Identification of candidate genes for pathogenicity of influenza A H1N1 virus infection
OBJECTIVE To conduct a genetic screen by systematic analysis of the phenotypes associated with influ-enza infection in the C57BL/6J(B6)and DBA/2J(D2)parental strains of mice and the lung transcript data of in-bred offspring BXD mice,and in order to find candidate genes that play a role in influenza virus infection.METHODS A total of 41 female BXD mice and parental strains B6 and D2 were selected and given influenza virus type A murine lung-adapted strains(H1N1,PR8M)between 8 and 12 weeks of age to obtain relevant phenotypic and gene expression quantity data,which were subjected to clustering analysis and weighted gene co-expression network analysis to conduct the correlations between modular trait values and viral load in mice.After expression quantitative trait seating analysis,Pearson correlation analysis,combined with information from three gene data-bases,namely,Genome-Wide Association Study(GWAS),Mouse Genome Informatics(MGI),and International Mouse Phenotyping Consortium(IMPC),the candidate functional genes related to influenza virus infection were analyzed and screened,and the genetic regulation of the genes was determined.Finally,the selected genes were subjected to pathway enrichment analysis.RESULTS The 24 219 genes were classified into 23 modules by cluste-ring analysis and weighted gene co-expression network analysis.Through the correlation analysis between modules and phenotypes,the MEred,MEgreen,and MEmagenta modules were found to be closely related to infection,and were considered as the core modules.The results KEGG and MPO enrichment analysis of the genes in the core module showed that influenza virus-related genes were significantly involved in several cellular immune-related pathways such as MAPK signaling pathway and TNF signaling pathway.Correlation analysis of genes in the core module with three phenotypes of influenza virus infection in BXD mice(body mass reduction,mean time to death and median body mass reduction after infection)revealed that the lung mRNA expression levels of 21 genes were correlated with all three phenotypes(P＜0.05).Further,the quantitative trait seating analysis of these 21 genes by GEMMA algorithm in GeneNetwork showed that Acpl2 was regulated by cis-genetic inheritance,and Dusp12,Ovol2,Catsper4,Tmc5,Acsm1,Fam81a,Rtn4,Rhpn1 were regulated by trans-genetic inheritance.Some of the genes were found to play a role in the immune pathway by combining the information from three gene databas-es,MGI,IMPC,and GWAS.CONCLUSION Through phylogenetic analysis,21 candidate genes related to influ-enza virus infection were identified in the mouse genome,and further functional validation should be performed to elucidate the genetic regulatory mechanisms involved in influenza virus infection.
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