International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


POSTER 5 - A POTENT MODIFIER OF LIVER TUMOR MULTIPLICITY, BUT NOT RAS MUTATION PREVALENCE, IN A 7 MB INTERVAL ON CHROMOSOME 1

A Bilger
McArdle Laboratory for Cancer Research

Drew J, Drinkwater N, Schneider A, Luetkehoelter K
UW-Madison

We have used both classical genetics and sequence-based genomics in search of mouse modifiers of liver tumorigenesis.  The dramatic 20-50-fold difference in tumor multiplicity between carcinogen-treated male C57BL/6 (B6) and C3H/HeJ (C3H) mice has been shown to map mainly to distal chromosome 1.  We have bred congenic animals carrying 70cM of chromosome 1 from C3H on an otherwise B6 genetic background.  Relative to B6 animals, these B6.C31 mice developed up to 14-fold more liver tumors.  Analysis of recombinant animals carrying smaller portions of the C3H congenic region suggests the presence of two modifiers, one of which has a 5-8-fold effect on tumor multiplicity and lies in a 7 Mb region on distal chromosome 1.  Ras mutations are more prevalent in C3H tumors than in B6.  By comparing ras mutations in tumors from the B6.C31and parental strains, we have shown that the C3H alleles on distal chromosome 1 are not sufficient to recapitulate the high ras mutant frequency of C3H tumors, despite their strong effect on tumor multiplicity.Analysis of simple sequence repeats in 40 Mb of distal chromosome 1 reveals a non-random pattern of polymorphisms.  Blocks of highly polymorphic sequence alternate with blocks of non-polymorphic sequence.  This distribution suggests that SSR polymorphism patterns reflect linkage disequilibrium between the strains, a hypothesis supported by the correlation between SSR polymorphisms and single nucleotide polymorphisms in this region.  We are using these data to identify regions of divergent ancestry between B6 and C3H and thereby narrow our search for the chromosome 1 modifier.


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