TY - JOUR
T1 - Expression quantitative trait loci for extreme host response to influenza A in pre-collaborative cross mice
AU - Bottomly, Daniel
AU - Ferris, Martin T.
AU - Aicher, Lauri D.
AU - Rosenzweig, Elizabeth
AU - Whitmore, Alan
AU - Aylor, David L.
AU - Haagmans, Bart L.
AU - Gralinski, Lisa E.
AU - Bradel-Tretheway, Birgit G.
AU - Bryan, Janine T.
AU - Threadgill, David W.
AU - De Villena, Fernando Pardo Manuel
AU - Baric, Ralph S.
AU - Katze, Michael G.
AU - Heise, Mark
AU - McWeeney, Shannon K.
PY - 2012/2
Y1 - 2012/2
N2 - 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.
AB - 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.
KW - Collaborative cross
KW - EQTL
KW - Host response
KW - Influenza
KW - Mouse Collaborative Cross
KW - Mouse Genetic Resource
KW - SEM
UR - http://www.scopus.com/inward/record.url?scp=84863996209&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863996209&partnerID=8YFLogxK
U2 - 10.1534/g3.111.001800
DO - 10.1534/g3.111.001800
M3 - Article
C2 - 22384400
AN - SCOPUS:84863996209
SN - 2160-1836
VL - 2
SP - 213
EP - 221
JO - G3: Genes, Genomes, Genetics
JF - G3: Genes, Genomes, Genetics
IS - 2
ER -