title: Genetic basis of HDL variation in 129/SvImJ and C57BL/6J mice: importance of testing candidate genes in targeted mutant mice.
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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Su
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Wang
authors.forename: Shirng-Wern
authors.initials: SW
authors.lastname: Tsaih
authors.forename: Aihong
authors.initials: A
authors.lastname: Zhang
authors.forename: Allison
authors.initials: A
authors.lastname: Cox
authors.forename: Susan
authors.initials: S
authors.lastname: Sheehan
authors.forename: Beverly
authors.initials: B
authors.lastname: Paigen
mesh_terms: D000818:Animals; D003433:Crosses, Genetic; D004036:Diet, Atherogenic; D005260:Female; D014644:Genetic Variation; D016678:Genome; D005838:Genotype; D006239:Haplotypes; D008075:Lipoproteins, HDL / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D040641:Quantitative Trait Loci
chemical_list: D008075:Lipoproteins, HDL
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