synchronizing allelic effects of opposing quantitative trait loci confirmed a major epistatic interaction affecting acute lung injury survival in mice同步等位反对证实一个主要数量性状的影响上位相互作用影响急性肺损伤小鼠的生存.pdf

Synchronizing Allelic Effects of Opposing Quantitative Trait Loci Confirmed a Major Epistatic Interaction Affecting Acute Lung Injury Survival in Mice 1,2 2 2 Daniel R. Prows *, William J. Gibbons Jr. , Benjamin B. Burzynski 1 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America, 2 Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America Abstract Increased oxygen (O ) levels help manage severely injured patients, but too much for too long can cause acute lung injury 2 (ALI), acute respiratory distress syndrome (ARDS) and even death. In fact, continuous hyperoxia has become a prototype in rodents to mimic salient clinical and pathological characteristics of ALI/ARDS. To identify genes affecting hyperoxia-induced ALI (HALI), we previously established a mouse model of differential susceptibility. Genetic analysis of backcross and F2 populations derived from sensitive (C57BL/6J; B) and resistant (129X1/SvJ; X1) inbred strains identified five quantitative trait loci (QTLs; Shali1-5) linked to HALI survival time. Interestingly, analysis of these recombinant populations supported opposite within-strain effects on survival for the two major-effect QTLs. Whereas Shali1 alleles imparted the expected survival time effects (i.e., X1 alleles increased HALI resistance and B alleles increased sensitivity), the allelic effects of Shali2 were reversed (i.e., X1 alleles increased HALI sensitivity and B alleles increased resistance). For in vivo validation of these inverse allelic effects, we constructed reciprocal congenic lines to synchronize the sensitivity or resistance