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

ArticleinPhysiological Genomics 38(2):158-68 · June 2009with83 Reads
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.
    • "An initial screen of 6–12 week old females for 18 inbred mouse strains revealed that C57BL/6J inbred mice (B) had short survival times (i.e., sensitive), but 129X1/SvJ inbred mice (X1) survived considerably longer (i.e., resistant) [9]. Although penetrance of the prolonged resistance in X1 mice was only about 30–35%, two separate QTL analyses of large segregating populations (i.e., 840 F 2 and 935 N 2 backcross mice) generated from the B and X1 progenitor strains both identified the same two highly significant QTLs (Shali1 on Chr1 and Shali2 on Chr4; designated Survival time with hyperoxic acute lung injury) linked to differential survival time [8,10]. In silico analyses predicted that the major allelic effects of Shali1 and Shali2 on survival time opposed each other: X1 alleles of Shali1 and B alleles of Shali2 prolonged survival, whereas B alleles of Shali1 and X1 alleles of Shali2 reduced survival times. "
    [Show abstract] [Hide abstract] ABSTRACT: Mortality associated with acute lung injury (ALI) remains substantial, with recent estimates of 35–45% similar to those obtained decades ago. Although evidence for sex-related differences in ALI mortality remains equivocal, death rates differ markedly for age, with more than 3-fold increased mortality in older versus younger patients. Strains of mice also show large differences in ALI mortality. To tease out genetic factors affecting mortality, we established a mouse model of differential hyperoxic ALI (HALI) survival. Separate genetic analyses of backcross and F 2 populations generated from sensitive C57BL/6J (B) and resistant 129X1/SvJ (X1) progenitor strains identified two quantitative trait loci (QTLs; Shali1 and Shali2) with strong, equal but opposite, within-strain effects on survival. Congenic lines con
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    • "Our previous QTL analysis of a large F 2 population identified five putative QTLs affecting overall survival time to HALI [25]. Two of these QTLs, Shali1 and Shali2, were validated as major effectors in a separate large backcross analysis [26]. Results of these recombinant populations generated from the B and X1 progenitor strains suggested that Shali1 increased HALI resistance and MST when carried in homozygous X1 strain alleles, but Shali2 increased resistance when homozygous for B strain alleles. "
    [Show abstract] [Hide abstract] ABSTRACT: Increased oxygen (O(2)) levels help manage severely injured patients, but too much for too long can cause acute lung injury (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 F(2) 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 alleles of Shali1 and Shali2 within the same strain. Specifically, B-derived Shali1 or Shali2 QTL regions were transferred to X1 mice and X1-derived QTL segments were transferred to B mice. Our previous QTL results predicted that substituting Shali1 B alleles onto the resistant X1 background would add sensitivity. Surprisingly, not only were these mice more sensitive than the resistant X1 strain, they were more sensitive than the sensitive B strain. In stark contrast, substituting the Shali2 interval from the sensitive B strain onto the X1 background markedly increased the survival time. Reciprocal congenic lines confirmed the opposing allelic effects of Shali1 and Shali2 on HALI survival time and provide unique models to identify their respective quantitative trait genes and to critically assess the apparent bidirectional epistatic interactions between these major-effect loci.
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