Cdkn2a^Pctr1-DBA/2N
QTL Variant Detail

Summary

• QTL variant: Cdkn2a^Pctr1-DBA/2N
• Name: cyclin dependent kinase inhibitor 2A; DBA/2N
• MGI ID: MGI:3036106
• QTL: Cdkn2a Location: Chr4:89192710-89212856 bp, - strand Genetic Position: Chr4, 42.15 cM, cytoband C3-C6

Variant origin

• Strain of Specimen: DBA/2N

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers partial plasmacytoma resistance compared to BALB/cAnPt. (J:16958)

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

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: Becasue 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:16958

BALB/cAnPt mice are susceptibile to plasmacytomas whereas DBA/J mice are resistant. Genetic resistance to plasmacytomas was studied in mice made congenic between BALB/cAnPt and DBA/2N in which chromatin from DBA/2N was transferred to the BALB/cAnPt background. Two regions on Chromosome 4 of DBA/2 are involved in a partial resistant phenotype.

The first region defined by congenics C.D2-Tf3, C.D2-D4Lgm1A, C.D2-D4Lgm1b, C.D2-D4Lgm1C and C.D2-D4Lgm1H is bounded by Ifa and D4Rck41 and is designated Cdkn2a.

The second region defined by congenics C.D2 Fv1 and C.D2 Pnd7 is bounded by Tnfrsf1b and D4Smh6b and designated Pctr2.

J:56600

Authors screened DNAs from 73 T-cell lymphomas induced by gamma-rays in (C57BL/6J x BALB/cJ)F1 mice and the reciprocal (BALB/cJ x C57BL/6J) mice for loss of heterozygosity (LOH) with several polymorphic markers. Significant differences in LOH was observed with Chromosome 4 markers compared to markers on other chromosomes. 12 different patterns of LOH were seen with allele losses on Chromosome 4. Analysis of the LOH data revealed three different non-contiguous areas of allele loss. These were called Tlsr1(Chi square = 87.77, d.f. = 1, P<0.0000001), Tlsr4 (Chi square 106.16, d.f. = 1, P<0.0000001) and Tlsr5 (Chi square = 52.77, d.f. = 1, P<0.0000001). Analysis of LOH around the Tlsr1 region gave a probable order of markers in this region as: Centromere - D4Mit77 , D4Mit245 - Cdkn2b - (exon beta) - Cdkn2a (exon alpha) - D4Wsm1.

10.20.2015 Curator Note: Because Tlsr1 was originally mapped in J:31797 in 1996 using (C57BL/6J x RF/J)F1 mice, which differ from the population used here, we consider the current study a separate mapping experiment and have named this QTL Tlsr9.

The region centered at D4Mit116 was called Tlsr4 while the region encompassing D4Mit21 was called Tlsr5. To reinforce the signifance of allele losses at D4Mit21, additional allelotype analysis on 49 gama-radiation induce T-lymphomas of the (C57BL/6J x RF/J)F1 was performed. A higher Chi square value of 79.27 and p<0.0000001 was obtained. Tgfbr1 is a putative candidate for a tumor suppressor gene in the Tlsr5 region.

J:74369

Tlag2, a gene responsible for MNU-induced lymphoma susceptibility, was mapped to 53 cM on mouse Chromosome 4 in a AKR/J x (AKR/J x C57L/J)F1 backcross and confirmed in F2 and F3 animals. (Animals fixed for AKR/J-derived alleles at Tlag1 on mouse Chromosome 7 were used in the study.) Peak lymphoma susceptibility is associated with marker Pmv19 at 52.7 cM with the C57L/J-derived allele conferring dominant lymphoma susceptibility. Tlag1 and Tlag2 appear to interact. Animals homozygous for AKR-derived alleles at Tlag1 and heterozygous at Tlag2 exhibited the highest incidence of MNU-induced tumors. Several candidate genes mapping near Tlag2 are Cdkn2a, Cdkn2b, Lyr, Pcts, Tie1, Tek, Mycl1, Jun, Lck, Pctr1, Pctr2, and Tal1.

