Expression Quantitative Trait Loci for Extreme Host Response to Influenza A in Pre-Collaborative Cross Mice

G3: Genes, Genomes, Genetics

Michael G. Katze¹  Elizabeth Rosenzweig¹  Bart L. Haagmans³  Fernando Pardo-Manuel de Villena¹¹  Janine T. Bryan¹  Mark Heise⁷  Ralph S. Baric^2,8  Birgit G. Bradel-Tretheway¹  Daniel Bottomly⁴  Shannon K. McWeeney^2,9  Alan Whitmore⁵  David W. Threadgill²  Lauri D. Aicher¹  Martin T. Ferris⁵  David L. Aylor⁶  Lisa E. Gralinski¹⁰ 

[1] Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, 98195Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, 98195Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, 98195Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, 98195;Department of Genetics, North Carolina State University, Raleigh, North Carolina, 27695Department of Genetics, North Carolina State University, Raleigh, North Carolina, 27695Department of Genetics, North Carolina State University, Raleigh, North Carolina, 27695;Erasmus Medical Center, 3000 CA Rotterdam, the NetherlandsErasmus Medical Center, 3000 CA Rotterdam, the NetherlandsErasmus Medical Center, 3000 CA Rotterdam, the Netherlands;Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon 97239Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon 97239Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon 97239Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon 97239;Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599;Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, 27514Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, 27514Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, 27514Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, 27514;Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599;Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, 27599Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, 27599Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, 27599Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, 27599Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, 27599Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599;Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon 97239Division of Bioinformatics and Computational Biology, Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon 97239Division of Biostatistics, Public Health & Preventative Medicine, Oregon Health & Science University, Portland, Oregon 97239OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon 97239Division of Bioinformatics and Computational Biology, Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon 97239Division of Biostatistics, Public Health & Preventative Medicine, Oregon Health & Science University, Portland, Oregon 97239OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon 97239Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon 97239Division of Bioinformatics and Computational Biology, Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon 97239Division of Biostatistics, Public Health & Preventative Medicine, Oregon Health & Science University, Portland, Oregon 97239OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239Division of Bioinformatics and Computational Biology, Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon 97239Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon 97239Division of Bioinformatics and Computational Biology, Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon 97239Division of Biostatistics, Public Health & Preventative Medicine, Oregon Health & Science University, Portland, Oregon 97239OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239Division of Biostatistics, Public Health & Preventative Medicine, Oregon Health & Science University, Portland, Oregon 97239Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon 97239Division of Bioinformatics and Computational Biology, Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon 97239Division of Biostatistics, Public Health & Preventative Medicine, Oregon Health & Science University, Portland, Oregon 97239OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Oregon Clinical and Translational Research Institute, Oregon Health & Science University, Portland, Oregon 97239Division of Bioinformatics and Computational Biology, Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, Oregon 97239Division of Biostatistics, Public Health & Preventative Medicine, Oregon Health & Science University, Portland, Oregon 97239OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon 97239;Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, 27599Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, 27599Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, 27599Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, 27599;Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, 27514Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, 27514Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, 27514Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, 27514Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Portland, Oregon 97006Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, 27514

关键词: eQTL;    influenza;    collaborative cross;    host response;    SEM;    Mouse Collaborative Cross;    Mouse Genetic Resource;   

DOI  :  10.1534/g3.111.001800

学科分类：生物科学（综合）

来源: Genetics Society of America

【 摘 要 】

Outbreaks of influenza occur on a yearly basis, causing a wide range of symptoms across the human population. Although evidence exists that the host response to influenza infection is influenced by genetic differences in the host, this has not been studied in a system with genetic diversity mirroring that of the human population. Here we used mice from 44 influenza-infected pre-Collaborative Cross lines determined to have extreme phenotypes with regard to the host response to influenza A virus infection. Global transcriptome profiling identified 2671 transcripts that were significantly differentially expressed between mice that showed a severe (“high”) and mild (“low”) response to infection. Expression quantitative trait loci mapping was performed on those transcripts that were differentially expressed because of differences in host response phenotype to identify putative regulatory regions potentially controlling their expression. Twenty-one significant expression quantitative trait loci were identified, which allowed direct examination of genes associated with regulation of host response to infection. To perform initial validation of our findings, quantitative polymerase chain reaction was performed in the infected founder strains, and we were able to confirm or partially confirm more than 70% of those tested. In addition, we explored putative causal and reactive (downstream) relationships between the significantly regulated genes and others in the high or low response groups using structural equation modeling. By using systems approaches and a genetically diverse population, we were able to develop a novel framework for identifying the underlying biological subnetworks under host genetic control during influenza virus infection.

【 授权许可】

Unknown