Linkage disequilibrium and physical mapping of Pas1 in mice

Abstract

By using linkage disequilibrium (LD) analysis in 21 strains of known susceptibility to lung cancer and by assembling a YAC contig, we mapped to a approximately 1.5-Mb region on distal mouse chromosome 6 the Pas1 locus, the major determinant of lung cancer predisposition in mice. Our results, on the basis of haplotype and phenetic analysis, suggest that the Pas1(s) susceptibility allele is shared by several mouse-inbred strains of independent origin, which show either high or intermediate predisposition to lung tumorigenesis. Therefore, the Pas1(s) allele is probably derived from an ancestral mouse rather than from independent mutations of the same gene. We showed the feasibility of LD in common inbred strains for the fine mapping of disease loci, and provided the biological basis and the reagents for the cloning of the Pas1 gene.

Figure 1

Composite genetic and physical map of the telomeric region of mouse chromosome 6 for LD mapping of the Pas1 locus. Statistical significance of LD between marker polymorphisms and phenotype was estimated by Fisher’s exact test and expressed as negative logarithm of P values (−log P). The dotted line represents the P = 0.01 (−log P = 2) cutoff significance value. Each point represents either a single genetic marker or multiple markers in the same position with the same −log P value (Table 1).

Figure 2

Phenetic tree of a 21-mouse inbred strain of known susceptibility to lung carcinogenesis, obtained by the Fitch–Margoliash distance matrix method, with marker polymorphisms mapped in the YAC contig containing the Pas1 gene. The tree represents the estimated relationships among the strains for that short chromosomal region (∼1.5Mb), and it therefore provides an estimation of the phylogenetic origin of the Pas1^s allele. The gray box contains the putative Pas1^s mice, which include the A/J, SWR/J, and BALB/c strains proved by genetic linkage to carry the Pas1^s allele. Also, the putative Pas1^r strains include the C57BL/6J, C3H/HeJ, and M. spretus mice, established by genetic linkage studies as Pas1^r strains.