J:91118

Linkage analysis was performed on 34 BXD (B=C57BL/6J, D=DBA/2J) recombinant inbred (RI) strains to identify QTLs associated with growth factor induced angiogenesis. Corneas of BXD mice were implanted with FGF2 or VEGF slow release pellets and examined for neovascular formation. The mean vessel length of parental strain C57BL/6J is 0.47mm and the mean vessel length of parental strain DBA/2J is 0.61mm. (C57BL/6J x DBA/2J)F1 hybrids have a mean vessel length of 0.57mm. Significant linkage to FGF2-induced angiogenesis mapped to mouse Chromosomes 4, 13, 15, and 18. These loci were named Angfq1, Angfq2, Angfq3, and Angfq4, respectively.

Angfq1 mapped to 7.5 cM on mouse Chromosome 4 near D4Mit193. Potential candidate genes mapping near Angfq1 are Mmp16, Epha7,Map3k7, and Tpm2. Several previously identified QTLs map near Angfq1. These are Bgeq3, Bglq4, Bwq1, Lgth3, Wta1, Stheal3, Pas9, Sluc18, Mmtg1, Cdkn2a, and Pcyts2.

Angfq2 mapped to 12 cM on mouse Chromosome 13 near Hist1h3f. Potential candidate genes for Angfq2 are Hist1h3f, the serpin gene cluster at 12 cM - 13 cM, and the prolactin gene cluster at 13 cM. Angfq2 maps near previously identified QTLs Bglq10, Bw10, and Heal2.

Angfq3 mapped to 29.7 cM on mouse Chromosome 15 near D15Mit232. Potential candidate genes for Angfq3 are Sema5a, Fzd6, Tnfrsf11b, Agpt, Enpp2, Has2, and Myc. Angfq3 maps near previously identified QTLs Bwtq6, Egrd2, Lwq5, Fob3, Apmt1, Gct3, and Sluc25.

Angfq4 mapped to 50 cM on mouse Chromosome 18 near D18Mit80. Potential candidate genes for Angfq4 are Lipg, Atp5a1, and Pstpip2. Angfq4 maps near previously identified QTLs Sluc28 and Pas7.

J:22501

Linkage analysis was performed on 71 (DBA/2J x C57BL/6J)F1 x C57BL/6J backcross animals to identify QTLs associated with resistance or susceptibility to hepatocarcinogens. Male animals were treated with N,N-diethylnitrosamine (DEN) at 12 days of age and assessed for liver tumors at 32 weeks. Males from parental strain DBA/2J is 20 times more susceptible to liver tumor development compared to males from C57BL/6J. 100 polymorphic markers with 95% genome coverage were used for linkage analysis.

Significantlinkage to hepatocarcinogen resistance mapped to 51 cM on mouse Chromosome 4 near D4Mit31 (LOD=3.1) and to 35 cM on mouse Chromosome 10 near D10Mit15 (LOD=3.0). The chromosome 4 locus was named Hpcr1 (hepatocarcinogen resistance 1) and the chromosome 10 locus was named Hprc2. DBA/2J-derived alleles confer a 60% reduction in liver tumor incidence at Hpcr1 and a 50% reduction in liver tumor incidence at Hpcr2. Hpcr1 and Hpcr2 appear to have an additive effect. Animals heterozygous at both loci exhibit the lowest incidence of liver tumors whereas animals homozygous for C57BL/6J-derived alleles at both loci exhibit the highest incidence of liver tumors. Suggestive linkage to hepatocarcinogen susceptibility was detected at Zp3 (77 cM, LOD=1.2) on mouse Chromosome 5 and D12Mit3 (32 cM, LOD=1.7) on mouse Chromosome 12.

Hpcr1 and Hpcr2 were confirmed by selective genotyping of 46 (DBA/2J x C57BL/6J)F2 animals. Peak linkage for Hpcr1 occurred at D4Mit9 (44.5 cM, LOD=3.3) and D4Mit71 (61.9 cM, LOD=2.2). Homozygosity for DBA/2J-derived alleles at both markers confers a 60%-70% reduction in liver tumor incidence compared to animals homozygous for C57BL/6J-derived alleles. Hpcr2 was confirmed at D10Mit15 (LOD=1.3). DBA/2J-derived alleles are also associated with a 60%-70% reduction in liver tumor incidence at Hpcr2 compared to animals homozygous for C57BL/6J-derived alleles. The loci at chromosomes 5 and 12 did not show linkage to hepatocarcinogen susceptibility in this cross.

