Genetic control of neuroadapted Sindbis virus replication in female mice maps to chromosome 2 and associates with paralysis and mortality

Neuroadapted Sindbis virus (NSV) infection of mice causes hindlimb paralysi s and 100% mortality in the C57BL/6 mouse strain, while adults of the BALB/ cBy mouse strain are resistant to fatal encephalomyelitis. Levels of viral RNA are higher in the brains of infected C57BL/6 mice than in BALB/cBy mice (D. C. Thach et al., J. Virol. 74:6156-6161, 2000). These phenotypic diffe rences between the two strains allowed us to map genetic loci involved in m ouse susceptibility to NSV and to find relationships between mortality, par alysis, and viral RNA levels. Analysis of percent mortality in H2-congenic and F-1 mice suggested that the H2 locus, sex linkage, and imprinting were not involved in determining susceptibility and that resistance was partiall y dominant over susceptibility. Segregation analysis using CXB recombinant inbred (RI) mice indicated that the percent mortality was multigenic. Inter val mapping detected a suggestive quantitative trait locus (QTL) on chromos ome 2 near marker D2Mit447. Analysis of paralysis in the RI mice detected t he same suggestive QTL. Viral RNA level in F-1 mice was intermediate. Inter val mapping using viral RNA levels in RI mice detected a significant QTL ne ar marker D2Mit447 that explained 69% of the genetic variance. This QTL was confirmed in F2 mice and was designated as Nsv1. Viral RNA level, percent paralyzed, and percent mortality were linearly correlated (r = 0.8 to 0.9). These results indicate that mortality, paralysis, and viral RNA levels are related complex traits and that Nsv1 controls early viral load and determi nes the likelihood of paralysis and death.