Experiment
Yersinia pestis is a Gram-negative bacterium agent of the bubonic and pneumonic plague. In this study Mus-spretus derived SEG/Pas mice, which are exceptionally resistant to Y. pestis, and C57BL/6J mice, which are highly susceptible, were backcrossed to identify QTL accounting for the differences in susceptibility. The phenotype was scored as a binary trait, death or survival.
322 female (C57BL/6J x SEG/Pas) x C57BL/6J backcrossed mice were challenged subcutaneously with Y.pestis CO92. 190 females survived the infection, 59%. SNP genotyping was performed using 721polymorphic markers covering the entire genome of the backcrossed females. Three QTL significantly associated with survival were identified on Chromosomes 3, 4 and 6, all with dominant, SEG/Pas, protective alleles.
Yprl1, Y. pestis resistance locus 1, was identified on mouse Chromosome 3 with a LOD=>2.77, peaking at 116.0 Mb with a confidence interval between 89.0-139.0 Mb. The effect on survival was estimated at 20.6% with a highly significant increase in resistance rising from 48.5% in mice homozygous for the B6 allele, to 68.1% in the B/S heterozygous mice. [Fig 3. Table 1.] Il6ra maps close to Yplr1 and has been shown to have a role in resistance to bacteria or viruses.
Yprl2, Y pestis resistance locus 2, was identified on mouse Chromosome 4 with a LOD=2.77, peaking with maker Tlr4 at 62.0 Mb, with a confidence interval of 6.0-90.0 Mb. The effect on survival was also estimated at 20.3% with the SEG/Pas allele conferring increased resistance. [Fig 3. Table 1.] The main candidate gene in the Yplr2 region is the toll-like receptor 4 gene (Tlr4), involved in the recognition of the outer membrane of Gram-negative bacteria.
Yprl3, Y. pestis resistance locus 3, was identified on mouse Chromosome 6, also with a LOD=>2.77. It peaked at 95.0 Mb with a confidence interval between 53.0-134.0 Mb and accounted for 20.4% of increased resistance. [Fig 3. Table 1.] QTL Msts2 maps close to Yplr3 and influences survival following exposure to bacterial diseases. Nod1 is a candidate gene, Nod1 deficiency results in increased susceptibility to various Gram-negative bacteria.
Yplr1, Yplr2 and Yplr3 appear to function independently from one another and to function additively conferring increased survival. However, as mice homozygous for the B6 allele
at the 3 QTL were significantly more resistant than B6 mice, other resistance genes remain to be identified.
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