Par8^SM/J
QTL Variant Detail

Summary

• QTL variant: Par8^SM/J
• Name: pulmonary adenoma resistance 8; SM/J
• MGI ID: MGI:5707300
• QTL: Par8 Location: Chr11:94063779-94063918 bp Genetic Position: Chr11, Syntenic

Variant origin

• Strain of Specimen: SM/J

Variant description

• Allele Type: QTL
• Inheritance: Dominant

Notes

SM/J-derived alleles confer dominant resistance to pulmonary adenomas at Par8 and Par3.

Candidate Genes

J:78525

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.

Pas1 is located between 48.2 cM and 75 cM on mouse Chromosome 6 and was identified in a cross between A/J and C57BL/6J. Candidate oncogenic genes identified by microarray analysis are hes related protein (**Note- this gene is not found in MGD), Ppih (cyclophilin H **Note-this gene is positioned on mouse Chromosome 4 in MGD), Ptpro, Mglap, Recql, and Bcat1 (ECA39). Other candidate genes identified via differential expression are Ccnd2 (cyclin D2) and high mobility group protein 2A,4 (**Note-this gene is not found in MGD). K-ras, a positional candidate gene, did not show significantly different expression between A/J and C57BL/6J.

Pas2 is located between 17 cMand 23.2 cM on mouse Chromosome 17 and was identified in crosses involving A/J and C57BL/6J. Candidate oncogenic genes identified by microarray analysis are Notch4, Hnrpk (**Note-this gene is positioned on mouse Chromosome 13 in MGD), and Enpp4. Other candidate genes identified via differential expression are Cdc5l, Tapbp (tapasin), H2-Ke2, Rbx1 (regulator of cullins 1 **Note- this gene is found on mouse Chromosome 15 in MGD), Psors1c2, H2-Ke6, and H2-M9. Positional candidate genes Tnf (Tnfa) and Lta (Tnfb) did not show significantly different expression between A/J and C57BL/6J.

Pas3 is located between 2 cM and 25 cM on mouse Chromosome 19 and was identified in a cross between A/J and C57BL/6J. Candidate oncogenic genes identified by microarray analysis are golgi specific Gbf1 (brefeldin A resistance factor 1) and Sema4g. Other candidate genes identified via differential expression are Pdcd4, Adrb1, and Cdc25l.

Pas4 is located between 42 cM and 72 cM on mouse Chromosome 9 and was identified in a cross between A/J and C57BL/6J. Candidate oncogenic genes identified by microarray analysis are Nck1, Pthr1, and Topbp1. Candidate tumor suppressor genes for Pas4 are G protein alpha I 2 (**Note-this gene is not found in MGD), Cdk5 (**Note-this gene is positioned on mouse Chromosome 5 in MGD), Smarcd3 (**Note-this gene is positioned on mouse Chromosome 5 in MGD), and Nckipsd. Another candidate gene identified via differential expression is Stag1.

Par1 is located between 37 cM and 59 cM on mouse Chromosome 11 and was identified in a cross between A/J and SM/J. Candidate oncogenic genes identified by microarray analysis are Alox12 (12-lipoxygenase), Zfp617 (zinc finger protein s11-6), Grn, and Rpl29 (**Note-this gene is positioned on mouse Chromosome 9 in MGD). A tumor suppressor candidate gene for Par1 is Spop.

02.05.2016 Curator Note: Because Par1 was originally mapped in J:32079 using an (A/J x M. spretus) x C57BL/6J interspecific backcross, which differs from the cross used here, we have equated this QTL with Par8 which was mapped using A/J and SM/J mice, see J:41849.

Par2 is located between 32 cM and 57 cM on mouse Chromosome 18 and was identified in a cross between A/J and BALB/cJ. Candidate oncogenic genes identified by microarray analysis are Adrb2, Mbd2, Htr4, Hmgb1-rs12, and Iigp1. Dcc is an expected candidate gene of Par2 but its expression pattern (A/J=high expression) is not consistent with its effect on tumor resistance/susceptibility. Mc2r is another candidate gene identified via differential gene expression between A/J and SM/J.

