Par2^BALB/cByJJcl
QTL Variant Detail

Summary

• QTL variant: Par2^BALB/cByJJcl
• Name: pulmonary adenoma resistance 2; BALB/cByJJcl
• MGI ID: MGI:3586643
• QTL: Par2 Location: Chr18:70362333-76707156 bp Genetic Position: Chr18, cM position of peak correlated region/allele: 44.19 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: BALB/cByJJcl

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers resistance to pulmonary adenomas compared to A/JSlc. (J:70565)
• Inheritance: Dominant

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

This allele reduces pulmonary adenoma multiplicity by 65% in males and by 51% in females compared to the A/JSlc allele.

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.

J:98656

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 markers

J:36219

One 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:67467

Study 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:70565

The 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-Par2^C57BL/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.

References

• Original: J:70565 Lee GH, et al., Fine chromosomal localization of the mouse Par2 gene that confers resistance against urethane-induction of pulmonary adenomas. Oncogene. 2001 Jul 5;20(30):3979-85
• All: 1 reference(s)