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Variant origin |
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Variant description |
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Phenotypes |
View phenotypes and curated references for all genotypes (concatenated display).
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Notes |
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. In a previous study, the Par2 (pulmonary adenoma resistance 2) locus was localized to a 2.4 Mb interval between D18Mit103 (44 cM) and D18Mit188 (47 cM). The current study examines possible candidate genes found within the Par2 critical region. These genes are 2310002L13Rik, Stard6 (44 cM), Poli, Mbd2 (44 cM), and Dcc (45 cM). Poli shows the strongest evidence as a Par2 candidate gene. Sequence analysis revealed 25 nucleotide polymorphisms between lung tumor susceptible strain A/J and lung tumor resistantstrain BALB/cJ resulting in 10 amino acid differences. Two different Poli alternative transcripts (exon 4a and exon 2d) were also observed in lung mRNA of A/J and BALB/cJ animals. The exon 4a isoform encodes a truncated protein due to a premature stop codon, and the exon 2d isoform results in the splicing out of exon 2 without disruption of the reading frame. Resistant strain BALB/cJ produces decreased levels of functional Poli protein due to increased expression of the exon 4a isoform. The Poli protein also displays functional differences and substrate preference between A/J and BALB/cJ strains.
Mapping and Phenotype information for this QTL, its variants and associated markersJ:36219One hundred thirty (A/JSlc x BALB/cByJJcl)F1 x A/JSlc backcross mice exhibiting extremes of tumor multiplicity after i.p. injection of urethane were genotyped for 63 simple sequence repeat (SSR) loci. Statistical analysis indicated significant linkage of the tumor resistance gene (Par2) to mouse Chromosome 18, primarily at the D18Mit103 locus with a maximun LOD score of 12 (p<0.000001).J:67467Study of 81 recombinant congenic strains localized the Par2 locus to a 6 cM interval on mouse Chromosome 18 spanning 44 cM - 50 cM flanked by D18Mit103 and D18Mit162. Congenic strains were constructed by backcrossing susceptible donor strain A/J to resistant recipient strain BALB/c for 9 generations, selecting for the Par2 region and recombination events across the Par2 region at each generation. Parental strain A/J develops more lung tumors when induced with urethane compared to BALB/c. Susceptibility to pulmonary adenoma after treatment with urethane was observed in congenic animals retaining A/J-derived DNA across D18Mit103 and D18Mit162. Possible candidate genes in the Par2 interval include Smad4, Smad2, and Dcc. J:70565The Par2 locus was refined to a 0.5 cM interval on mouse Chromosome 18 between D18Mit103 (44 cM) and D18Mit188 (47 cM) by recombinant congenic analysis. Semi-congenic lines were constructed by introgression of the Par2 locus (approximately 25 cM from D18Mit123 to D18Mit144) from adenoma resistant inbred strain BALB/cByJJcl onto the genetic background of adenoma susceptible inbred strain A/JSlc for 4-5 backcross generations. Nine male mice congenic (N6-N7) for segments of the Par2 interval from C57BL/6JJcl on a BALB/cByJJcl background were bred to female A/JSlc mice [(A/JSlc x CByJJcl.B6-Par2C57BL/6JJcl)F1] and the resulting 197 progeny were used to fine map the locus. Four microsatellite markers showed tight linkage to Par2. D18Mit103 and D18Mit188 flank the Par2 interval while D18Mit141 and D18Mit186 are internal to the Par2 interval. The BALB/cJJcl-derived allele at Par2 appears to have a dominant effect on urethane-induced lung tumor resistance. The presence of one BALB/cJJcl-derived Par2 allele reduces tumor multiplicity by 65% in male animals and by 51% in female animals. Dcc at 45 cM maps within the 0.5 cM Par2 interval and is considered a possible candidate gene. |
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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 10/29/2024 MGI 6.24 |
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