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Congenic and bioinformatics analyses resolved a major-effect Fob3b QTL on mouse Chr 15 into two closely linked loci

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Abstract

We previously identified a Chr 15 quantitative trait locus (QTL) Fob3b in lines of mice selected for high (Fat line) and low (Lean line) body fat content that represent a unique model of polygenic obesity. Here we genetically dissected the Fob3b interval by analyzing the phenotypes of eight overlapping congenic lines and four F2 congenic intercrosses and prioritized candidates by bioinformatics approaches. Analyses revealed that the Fob3b QTL consists of at least two separate linked QTLs Fob3b1 and Fob3b2. They exhibit additive inheritance and are linked in coupling with alleles originating from the Lean line, decreasing obesity-related traits. In further analyses, we focused on Fob3b1 because it had a larger effect on obesity-related traits than Fob3b2, e.g., the difference between homozygotes for adiposity index (ADI) percentage was 1.22 and 0.77% for Fob3b1 and Fob3b2, respectively. A set of bioinformatics tools was used to narrow down positional candidates from 85 to 4 high-priority Fob3b1 candidates. A previous single Fob3b QTL was therefore resolved into another two closely linked QTLs, confirming the fractal nature of QTLs mapped at low resolution. The interval of the original Fob3b QTL was narrowed from 22.39 to 4.98 Mbp for Fob3b1 and to 7.68 Mbp for Fob3b2, which excluded the previously assigned candidate squalene epoxidase (Sqle) as the causal gene because it maps proximal to refined Fob3b1 and Fob3b2 intervals. A high-resolution map along with prioritization of Fob3b1 candidates by bioinformatics represents an important step forward to final identification of the Chr 15 obesity QTL.

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Acknowledgments

This project was supported by the Slovenian Research Agency (ARRS) young investigator grant and program grant P4-0220. Sincere thanks to all members of Beverly Paigen’s lab at the Jackson Laboratory for help with the bioinformatics. We thank Dr. McWhir for critical review of the manuscript and Ana Zanjkovic for excellent technical assistance with the mouse colony. Finally, we are grateful to two anonymous reviewers for meticulous review and constructive criticism that helped us improve the article.

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Authors and Affiliations

  1. Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Groblje 3, 1230, Domžale, Slovenia

    Zala Prevoršek, Gregor Gorjanc & Simon Horvat

  2. The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA

    Beverly Paigen

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  1. Zala Prevoršek
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  2. Gregor Gorjanc
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  4. Simon Horvat
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Correspondence to Simon Horvat.

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Prevoršek, Z., Gorjanc, G., Paigen, B. et al. Congenic and bioinformatics analyses resolved a major-effect Fob3b QTL on mouse Chr 15 into two closely linked loci. Mamm Genome 21, 172–185 (2010). https://doi.org/10.1007/s00335-010-9252-z

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