Abstract
To evaluate the effect of genetic background on high-density lipoprotein cholesterol (HDL) levels in Soat1(-/-) mice, we backcrossed sterol O-acyltransferase 1 (Soat1)(-/-) mice, originally reported to have elevated HDL levels, to C57BL/6 mice and constructed a congenic strain with only a small region (3.3Mb) of 129 alleles, specifically excluding the nearby apolipoprotein A-II (Apoa2) gene from 129. HDL levels in these Soat1(-/-) mice were no different from C57BL/6, indicating that the passenger gene Apoa2 caused the previously reported elevation of HDL in these Soat1(-/-) mice. Because many knockouts are made in strain 129 and then subsequently backcrossed into C57BL/6, it is important to identify quantitative trait loci (QTL) that differ between 129 and C57BL/6 so that one can guard against effects ascribed to a knockout but really caused by a passenger gene from 129. To provide such data, we generated 528 F(2) progeny from an intercross of 129S1/SvImJ and C57BL/6 and measured HDL concentrations in F(2) animals first fed chow and then atherogenic diet. A genome wide scan using 508 single-nucleotide polymorphisms (SNPs) identified 19 QTL, 2 of which were male specific and 2 were female specific. Using comparative genomics and haplotype analysis, we narrowed QTL on chromosomes 3, 5, 8, 17, and 18 to 0.5, 6.3, 2.6, 1.1, and 0.6 Mb, respectively. These data will serve as a reference for any effort to test the impact of candidate genes on HDL using a knockout strategy.
Highlights
To evaluate the effect of genetic background on high-density lipoprotein cholesterol (HDL) levels in Soat12/2 mice, we backcrossed sterol O-acyltransferase 1 (Soat1)2/2 mice, originally reported to have elevated HDL levels, to C57BL/6 mice and constructed a congenic strain with only a small region (3.3Mb) of 129 alleles, excluding the nearby apolipoprotein A-II (Apoa2) gene from 129
HDL cholesterol is elevated in Soat12/2 mice both in the original report with homozygous mice in a mixed genetic background (83 6 19 mg/dl in female Soat12/2 vs. 48 6 12 mg/dl in female controls) [13] and after these mice had been backcrossed for 11 generations (N11) to C57BL/6 by The Jackson Laboratory (Table 1)
Because Soat1 and Apoa2 are only 15 Mb apart and because the 129 allele (Val61) of Apoa2 leads to higher HDL [14], the increased HDL in Soat12/2 mice could be caused by the Apoa2 gene, by the Soat1 knockout, or both
Summary
To evaluate the effect of genetic background on high-density lipoprotein cholesterol (HDL) levels in Soat12/2 mice, we backcrossed sterol O-acyltransferase 1 (Soat1)2/2 mice, originally reported to have elevated HDL levels, to C57BL/6 mice and constructed a congenic strain with only a small region (3.3Mb) of 129 alleles, excluding the nearby apolipoprotein A-II (Apoa2) gene from 129. Because many knockouts are made in strain 129 and subsequently backcrossed into C57BL/6, it is important to identify quantitative trait loci (QTL) that differ between 129 and C57BL/6 so that one can guard against effects ascribed to a knockout but really caused by a passenger gene from 129. To provide such data, we generated 528 F2 progeny from an intercross of 129S1/SvImJ and C57BL/6 and measured HDL concentrations in F2 animals first fed chow and atherogenic diet.
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