Submitted on April 19, 2006
Revised on June 7, 2006
Accepted on June 7, 2006
Two loci on chromosome 9 control bile acid composition in a C57BL/6J X CASA/Rk intercross: Evidence that a strong candidate gene, Cyp8b1, is not the culprit
Ephraim Sehayek, Lee R. Hagey, Yee-Yan Fung, Elizabeth M. Duncan, Hannah J. Yu, Gösta Eggertsen, Ingemar Björkhem, Alan F. Hofmann, and Jan L. Breslow
Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, NY 10021
Corresponding Author: sehayee{at}rockefeller.edu
The genetics of biliary bile acid composition was studied in an intercross between mouse strains C57BL/6J and castaneus (CASA/Rk). C57BL/6J males but not females had 14% more % cholic acid (CA) and 27% less % -muricholic acid (MC). Linkage analysis in F2 females, but not in F2 males, revealed loci on chromosome 9 for %CA at 72cM (LOD 5.89) and %MC at 54cM (LOD 4.09). Studies in a chromosome 9 congenic strain, that covers the loci at 54cM and 72cM, and in a subcongenic strain, that covers only the locus at 72cM, indicated that in females composition was determined by the loci at 54cM and 72cM whereas in males composition was dependent only on the locus, at 72cM. At chromosome 9 sterol 12-hydroxylase (Cyp8b1), is located at 73cM. However, studies in parentals, F2s, congenic and subcongenic strains found no differences in Cyp8b1 mRNA and enzymatic activity. Moreover, a single amino acid difference between C57BL/6J and CASA/Rk Cyp8b1, lys242glu, showed no correlation with bile acid composition or enzymatic Cyp8b1 activity. In summary, two chromosome 9 loci control sexually dimorphic effects on biliary bile acid composition. Cyp8b1, a strong candidate does not appear to be the responsible gene in this cross.
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