Hcs7^C3H/HeJ
QTL Variant Detail

Summary

• QTL variant: Hcs7^C3H/HeJ
• Name: hepatocarcinogenesis susceptibility 7; C3H/HeJ
• MGI ID: MGI:2154096
• QTL: Hcs7 Location: Chr1:156602037-168186402 bp Genetic Position: Chr1, Syntenic

Variant origin

• Strain of Specimen: C3H/HeJ

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers hepatocarcinogenesis susceptibility compared to C57BL/6J. (J:31507)
• Inheritance: Semidominant

Notes

This allele appears to exhibit dominant inheritance in males and semidominant inheritance in females.

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

J:31507

Authors mapped Hsc7 to mouse Chromosome 1 using quantitative trait loci and PCR analysis of 84 progeny from a (C57BL/6J x C3H/HeJ)F1 x C57BL/6J backcross.

J:18565

58 male backcross mice (C57BL/6J x C3H)F1 x C57BL/6J were treated with DEN. At 32 weeks of age the animals were sacrificed to determine liver tumor multiplicity. DNA samples were isolated from individual animals and analyzed for their genotypes at 94 SSLP loci. A highly significant LOD score of 3.99 for the interval between D1Mit14 and D1Mit15 (on the distal third of Chromosome 1) was observed. Using quantitative trait loci analysis. This analysis allowed the authors to determine the following order of loci on mouse Chromosome 1: D1Mit14, Hsc7, D1Mit15.

J:91132

A previously identified QTL for liver cancer susceptibility, Hcs7, was detected in genome scans of two intercrosses and two backcrosses involving C57BL/6J, CBA/J, and C3H/HeJ. Parental strains CBA/J and C3H/HeJ are susceptible to spontaneous and induced hepatocarcinoma compared to parental strain C57BL/6J.

53 (C57BL/6J x C3H/HeJ)F1 x C57BL/6J animals were injected with N,N-diethylnitrosamine (DEN) at 12 days of age and screened for 107 polymorphic markers at a resolution of 15 cM. Significant linkage mapped to 88 cM on mouse Chromosome 1 near D1Mit15 (LOD=3.06). Heterozygosity at D1Mit15 confers 2-fold increased tumor incidence compared to C57BL/6J homozygotes. This locus is Hcs7. Next, 53 (C57BL/6J x C3H/HeJ)F2 animals were analyzed in the same fashion and linkage to liver tumor susceptibility mapped to 63 cM near D1Mit13 (LOD=2.85). Heterozygosity confers a 3-fold increase in liver tumor incidence and homozygosity for C3H/HeJ-derived alleles confers a 5-fold increase in liver tumor incidence at D1Mit13.

Linkage analysis was also performed on 53 (C57BL/6J x CBA/J)F1 x C57BL/6J backcross animals and 95 (C57BL/6J x CBA/J)F2 intercross animals using 74 microsatellite markers at a resolution of 20 cM. Again, a locus mapped to distal mouse Chromosome 1 at 93 cM near D1Mit113 (LOD=3.29) in the backcross, and to 82 cM near D1Mit33 (LOD=3.21) in the intercross. CBA/J-derived alleles confer increased incidence of liver tumors with dominant inheritance at this locus.

10.16.2015 Curator Note: Because Hcs7 was originally mapped using the C57BL/6J x C3H/HeJ population, which differs from the C57BL/6J x CBA/J population, we consider this second cross a separate mapping experiment and have named this QTL, mapping to Chr 1 near D1Mit113 with a LOD=3.29, Hcs8 .

Two congenic lines were constructed carrying C3H/HeJ-derived DNA or C57BR/cdJ-derived DNA from D1Mit5 (32.8 cM) to Tgfbm2 (106.3 cM) on a C57BL/6J genetic background. Parental strain C57BR/cdJ is up to 50-fold more susceptible to liver tumors compared to C57BL/6J.

B6.C3-(D1Mit5-Tgfbm2) congenic males exhibit a 13-fold increase in liver tumor susceptibility and females exhibit a 4-fold increase in liver tumor susceptibility.

B6.BR-(D1Mit5-Tgfbm2) congenic males exhibit a 6-fold increase in liver tumor susceptibility while females exhibit a 3-fold increase in liver tumor susceptibility. The C3H/HeJ and the C57BR/cdJ alleles of Hcs7 and of Hcs9 appear to have a semidominant mode of inheritance in females and a dominant mode of inheritance in males.

10.16.2015 Curators Note: Because the mice used in the B6.BR-(D1Mit5-Tgfbm2) congenic map study differ from those used to map both Hcs7 and Hcs8 we have also given the QTL identified in this congenic study a unique symbol, Hcs9.

Hcs7 is syntenic to human Chromosome 1q21-q23. Potential candidate genes mapping near Hcs7 include Pbx1 (88.1 cM), Rgs4 (86.5 cM), Rgs5 (86.5), Dedd, Ddr2 (90 cM), Atf6, and Fasl (85 cM). Hsc7 colocalizes with Hcif2, a hepatocarcinoma susceptibility QTL near D1Mit33 that wasidentifiedin C57BL/6J and C57BR/cdJ mice. Authors offer the possibility that Hcs7 and Hcif2 may be the same QTL.

References

• Original: J:31507 Bennett LM, et al., A gene that determines the high susceptibility of the C3H/HeJ strain of mouse to liver tumor induction is located on Chromosome one. Proc Am Assoc Cancer Res. 1993;34:144 (Abstr.)
• All: 3 reference(s)