Par3 is located between 13 cM and 44 cM on mouse Chromosome 12 and was identified in a cross between A/J and SM/J. Only one candidate oncogenic gene was identified for Par3. This is placental growth factor, Pgf.

Par4 is located between 10.6 cM and 42.5 cM on mouse Chromosome 4 and was identified in a cross between A/J and BALB/cJ. Candidate tumor suppressor genes identified via differential gene expression are Cdkn2a, Egfl5, Ambp (bikunin), Pole3, Tyrp1, Ifnab, and Igfbpl1.Candidate oncogenes are T complex protein 1 alpha (**Note-this gene is not found in MGD) and Stmn1. Another candidate gene identified via differential expression between A/J and SM/J is Ptprd.

Mapping and Phenotype information for this QTL, its variants and associated markers

J:41849

Unlike A/J, SM/J mice rarely develope spontaneous pulmonary adenomas (PA) and are resistant to PA induction by carcinogens. The incidence of PA in 20 SMXA RI strains was first examined. SMXA24 was highly resistant to PA despite having A/J derived alleles at all 4 susceptible Pas regions, Pas1-4.

Results from 188 (SMXA24 x A/J)F1 x A/J and A/J x (SMXA24 x A/J)F1 backcrossed mice were pooled and analyzed. Linkage analysis reveal two QTL.

A resistant QTL mapped to Chr 11 between markers D11Mit14 and D11Mit70 with a LOD score of 4.35, p=0.0012, accounting for 10.2% of the trait variance. Authors speculate that the QTL may be the previously identified Par1 QTL becuase of its proximity.

02.04.2016 Curator Note: Because Par1 was originally mapped in J:32079 using an (A/J x M. spretus) x C57BL/6J interspecific backcross, which differs from the mapping population used here, we consider the current study a separate experiment and have named the the QTL Par7.

Another resistance QTL mapped to Chr 12 with marker a LOD score of 6.47 at marker D12Mit5, p=0.00015. This locus accounted for 14.7% of the trait varaince and was designated Par3, pulmonary adenoma resistance 3.

SM/J derived alleles effectively reduced the number of pulmonary adenomas at each locus.

J:67468

188 (SMXA24 x A/J)F1 x A/J backcross animals were typed for 75 microsatellite markers to detect loci associated with resistance to urethan-induced pulmonary adenomas. SMXA24 is a recombinant inbred (RI) strain derived from progenitor strains SM/J and A/J. SMXA24 is resistant to pulmonary adenomas as is progenitor strain SM/J. Progenitor strain A/J is susceptible to pulmonary adenomas. Linkage analysis detect 2 loci associated with resistance to pulmonary adenomas on mouse Chromosomes 11 and 12 and are said to be identical to previously identified QTLs Par1 and Par3, respectively (Manenti et al, J:32079). In this study, Par1 gave a LOD score of 4.35 at D11Mit70 and Par3 gave a LOD score of 6.47 at D12Mit5. SM/J-derived alleles confer dominant resistance to pulmonary adenomas at Par1 and Par3. A possible candidate gene for Par3 is protein kinase C, eta (Prkch). Par1 and Par3 regions of synteny at 17q11-q23 and 14q11-q24, respectively, appear to be associated with loss of heterozygosity in human lung cancer.

02.05.2016 Curator Note: Because Par1 was originally mapped in J:32079 using an (A/J x M. spretus) x C57BL/6J interspecific backcross, which differs from the mapping population used here, we have equated this QTL with Par8 which was mapped in an identical population in J:41849.

References

• Original: J:41849 Pataer A, et al., Genetic resistance to urethan-induced pulmonary adenomas in SMXA recombinant inbred mouse strains. Cancer Res. 1997 Jul 15;57(14):2904-8
• All: 2 reference(s)