Summary |
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Variant origin |
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Variant description |
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Notes |
Pas1 exhibits additive inheritance.
Candidate Genes
Microarray gene expression analysis was used to identify candidate genes for tumor resistant and tumor susceptibility QTLs Par8,2,3,4 and and Pas1-4, respectively. Transcripts found within the flanking markers of each QTL were identified and matched to transcripts from Affymetrix probe sets. RNA from A/J, BALB/cJ, C57BL/6J, and SM/J were used for analysis. Mapping and Phenotype information for this QTL, its variants and associated markersJ:56444The authors constructed an ~1.5-2 Mb YAC contig around the Pas1 susceptibility region on mouse Chromosome 6. The order of markers in this contig was: D6Mit57 - Kras - D6Mit14 - D6Mit303 - Y95m1f5 - Y95m5e3 - Krag - D6Mit200 - D6Mit137 - Pas1 - Y94m2h10 -Y83m2c2 - D6Mit371 - D6Mit294 - D6Mit295 - D6Mit15 - D6Mit201 - Y78m6g9 - D6Mit373 - D6Mit26 - Y97m1a3 - Y88m6a6 - Y91m8f11 - D6Mit304. The authors then performed linkage disquilibrium (LD) analysis in 21 strains of known susceptibility to lung cancer. A significant LD was found for markers extending across the whole YAC contig. The two highest LD values were associated with the Kras2 and D6Mit26 markers. The possibility that two Pas1 genes might exist located near both markers could not be ruled out. J:48996Linkage analysis of AXB and BXA RI (recombinant inbred) strains confirmed Pas1 and revealed 3 new loci (Pas11, Pas12, Pas13) modifying pulmonary adenoma susceptibility. Progenitor strain A/J (A) is highly susceptible to both spontaneous and chemically induced lung tumors while progenitor strain C57BL/6J (B) is highly resistant. Analysis of 458 microsatellite markers confirmed Pas1 association (LOD = 5.9 at Kras2) with disease phenotype on mouse chromosome 6 at 72.2 cM. Authors propose Kras (71.2 cM) as the gene for Pas1. Pas11 maps to mouse chromosome 10 at 21 cM (LOD = 2.4 at D10Mit126). Pas12 (LOD = 2.4 at D17Mit11) maps to 21.95 cM on mouse chromosome 17, and Pas13 (LOD = 2.4 at D19Mit10) maps to 47 cM on mouse chromosome 19. Pas11, Pas12, and Pas13 are believed to be modifiers of Pas1.J:21801Linkage analysis was performed on 37 AXB and BXA (A= A/J, B= C57BL/6J) recombinant inbred strains to identify QTLs associated with pulmonary adenoma susceptibility. Significant association was detected at 71 cM on mouse Chromosome 6 near Kras (P<0.01) and at 23 cM on mouse Chromosome 17 near the H2 locus (P<0.01). These loci are named Pas1 and Pas2, respectively. Animals homozygous for A/J-derived alleles at Pas1 exhibit increased frequency of pulmonary adenomas. Pas1 accounted for 40% of the phenotypic variance. Animals homozygous for A/J-derived alleles at Pas2 exhibit increased frequency of pulmonary adenomas. Pas2 accounted for 18% of the phenotypic variance. A (C57BL/6JOlaHsd x A/JOlaHsd)F2 intercross population and (C57BL/6JOlaHsd x A/JOlaHsd)F1 x A/JOlaHsd and (C57BL/6JOlaHsd x A/JOlaHsd)F1 x C57BL/6JOlaHsd backcross populations were also analyzed for linkage to pulmonary adenoma susceptibility. Significant association was identified at Pas1 (71 cM) on chromosome 6 (P<0.000 at Kras), Pas2 (19 cM) on chromosome 17 (P<0.000 at Lta),Pas3 (15 cM) on chromosome 19 (P<0.049 at D19Mit16) and Pas4 (48 cM) on chromosome 9 (P<0.000 at D9Mit11).All four loci appear to exhibit an additive mode of inheritance. Variation at Kras locus accounted for 60% of the total variation in this cross while the other three loci (Pas2, Pas3, Pas4) combined account for 15% of the total variation. Pas3 alone accounts for 1.8% of the phenotypic variation while Pas4 alone accounts for 3.7% of the phenotypic variation.J:17778Analysis of a series of recombinant inbred strains (AXB, BXA) that developed from reciprocal crosses between a highly susceptible strain A/J and a highly resistant strain C57BL/6J, revealed a statistically significant three fold difference in lung tumor susceptibility on the basis of the Kras genotype. Further analysis of individual mice from an (C57BL/6J x A/J)F2 cross also demonstrated a three fold difference in tumor susceptibility on the basis of Kras alleleic variation.F2 data suggest that the A/J allele of Kras is dominant over the allele for C57BL/6J.However, data also show that there is not a direct correspondence between Kras genotype and lung tumor susceptibility. In an indiviual animal or single inbred strain the Kras genotype alone is not predictive. This finding is probably a reflection of the polygenic nature of of the inheritance of lung tumor susceptibility.A three-locus genetic model derived from analysis of the AXB and BXA RI strains proposes one dominant locus (Pas1) and two minor loci Pas2 and Pas3 determining lung tumor susceptibility. See J:8075. |
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References |
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Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO) |
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last database update 10/22/2024 MGI 6.24 |
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