Collaborative Cross mice and their power to map host susceptibility to Aspergillus fumigatus infection
- Caroline Durrant1,
- Hanna Tayem2,
- Binnaz Yalcin1,
- James Cleak3,
- Leo Goodstadt3,
- Fernando Pardo-Manuel de Villena4,
- Richard Mott1 and
- Fuad Iraqi2,5
- 1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK;
- 2 Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University;
- 3 Wellcome Trust Centre for Human Genetics;
- 4 Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
- *↵ Corresponding author; email: fuadi{at}post.tau.ac.il
Abstract
The Collaborative Cross (CC) is a genetic reference panel of recombinant inbred lines of mice, designed for the dissection of complex traits and gene networks. Each line is independently descended from eight genetically diverse founder strains such that the genomes of the CC lines, once fully inbred, are fine-grained homozygous mosaics of the founder haplotypes. We present an analysis of the genomes of 120 lines from a cohort of the CC being bred at Tel Aviv University in collaboration with University of Oxford, which at the time of this study were between the 6th and 12th generations of inbreeding and substantially homozygous based on high-density genotyping at 170,000 SNPs. We show how their genomes may be decomposed into mosaics, and identify loci that carry a deficiency or excess of a founder, many of which are deficient for the wild-derived strains WSB/EiJ and PWK/PhJ. To demonstrate the utility of the CC, we phenotyped 371 mice from 66 CC lines for susceptibility to Aspergillus fumigatus infection. The survival time after infection ranged from 4 to 28 days and varied significantly between CC lines. Quantitative Trait Locus (QTL) mapping based on survival analysis and ancestral haplotype reconstruction of the CC genomes identified genome-wide significant QTLs on chromosomes 2, 3, 8, 10 (two QTLs), 15 and 18. Simulations show QTL mapping resolution (the median distance between the QTL peak and simulated true location) varied between 0.47 and 1.18Mb. Most of the QTLs involved contrasts between wild-derived founder strains and therefore would not segregate in a comparison of classical inbred strains. Use of variation data from the genomes of the CC founder strains refined these QTLs further and suggested several candidate genes. These results support the use of the CC for dissecting host susceptibility to infectious disease and other complex traits.
- Received December 3, 2010.
- Accepted April 4, 2011.
- Copyright © 2011, Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
