High resolution mapping of trypanosomosis resistance loci Tir2 and Tir3 using F12 advanced intercross lines with major locus Tir1 fixed for the susceptible allele

Abstract

Background: Trypanosomosis is the most economically important disease constraint to livestock productivity in Africa. A number of trypanotolerant cattle breeds are found in West Africa, and identification of the genes conferring trypanotolerance could lead to effective means of genetic selection for trypanotolerance. In this context, high resolution mapping in mouse models are a promising approach to identifying the genes associated with trypanotolerance. In previous studies, using F2 C57BL/6J x A/J and C57BL/6J x BALB/cJ mouse resource populations, trypanotolerance QTL were mapped within a large genomic intervals of 20-40 cM to chromosomes MMU17, 5 and 1, and denoted Tir1, Tir2 and Tir3 respectively. Subsequently, using F6 C57BL/6J x A/J and C57BL/6J x BALB/cJ F6 advanced intercross lines (AIL), Tir1 was fine mapped to a confidence interval (CI) of less than 1 cM, while Tir2 and Tir3, were mapped within 5-12 cM. Tir1 represents the major trypanotolerance QTL.

Results: In order to improve map resolutions of Tir2 and Tir3, an F12 C57BL/6J x A/J AIL population fixed for the susceptible alleles at Tir1 QTL was generated. An F12 C57BL/6J x A/J AIL population, fixed for the resistant alleles at Tir1 QTL was also generated to provide an additional estimate of the gene effect of Tir1. The AIL populations homozygous for the resistant and susceptible Tir1 alleles and the parental controls were challenged with T. congolense and followed for survival times over 180 days. Mice from the two survival extremes of the F12 AIL population fixed for the susceptible alleles at Tir1 were genotyped with a dense panel of microsatellite markers spanning the Tir2 and Tir3 genomic regions and QTL mapping was performed. Tir2 was fine mapped to less than 1 cM CI while Tir3 was mapped to three intervals named Tir3a, Tir3b and Tir3c with 95% confidence intervals (CI) of 6, 7.2 and 2.2 cM, respectively.

Conclusions: The mapped QTL regions encompass genes that are vital to innate immune response and can be potential candidate genes for the underlying QTL.

Figure 1

Percentage survival over time following T. congolense challenge of (a) A/J, (b) C57BL/6J, (c) F12 AIL fixed for A/J alleles on Tir1 QTL (D17SS) and (d) F12 AIL fixed for C57BL/6J alleles on Tir1 (D17RR).

Figure 2

(A) Likelihood plot across Tir3 region and (B) Likelihood plot across Tir2 region. (A) LOD scores associated with microsatellite markers on MMU1 are shown for the genotyped F12 D17SS AIL. Only marker driven peaks above the experimental threshold labeled as a, b and c were accepted as putative QTL with the others being disregarded. (B) LOD scores associated with microsatellite markers of MMU5 are shown for the genotyped F12 D17SS AILs.