First Genomic Research Studies Published Utilizing Collaborative Cross Mice

The Collaborative Cross (CC) represents a large collection of new inbred mouse strains created by the mouse genetics community aimed at transforming the study of complex genetic traits and diseases. Derived from classical inbred strains and wild-derived strains, the CC captures nearly 90% of known genetic variation in laboratory mice, far exceeding more commonly used inbred strains.

The CC is a tool to integrate studies of gene function and gene networks, allowing the prediction and testing of biologic models based on the whole organism, vital to the development of customized therapies for humans. The journal Genome Research has published three articles online utilizing strains from the emerging Collaborative Cross mouse strains.

The first study concerns Collaborative Cross strains facilitate mapping of causative loci; In this work, published in the April 2011 issue of Genome Research, Dr. Katherine I. Fisher-Aylor and colleagues from the California Institute of Technology (Caltech; Pasadena, USA), Systemix Institute (Redmond, WA, USA), and the Lawrence Berkeley National Laboratory (Berkeley, CA, USA) performed an experiment called the pre-CC study, the first genetic data and analysis from the emerging strains of the CC. Their research revealed that the genomes of CC strains are genetically diverse and contain balanced contributions from each founding strain.

Highlighting the statistical power provided by the CC, Dr. Aylor and colleagues utilized ancestry data of the CC strains to map genetic loci for a Mendelian trait (white head-spotting), a complex trait (body weight), and a molecular trait (gene expression in the liver), demonstrating the ancestry-based approach to be superior to established marker-based methods for trait loci discovery.

The development of the Collaborative Cross presents a unique opportunity to investigate how the breeding of inbred strains affects genetic structure and the diversity of phenotypes. In another article, published online July 6, 2011, Dr. Vivek M. Philip and colleagues from the Systems Genetics Group, biosciences division, Oak Ridge National Laboratory (Oak Ridge, TN, USA) and the University of Tennessee (Knoxville, TN, USA) have evaluated the range of many traits in late inbreeding populations of the CC, including such phenotypes as body weight, tail length, heart weight, and behavioral traits. In spite of the influence of breeding selection in the CC lines, detection of major genetic loci regulating trait variation remained possible. This analysis revealed the scope of phenotypic variation that will be present in the finished strains of the CC.

Aspergillosis is a serious disease in humans, particularly in immune-compromised individuals, caused by infection with the fungus Aspergillus. The mouse has been an important model for studying Aspergillus infection, but classical laboratory strains of mice used in these studies arose from a small set of founders and lack most of the genetic variation present in wild mice, limiting researchers’ ability to identify additional genetic loci relevant to disease.

In the last study, published online April 14, 2011, issue of Genome Research, Dr. Caroline Durrant, from Wellcome Trust Center for Human Genetics, University of Oxford, UK), and colleagues from the department of clinical microbiology and immunology, Sackler Faculty of Medicine, Tel Aviv University (Tel Aviv, Israel), and the department of genetics, University of North Carolina (Chapel Hill, NC, USA) utilized inbred mouse strains from the Collaborative Cross, exploiting the genetic contribution of wild-derived strains, to identify novel loci that confer susceptibility to infection with the fungus Aspergillus.

By integrating genetic variation data from the genomes of the founding strains of the CC, Dr. Durrant and colleagues additionally modified the genetic loci associated with Aspergillus susceptibility to suggest specific candidate genes.

Related Links:
California Institute of Technology
Ridge National Laboratory
Wellcome Trust Center for Human Genetics