for 74.2% of total variation explained. Dams from strains C57BL/6J and NOD/ShiLtJ increased the expected litter size by a mean of 1.66 and 1.79 pups, whereas dams from strains WSB/EiJ, PWK/PhJ, and CAST/EiJ reduced expected litter size by a mean of 1.51, 0.81, and 0.90 pups. Finally, there was no strong evidence for strain-specific effects on sex ratio distortion. Overall, these results demonstrate that strains vary substantially in their reproductive ability depending on their genetic background, and that litter size is largely determined by dam's strain rather than sire's strain effects, as expected. This analysis adds to our understanding of factors that influence litter size in mammals, and also helps to explain breeding successes and failures in the extinct lines and surviving CC strains.


Assuntos
Alelos , Animais Geneticamente Modificados , Camundongos de Cruzamento Colaborativo/genética , Tamanho da Ninhada de Vivíparos/genética , Herança Materna , Algoritmos , Animais , Cruzamentos Genéticos , Meio Ambiente , Interação Gene-Ambiente , Testes Genéticos , Camundongos , Camundongos Endogâmicos , Modelos Genéticos , Fenótipo , Razão de Masculinidade , Especificidade da Espécie
20.
G3 (Bethesda) ; 9(5): 1707-1727, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-30914424

RESUMO

The Collaborative Cross (CC) is a mouse genetic reference population whose range of applications includes quantitative trait loci (QTL) mapping. The design of a CC QTL mapping study involves multiple decisions, including which and how many strains to use, and how many replicates per strain to phenotype, all viewed within the context of hypothesized QTL architecture. Until now, these decisions have been informed largely by early power analyses that were based on simulated, hypothetical CC genomes. Now that more than 50 CC strains are available and more than 70 CC genomes have been observed, it is possible to characterize power based on realized CC genomes. We report power analyses from extensive simulations and examine several key considerations: 1) the number of strains and biological replicates, 2) the QTL effect size, 3) the presence of population structure, and 4) the distribution of functionally distinct alleles among the founder strains at the QTL. We also provide general power estimates to aide in the design of future experiments. All analyses were conducted with our R package, SPARCC (Simulated Power Analysis in the Realized Collaborative Cross), developed for performing either large scale power analyses or those tailored to particular CC experiments.


Assuntos
Mapeamento Cromossômico , Camundongos de Cruzamento Colaborativo/genética , Cruzamentos Genéticos , Locos de Características Quantitativas , Alelos , Animais , Cromossomos , Frequência do Gene , Genética Populacional , Genoma , Estudo de Associação Genômica Ampla , Haplótipos , Camundongos , Modelos Genéticos , Fenótipo , Reprodutibilidade dos Testes
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