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. 2012 Jan;2(1):115-21.
doi: 10.1534/g3.111.001610. Epub 2012 Jan 1.

Chromosome y regulates survival following murine coxsackievirus b3 infection

Laure K Case, Leon Toussaint, Mohamad Moussawi, Brian Roberts, Naresha Saligrama, Laurent Brossay, Sally A Huber, Cory Teuscher

Chromosome y regulates survival following murine coxsackievirus b3 infection

Laure K Case et al. G3 (Bethesda). 2012 Jan.

Abstract

Coxsackievirus B3 (CVB3) contributes to the development of myocarditis, an inflammatory heart disease that predominates in males, and infection is a cause of unexpected death in young individuals. Although gonadal hormones contribute significantly to sex differences, sex chromosomes may also influence disease. Increasing evidence indicates that Chromosome Y (ChrY) genetic variants can impact biological functions unrelated to sexual differentiation. Using C57BL/6J (B6)-ChrY consomic mice, we show that genetic variation in ChrY has a direct effect on the survival of CVB3-infected animals. This effect is not due to potential Sry-mediated differences in prenatal testosterone exposure or to differences in adult testosterone levels. Furthermore, we show that ChrY polymorphism influences the percentage of natural killer T cells in B6-ChrY consomic strains but does not underlie CVB3-induced mortality. These data underscore the importance of investigating not only the hormonal regulation but also ChrY genetic regulation of cardiovascular disease and other male-dominant, sexually dimorphic diseases and phenotypes.

Keywords: heart disease; heterochromatin; sexual dimorphism.

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Figures

Figure 1
Figure 1
ChrY polymorphism influences susceptibility to CVB3-induced mortality. B6 and B6-ChrY consomic strains were infected with 100 or 50 PFU CVB3 and monitored for survival. Significance of observed differences were determined using a log-rank (Mantel-Cox) test (n = 5–20). The legend labels indicate the mouse strain donating ChrY to B6. P values in graph title represent overall P values, and asterisks in the legend labels represent significant differences in survival between B6 and the B6-ChrY consomic strains at the indicated virus dose. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.
Figure 2
Figure 2
CVB3-induced mortality exhibits a continuous distribution across the B6-ChrY consomic strains. The survival data obtained from the infection with 100 and 50 PFU in Figure 1 was combined for each consomic strain and plotted in a single graph. The legend labels indicate the mouse strain donating ChrY to B6. Significance of observed differences measured using a log-rank (Mantel-Cox) test (n = 5–20).
Figure 3
Figure 3
YNkt polymorphism influences the frequency of iNKT cells in B6-ChrY consomic strains. (A) Thymocytes were analyzed by flow cytometry for the percentage of iNKT cells by staining for TCRβ- and CD1d-expressing cells for each B6-ChrY consomic strain and then normalizing to B6 controls. The data are represented as the difference in the percentage iNKT from B6 (B6 is the baseline). The X-axis labels indicate the mouse strain donating ChrY to B6. The hatched line represents the normalized percentage of iNKT cells seen in B6-ChrYNkt-129/Pas mice. The significance of observed differences among the strains was determined by one-way ANOVA followed by Bonferroni's multiple comparison test. (B) Representative liver and thymus staining from (left) male B6-ChrY129F11/Pas inheriting the ChrY129F11/Pas from mice by natural breeding and (right) male B6-ChrYNkt-129/Pas mice carrying the ChrY129/Pas transmitted from male founder mice derived from 129/Pas embryonic stem cells. n ≥ 4 mice per group. **P < 0.01; ***P < 0.001; ****P < 0.0001.
Figure 4
Figure 4
Differences in CVB3-induced mortality are not the result of changes in adult serum testosterone levels among the B6-ChrY consomic strains. Serum testosterone was measured in 8-week-old B6-ChrY consomic male mice and compared with wild-type B6 by EIA. X-axis labels indicate the mouse strain donating ChrY to B6. Only B6-ChrYRF mice exhibited a significant elevation in testosterone compared with B6. Significance of observed differences was determined by one-way ANOVA, followed by a Dunnett’s multiple comparison test. n = 5 mice per strain. ***P ≤ 0.001.
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