Pas15^A/J
QTL Variant Detail

Summary

• QTL variant: Pas15^A/J
• Name: pulmonary adenoma susceptibility 15; ^A/J
• MGI ID: MGI:5699082
• QTL: Pas15 Location: Chr6:145180868-145181064 bp Genetic Position: Chr6, Syntenic

Variant origin

• Strain of Specimen: A/J

Variant description

• Allele Type: QTL
• Mutation: Undefined
• Mutation details:

  Pas15 and Pas16 appear to interact. Heterozygosity at both Pas15 and Pas16 confers increased tumor count compared to the other genotypes.

  (J:22173)

Notes

Candidate Genes

J:90940

The Pas15 lung tumor susceptibility locus was localized to a 486 kb region on mouse Chromosome 6 by fine mapping of the recombinant congenic (RC) strain CXB5/ByJ. CXB5/ByJ is derived from BALB/cJ and C57BL/6J progenitor strains and is highly resistant to lung tumor development. Genotyping of 65 markers in 29 inbred strains for a 1 Mb region around Pas15 revealed a core haplotype that is either C57BL/6-derived or A/J-derived. The Pas1 critical region contains 6 candidate genes: Bcat1, Lrmp, Kras, Casc1, 4933403M22Rik, and 4930469P12Rik. In lung tumors from (A/J x C57BL/6J)F1 mice, Casc1 appears to be expressed solely from the A/J allele and expression of 4933403M22Rik appears to be completely downregulated.

J:108212

Previously identified QTL Pas15 (pulmonary adenoma susceptibility 1) maps to a 468 kb interval on mouse Chromosome 6. This region contains six candidate genes: Lrmp, Casc1, 4930469P12Rik (aka Ghiso), and 4933403M22Rik (aka Lmna-rs1). Allele-specific expression constructs of each of the candidate genes were derived from lung mRNA from inbred strains A/J (pulmonary adenoma susceptible) and C57BL/6J (pulmonary adenoma resistant). The expression constructs were transfected into 2 human small-cell lung carcinoma cell lines and assayed for transformation. The ability of Lrmp and 4930469P12Rik constructs to transform human lung carcinoma cells did not differ between A/J and C57BL/6J alleles. However, the A/J allele of Casc1 produced fewer transformed human cells compared to the C57BL/6J allele, and the A/J allele of 4933403M22Rik produced more transformed human cells compared to the C57BL/6J allele. Casc1 was observed preferentially expressed in lung tumors of the A/J-derived allele. 4933403M22Rik expression was not observed in mouse lung tumors of any genotype. Authors state that the experimental results do not necessarily preclude Lrmp and 4930469P12Rik as candidate genes for Pas1.

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

J:83970

Previously identified QTLs Pas1 and Pas2 were confirmed and fine mapped using (A/J x C57BL/6) advanced intercross lines (AIL) at the F11 generation. Parental strain A/J is susceptible to lung tumors where as parental strain C57BL/6 is resistant.

Pas1 was resolved to a 1 cM - 1.3 cM interval on mouse Chromosome 6 near Kras with a LOD score > 150 at D6Mit57 (71.7 cM).

1.7.2016 - Curator Note: Because Pas1 was orginally mapped in J:17778, in 1997 using an (C57BL/6J x A/J)F2 intercross, which differs in direction from the cross used here, we consider the current study a separate mapping experiment and have named this QTL Pas15 .

Candidate genes in the region of Pas15 include Lrmp, 4933403M22Rik, 4930469P12Rik, Bcat1 (Eca39), 5133400D11Rik (mHoj-1), and Sspn (Krag). SNP analysis of these candidate genes revealed coding region polymorphisms in Lrmp, 4933403M22Rik, and 4930469P12Rik, but not in Bcat1 (Eca39), 5133400D11Rik (mHoj-1), or Sspn (Krag). Candidate gene 4933403M22Rik is highly associated with Pas15 and is referred to by the authors as Pas1c1 (Pas1 candidate gene 1). Semi-quantitative RT-PCR analysis of 4933403M22Rik revealed the presence of different isoform transcripts in C57BL/6 and A/J.

Pas2 was localized to a 7.6 Mb region on mouse Chromosome 17 between D17Mit23 and D17Mit231 with the strongest association (LOD=3.0) at D17Mit16 (17.4 cM). There may be a possible interaction between Pas1 and Pas2.

1.4.2016 - Curator Note: Because Pas2 was originally mapped in J:21801 using (C57BL/6JOlaHsd x A/JOlaHsd)F2 intercross and backcross populations, which differ in direction from the cross used here, we consider the current study a separate mapping experiment and have named the QTL, Pas19.

Pas3 was not detected in this study using advanced intercross lines.

J:22173

Linkage analysis using 77 polymorphic markers was performed on a population of (A/J x C57BL/6J)F1 x C57BL/6J backcross animals to identify QTLs associated with pulmonary adenoma susceptibility. Parental strain A/J is susceptible to ENU-induced pulmonary adenomas whereas parental strain C57BL/6J is resistant.

A QTL, peak LOD=4.78 was localized to a region of Chromosome 6 flanked by Kras and closely linked distal markers linked with D6Int1.

12.14.2015. Curator Note: Authors have equated this QTL with Pas1. However, since Pas1 was orginally mapped in J:17778, in 1997 using an (C57BL/6J x A/J)F2 intercross where the direction of the cross varied from that of the cross used here we consider this a separate map experiment and have labeled this QTL, Pas15. This locus is 50% of the genetic variance.

Significant association mapped to approximately 16 cM on mouse Chromosome 19 between D19Mit42 and D19Mit19. This locus is called Pas3 and explains 10% of the genetic variance. Candidate genes mapping near Pas3 are Tnfrsf6 (formerly Fas) and Slc3a2 (formerlyMdu1).

12.14.2015. Curator Note: Pas3 was originally mapped in J:21801 using pooled results from 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. Because the direction of the cross used to generate the F1 female differs in this study we consider this a separate map experiment and have named the QTL Pas16.

Pas15 and Pas16 appear to interact. Heterozygosity at both Pas15 and Pas16 confers increased tumor count compared to the other genotypes.

References

• Original: J:22173 Devereux TR, et al., Assignment of a locus for mouse lung tumor susceptibility to proximal chromosome 19. Mamm Genome. 1994 Dec;5(12):749-55
• All: 3 reference(s)