Reciprocal backcross mice confirm major loci linked to hyperoxic acute lung injury survival time

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Physiological Genomics (Impact Factor: 2.37). 06/2009; 38(2):158-68. DOI: 10.1152/physiolgenomics.90392.2008
Source: PubMed


Morbidity and mortality associated with acute lung injury (ALI) and acute respiratory distress syndrome remain substantial. Although many candidate genes have been tested, a clear understanding of the pathogenesis is lacking, as is our ability to predict individual outcome. Because ALI is a complex disease, single gene approaches cannot easily identify effectors that must be treated concurrently. We employed a strategy to help identify critical genes and gene combinations involved in ALI mortality. Using hyperoxia to induce ALI, a mouse model for genetic analyses of ALI survival time was identified: C57BL/6J (B) mice are sensitive (i.e., die early), whereas 129X1/SvJ (S) mice are significantly more resistant, but with low penetrance. Segregation analysis of reciprocal F(2) mice generated from B and S strains revealed significant sex, cross, and parent of origin effects. Quantitative trait locus (QTL) analysis identified five chromosomal regions significantly linked to hyperoxic ALI survival time (named Shali1-Shali5). Further analyses demonstrated that both parental strains contribute resistance alleles to their offspring and that the phenotype demonstrated parent of origin effects. To validate earlier findings, we generated and tested mice from all eight possible B-S-derived backcrosses. Results from segregation and QTL analyses of 935 backcrosses, alone and combined with the previous 840 B-S-derived F(2) population, further supported the highly significant QTLs on chromosomes 1 (Shali1) and 4 (Shali2) and confirmed that the sex, cross, and parent of origin all contribute to survival time with hyperoxic ALI.

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    • "Analysis of F2 mice identified 5 QTLs (designated Shali for Survival time with hyperoxic acute lung injury) significantly linked to HALI survival time on Chr 1 (Shali1 and the male-specific QTL, Shali5), Chr 4 (Shali2), Chr 9 (Shali4), and Chr 15 (Shali3) [25]. The large backcross population also identified Shali1, Shali2, and Shali3 and, along with the F2 data, consistently suggested that the Shali1 locus on Chr 1 and the Shali2 locus on Chr 4 had opposing allelic effects on overall HALI survival time within each inbred strain [26]. Specifically, QTL analysis of recombinants derived from the X1 and B progenitor strains determined that Shali1 directly correlated with the overall survival time trait of the parental strains, with resistant X1 strain alleles leading to an increased mean HALI survival time and sensitive B strain alleles yielding increased sensitivity. "
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