Experiment
The systemic inoculation of mice with Rift Valley fever virus (RVFV) produces major pathological features of sever human disease, notably hepatitis and encephalitis.
Owing to the possibility of acute disease and the ease of aerosolization of infectious viral particles, RVFV outbreaks and research are carefully monitored by government agencies to prevent its potential use in bioterrorism.
Wild derived inbred MBT/Pas (MBT) mice are the most susceptible to infection with RVFV virulent strains, whereas BALB/cByJ (BALB/c) mice show the highest resistance among tested strains.
To identify the genetic components underlying the susceptibility to RVFV infection in the MBT mice a whole-genome scan was performed to evaluate 546 (BALB /MBT)) F2 progeny. The F2 population showed intermediate survival curves, significantly different from both parental strains. Male mice presented a shorter time to death and a higher mortality rate than females in the F2 population.
259 polymorphic markers on all autosomal chromosomes and on the X chromosome were assayed.
Of the 546 RVFV infected mice, 41 (7.5%) survived more than 9 days post infection. Nonparametic interval mapping, with the time of death after infection as a trait, was performed on the 505 non-surviving animals.
One significant QTL, Rvfv1 (Rift Valley fever susceptibility 1) was detected on Chr 2, with a peak LOD=4.58 at 168.2 Mb near, p=0.005; with a confidence interval spanning between D2Mit306 and rs3664044.
Two suggestive QTL were also detected:
Rvfs2, Rift Valley fever susceptibility 2, mapped to Chr 11, LOD=2.99, p=0.154 at 113.9 Mb; with a confidence interval spanning between rs13481186 and D11Mit69. And,
Rvfs3, Rift Valley fever susceptibility 3, mapped to Chr 5, LOD=2.95, p=0.160 at 61.6 Mb; with a confidence interval spanning between D5Mit125 and rs4225536.
In a two part model, combining the binary trait (survival/death) and the quantitative trait (survival time) one significant and one suggestive QTL were detected:
Rvfs4, Rift Valley fever susceptibility 4, mapped to Chr 11, LOD=5.12; p=0.022 at 112.8 Mb; and Rvfs5, Rift Valley fever susceptibility 5, mapped to Chr 2, LOD=4.55, p=0.075 at 68.2 Mb. The loci on Chr 2 and Chr 11 achieved the 5% genome-wide significance level only with the nonparametric interval mapping and the two part model, respectively. No QTL were found on the X chromosome which could have contributed to the sex difference in susceptibility.
The 3 QTL, Rvfs1-3, collectively explain 8.3% of the phenotypic variance in the F2 population whereas sex had the strongest effect on the phenotype, explaining 10.1% of the variance.
Congenic strains C.MBT-Rvfs1, C.MBT-Rvfs2 and C.MBT-Rvfs3 were generated to confirm the individual effects of the 3 QTL on the susceptibility to the RVFV infeection. The 3 congenic strains were challenged with 100 PFU of RVFV ZH548 strain. The results confirmed the effects of the three QTL on the susceptible phenotype. However, unexpectedly, C.MBT-Rvfs3 females survived significantly longer than BALB/c females. No significant differences were observed between BALB/c mice and animals heterozygous for the haplotypes of Rvfs1, Rvfs2, and Rvfs3; indicating that these QTL have a recessive effect while on the BALB/c genetic background.
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