Fine mapping and characterization of candidate lung tumor resistance genesfor the Par2 locus on mouse chromosome 18

In number of recent studies, a lung tumor resistance locus designated eithe r Par2 or Pas7 was mapped to distal chromosome 18 in crosses between suscep tible A/J and more resistant BALB/c mice. This locus is important in that i t accounts for as much as 60% of the difference in lung tumor susceptibilit y between the A/J and BALB/c mice, both of which contain the susceptible al lele of Kras2, a marker and strong candidate for the major lung tumor susce ptibility gene on mouse chromosome 6. We have now fine-mapped the Par2 locu s by using congenic mice that were constructed by placing part of chromosom e 18 from the susceptible A/J onto the genetic background of lung tumor-res istant BALB/c mice. After 7 generations of backcrossing, N7 mice that carri ed 28 cM of the A/J quantitative trait locus (QTL) region were crossed to t he BALB/c to generate the N8 generation. Congenic strains (N8) that contain various QTL regions were generated. N9 mice, generated from N8 males x 3 B ALB/c females, were genotyped in the region of the Par2 locus and treated w ith an initiating dose of urethane and allowed to form lung tumors over 6 m onths. The mice were killed and the lung tumors counted. With this cross th e Par2 locus was narrowed to a 6-cM region. Potential candidate genes in th is region include Smad4, Smad2 and Dcc. Previously, we excluded Smad4 and S mad2 as candidates for Par2 based on the lack of functional polymorphism(s) and differential expression in lungs from A/J and BALB/c mice. In this stu dy, no polymorphism of the coding sequence of Dcc was observed between A/J and BALB/c mice. Further, fine mapping and positional cloning are required for the identification of the Par2 gene.