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Synchronizing allelic effects of opposing quantitative trait loci confirmed a major epistatic interaction affecting acute lung injury survival in mice.

Prows DR, Gibbons WJ, Burzynski BB - PLoS ONE (2012)

Bottom Line: Interestingly, analysis of these recombinant populations supported opposite within-strain effects on survival for the two major-effect QTLs.Our previous QTL results predicted that substituting Shali1 B alleles onto the resistant X1 background would add sensitivity.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America. daniel.prows@cchmc.org

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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Genomic makeup of the Shali1 (Chr 1) and Shali2 (Chr 4) reciprocal congenic lines.A schematic overview comparing the 19 autosomes and X chromosome for the X1 (white) and B (black) control inbred strains along with the major Shali1 and Shali2 reciprocal congenic strains generated on the recipient X1 strain with B strain donor (X1.B-1A and X1.B-4BB) or recipient B strain with X1 strain donor (B.X1-1A and X1.B-4A). Small regions of unknown parental origin, which map between known SNP markers, are colored grey. MIT markers representing the peak linkage (LOD) score for the Shali1 and Shali2 QTLs are shown at the left, with approximate map location relative to chromosome and transferred region.
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pone-0038177-g002: Genomic makeup of the Shali1 (Chr 1) and Shali2 (Chr 4) reciprocal congenic lines.A schematic overview comparing the 19 autosomes and X chromosome for the X1 (white) and B (black) control inbred strains along with the major Shali1 and Shali2 reciprocal congenic strains generated on the recipient X1 strain with B strain donor (X1.B-1A and X1.B-4BB) or recipient B strain with X1 strain donor (B.X1-1A and X1.B-4A). Small regions of unknown parental origin, which map between known SNP markers, are colored grey. MIT markers representing the peak linkage (LOD) score for the Shali1 and Shali2 QTLs are shown at the left, with approximate map location relative to chromosome and transferred region.

Mentions: To validate these in vitro allelic predictions in vivo, we generated a pair of reciprocal congenic lines for these two QTLs on both parental background strains. Figure 2 displays a genomic overview of the most important reciprocal congenic strains for Shali1 (X1.B-1A and B.X1-1A) and Shali2 (X1.B-4BB and B.X1-4A) compared to each other and to the X1 and B inbred progenitor strains. Specific details of these lines are described below. From this illustration, one can quickly note the genomic differences between these congenic lines and their respective progenitor (recipient) strains.


Synchronizing allelic effects of opposing quantitative trait loci confirmed a major epistatic interaction affecting acute lung injury survival in mice.

Prows DR, Gibbons WJ, Burzynski BB - PLoS ONE (2012)

Genomic makeup of the Shali1 (Chr 1) and Shali2 (Chr 4) reciprocal congenic lines.A schematic overview comparing the 19 autosomes and X chromosome for the X1 (white) and B (black) control inbred strains along with the major Shali1 and Shali2 reciprocal congenic strains generated on the recipient X1 strain with B strain donor (X1.B-1A and X1.B-4BB) or recipient B strain with X1 strain donor (B.X1-1A and X1.B-4A). Small regions of unknown parental origin, which map between known SNP markers, are colored grey. MIT markers representing the peak linkage (LOD) score for the Shali1 and Shali2 QTLs are shown at the left, with approximate map location relative to chromosome and transferred region.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3362546&req=5

pone-0038177-g002: Genomic makeup of the Shali1 (Chr 1) and Shali2 (Chr 4) reciprocal congenic lines.A schematic overview comparing the 19 autosomes and X chromosome for the X1 (white) and B (black) control inbred strains along with the major Shali1 and Shali2 reciprocal congenic strains generated on the recipient X1 strain with B strain donor (X1.B-1A and X1.B-4BB) or recipient B strain with X1 strain donor (B.X1-1A and X1.B-4A). Small regions of unknown parental origin, which map between known SNP markers, are colored grey. MIT markers representing the peak linkage (LOD) score for the Shali1 and Shali2 QTLs are shown at the left, with approximate map location relative to chromosome and transferred region.
Mentions: To validate these in vitro allelic predictions in vivo, we generated a pair of reciprocal congenic lines for these two QTLs on both parental background strains. Figure 2 displays a genomic overview of the most important reciprocal congenic strains for Shali1 (X1.B-1A and B.X1-1A) and Shali2 (X1.B-4BB and B.X1-4A) compared to each other and to the X1 and B inbred progenitor strains. Specific details of these lines are described below. From this illustration, one can quickly note the genomic differences between these congenic lines and their respective progenitor (recipient) strains.

Bottom Line: Interestingly, analysis of these recombinant populations supported opposite within-strain effects on survival for the two major-effect QTLs.Our previous QTL results predicted that substituting Shali1 B alleles onto the resistant X1 background would add sensitivity.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America. daniel.prows@cchmc.org

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.

Show MeSH
Related in: MedlinePlus