Hpcr1^C57BL/6J
QTL Variant Detail

Summary

• QTL variant: Hpcr1^C57BL/6J
• Name: hepatocarcinogen resistance 1; C57BL/6J
• MGI ID: MGI:3046741
• QTL: Hpcr1 Location: unknown Genetic Position: Chr4, cM position of peak correlated region/allele: 50.04 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

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.

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

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.

References

• Original: J:22501 Lee GH, et al., Identification of hepatocarcinogen-resistance genes in DBA/2 mice. Genetics. 1995 Jan;139(1):387-95
• All: 1 reference(s)