In addition, BXD RI strains wereanalyzed for correlation to liver tumor development. Xmmv23 (65.7 cM) showed tight linkage to Hpcr1 on chromosome 4. Hpcr2 was not detected in the BXD population.

The Hpcr1 interval on chromosome 4 contains proto-oncogenes Jun (44.6 cM), Mycl1 (55 cM), and Fgr(64.6 cM). Hpcr1 also maps near previously identified plasymacytoma resistance QTLs Pctr1 (43 cM) and Pctr2 (74 cM), and the intestinal tumor suppressor gene Pla2g2a at 68 cM (formerly Mom1). Hpcr1 is syntenic to human Chromosome 1.

The Hpcr2 interval onmouse Chromosome 10 contains proto-oncogenes Fyn (25 cM) and Ros1 (28 cM). This locus is syntenic to human Chromosome 6.

J:103841

Linkage analysis was performed on 513 animals from a (SM/J x NZB/BlNJ)F2 intercross to identify QTL affecting obesity traits. Animals were placed on an atherogenic diet for 16 weeks before phenotyping. Parental strain SM/J exhibits smaller body size but higher adiposity compared to parental strain NZB/BlNJ.

On mouse Chromosome 4, Adip11 maps to 46 cM (D4Mit26, LOD=3.2) with a 95% confidence interval spanning 30 cM - 68 cM. SM/J-derived alleles at Adip11 confer increased inguinal and retroperitoneal fatpad weights with dominant inheritance. Adip11 appears central to a network of interacting loci, which include Obq22 (34 cM, chrX), Obwq3 (42 cM, chr6), and Bwtq12 (34 cM, chr15). Potential candidate genes for Adip11 include Cdkn2a (42.7 cM), Ifnb1 (42.6 cM), Jun (44.6 cM), Rraga, and Lepr (46.7 cM).

Adip12 maps to 70 cM (D4Mit312, LOD=2.6) with a 95% confidence interval spanning 52 cM - 80 cM. SM/J-derived alleles at Adip12 confer increased mesenteric fat pad weight with an additive mode of inheritance. Previously identified obesity QTL Dob1 (50 cM), Pfat1 (30 cM), Afw2 (66 cM), Afpq2 (66 cM) map near Adip11 and Adip12.

Bwtq9 maps to 24 cM near D4Mit44 (LOD=2.1) with a 95% confidence interval spanning approximately 0 cM - 44 cM. NZB/BlNJ-derived alleles at Bwtq9 confer increased lean body weight with a dominant mode of inheritance. Bw8q2 (66 cM) and Bwq1 (6.3 cM) are previously identified body weight QTL located near Bwtq9.

J:114158

Linkage analysis was performed on 117 (C57BL/6J x CBA/J)F2 animals to identify QTLs associated with silica-induced pulmonary fibrosis susceptibility. 167 microsatellite markers were used for the genome scan. Parental strain C57BL/6J is susceptible to silicosis whereas parental strain CBA/J is resistant. Animals were exposed to silica at 6-8 weeks of age and assessed for lung fibrosis and lung hydroxyproline content 28 days after exposure.

Significant linkage to silicosis susceptibility mapped to 44.5 cMon mouse Chromosome 4 near D4Mit9. This locus explains 9% of the phenotypic variance and is designated Slcs1 (silicosis susceptibility 1). Potential candidate genes mapping near Slcs1 include Jun (44.6 cM), Cdkn2a (42.7 cM), and Igfbpl1.

Suggestive linkage to silicosis susceptibility mapped to 61.8 cM on mouse Chromosome 3 near D3Mit319 and to 21 cM on mouse Chromosome 18 near D18Mit177.1. The Chr 3 locus explains 7% of the phenotypic variance and the Chr 18 locus explains 6% of the phenotypic variance.Potential candidate genes mapping near the Chr 18 locus include Fgf1 (19 cM) and Spry4 (18 cM). Pas9 (43 cM) is a previously identified pulmonary adenoma susceptibility locus mapping to Chr 18.

References

• Original: J:16958 Potter M, et al., Identification of two genes on chromosome 4 that determine resistance to plasmacytoma induction in mice. Cancer Res. 1994 Feb 15;54(4):969-75
• All: 2 reference(s)