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Published ahead of print on July 26, 2007, doi:10.1165/rcmb.2006-0162OC

Am. J. Respir. Cell Mol. Biol., Volume 38, Number 1, January 2008, 68-77

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Submitted on May 4, 2006
Revised on July 24, 2007

Reciprocal Congenic Lines of Mice Capture the Aliq1 Effect on Acute Lung Injury Survival Time

Daniel R Prows1*, Amanda P Hafertepen2, Abby V Winterberg2, William J Gibbons, Jr.2, Scott C Wesselkamper3, Jonathan B Singer4, Annie E Hill5, Joseph H Nadeau5, and George D Leikauf6

1 Division of Human Genetics, Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA; Department of Environmental Health, University of Cincinnati, Center for Environmental Genetics, Cincinnati, OH, USA, 2 Division of Human Genetics, Children's Hospital Medical Center, Cincinnati, OH, USA, 3 Department of Environmental Health, University of Cincinnati, Center for Environmental Genetics, Cincinnati, OH, USA, 4 Massachusetts Institute of Technology, Whitehead Institute for Biomedical Research, Cambridge, MA, USA, 5 Genetics Department, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Center for Human Genetics, University Hospitals of Cleveland, Cleveland, OH, USA, 6 Department of Environmental Health, University of Cincinnati, Center for Environmental Genetics, Cincinnati, OH, USA; Center for Human Genetics, University Hospitals of Cleveland, Cleveland, OH, USA; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA

* To whom correspondence should be addressed. E-mail: daniel.prows{at}cchmc.org.

Acute lung injury (ALI) is a devastating condition resulting from diverse causes. Genetic studies of human populations indicate that ALI is a complex disease with substantial phenotypic variance, incomplete penetrance, and gene-environment interactions. To identify genes controlling ALI mortality, we previously investigated mean survival time (MST) differences between sensitive A/J (A) and resistant C57BL/6J (B) mice in ozone using quantitative trait locus (QTL) analysis. MST was significantly linked to QTLs (Aliq1-3) on chromosomes 11, 13, and 17, respectively. Additional QTL analyses of separate and combined backcross and F2 populations supported linkage to Aliq1 and Aliq2, and established significance for previously suggestive QTLs on chromosomes 7 and 12 (named Aliq5 and Aliq6, respectively). Decreased MSTs of corresponding chromosome substitution strains (CSSs) verified the contribution of most QTL-containing chromosomes to ALI survival. Multi-locus models demonstrated that three QTLs could explain the MST difference between progenitor strains, agreeing with calculated estimates for number of genes involved. Based on results of QTL genotype analysis, a double CSS (B.A-6,11) was generated that contained Aliq1 and Aliq4 chromosomes. Surprisingly, MST and pulmonary edema following exposure of B.A-6,11 mice were comparable to B mice, revealing an unpredicted loss of sensitivity compared to separate CSSs. Reciprocal congenic lines for Aliq1 captured the corresponding phenotype in both background strains and further refined the QTL interval. Together, these findings support most of the previously identified QTLs linked to ALI survival and established lines of mice to further resolve Aliq1.






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