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Published Online March 18, 2004
Science DOI: 10.1126/science.1093139

Reports

Submitted on October 30, 2003
Accepted on March 9, 2004

Genetic Dissection of Complex Traits with Chromosome Substitution Strains of Mice

Jonathan B. Singer 1, Annie E. Hill 2, Lindsay C. Burrage 3, Keith R. Olszens 2, Junghan Song 4, Monica Justice 5, William E. O'Brien 5, David V. Conti 6, John S. Witte 7, Eric S. Lander 8*, Joseph H. Nadeau 9*

1 The Broad Institute, Cambridge, MA 02142, USA; Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA.
2 Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
3 Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Center for Computational Genomics and Systems Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Present address: Department of Laboratory Medicine, Seoul National University Bundang Hospital 300, Kumi-dong, Bundang-ku, Sungnam, Kyungki 463-707, Korea.
5 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
6 Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA; Present address: Department of Preventative Medicine, University of Southern California, Los Angeles, CA 90089, USA.
7 Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH 44106, USA.
8 The Broad Institute, Cambridge, MA 02142, USA; Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
9 Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Center for Computational Genomics and Systems Biology, Case Western Reserve University, Cleveland, OH 44106, USA; Center for Human Genetics, University Hospitals of Cleveland, Cleveland, OH 44106, USA.

* To whom correspondence should be addressed. E-mail: lander{at}genome.wi.mit.edu, jhn4{at}cwru.edu.

Chromosome Substitution Strains (CSSs) have been proposed as a simple and powerful way to identify quantitative trait loci (QTLs) affecting developmental, physiological and behavioral processes. Here, we report the construction of a complete CSS panel for a vertebrate species. The CSS panel consists of 22 mouse strains, each of which carries a single chromosome substituted from a donor strain (A/J) onto a common host background (C57BL/6J). A survey of 53 traits revealed evidence for 150 QTLs affecting serum levels of sterols and amino acids, diet-induced obesity, and anxiety. These results demonstrate that CSSs greatly facilitate detection and identification of genes that control the extraordinary diversity of naturally occurring phenotypic variation in the A/J and C57BL/6J inbred strains.


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