Pas1^C57BL/6J
QTL Variant Detail

Summary

• QTL variant: Pas1^C57BL/6J
• Name: pulmonary adenoma susceptibility 1; C57BL/6J
• MGI ID: MGI:5705643
• QTL: Pas1 Location: unknown Genetic Position: Chr6, cM position of peak correlated region/allele: 78.22 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: C57BL/6J

Variant description

• Allele Type: QTL

Notes

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:56444

The 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:48996

Linkage 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:21801

Linkage 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:17778

Analysis 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.

References

• Original: J:17778 Ryan J, et al., KRAS2 as a genetic marker for lung tumor susceptibility in inbred mice. J Natl Cancer Inst. 1987 Dec;79(6):1351-7
• All: 1 reference(s)