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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:678.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Novel Strategy Using F1-Congenic Mice for Validation of QTLs

Studies at the Proximal Chromosome 10 Atherosclerosis Susceptibility Locus

Daniel Teupser; Susanne Wolfrum; Marietta Tan; Adam D. Persky; Hayes M. Dansky; Jan L. Breslow

From the Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York. Current affiliation for D.T.: Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics, University Leipzig, Germany.

Correspondence to Jan L. Breslow, Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, 1230 New York Avenue, New York, NY 10021. E-mail breslow{at}rockefeller.edu

Objective— We have previously identified a quantitative trait locus (QTL) for atherosclerosis susceptibility on proximal chromosome 10 (Chr10) (Ath11) in independent crosses of FVB and C57BL/6 (B6) mice on the apolipoprotein E (ApoE^–/–) and LDL receptor (LDLR^–/–) deficient backgrounds. The aims of the current study were to (1) test a novel strategy for validating QTLs using interval-specific congenic strains that were heterozygous (F1) across the genome, (2) validate the Chr10 QTL, and (3) to assess whether the phenotype is transferable by bone marrow transplantation.

Methods and Results— We generated Chr10 (0 to 21 cM) interval-specific mice on the F1.ApoE^–/– background by crossing congenic FVB.ApoE^–/–Chr10^B6/FVB with B6.ApoE^–/–, and B6.ApoE^–/–Chr10^B6/FVB with FVB.ApoE^–/– mice. Lesion size was significantly larger in the resultant F1.ApoE^–/–Chr10^FVB/FVB mice compared to F1.ApoE^–/– Chr10^B6/FVB and F1.ApoE^–/–Chr10^B6/B6 mice, validating the Chr10 QTL. The effect of the congenic interval was more robust on the F1.ApoE^–/– than on the FVB.ApoE^–/– and B6.ApoE^–/– backgrounds. Bone marrow transplantation in congenic mice showed that the effect of the proximal Chr10 interval was not transferable by bone marrow–derived cells.

Conclusions— A novel strategy of congenic strains on an F1 background proved useful to validate an atherosclerosis susceptibility QTL on mouse proximal Chr10.

A novel method of testing genetic effects with interval-specific congenic strains heterozygous (F1) across the genome that allows for possible major genetic interactions not present on a pure background was used to validate an atherosclerosis susceptibility QTL on proximal Chr10.

Key Words: atherosclerosis • congenic mice • chromosome 10 • transplantation