The Genome Architecture of the Collaborative Cross Mouse Genetic Reference Population Collaborative Cross Consortium

The Collaborative Cross (CC) is a multiparental recombinant inbred panel derived from eight laboratory mouse inbred strains. Breeding of the CC lines was initiated with mice from The Jackson Laboratory at multiple international sites. Currently, we are breeding independent CC lines at the University of North Carolina (UNC), at Tel Aviv University (TAU) and at Geniad in Western Australia (GND). These institutions aim to make the completed CC lines, their genotypes and sequence information publicly available. We genotyped 458 samples from extant lines from UNC, TAU and GND using a custom genotyping array with 7,500 SNPs designed to be maximally informative in the CC, and used a novel algorithm to infer inherited haplotypes directly from hybridization intensity patterns. We identified lines with breeding errors and cousin lines that were generated by splitting incipient lines into two or more cousin lines at early generations of inbreeding. The genome architecture of 350 genetically independent CC lines was then characterized. Founder haplotypes are inherited at the expected frequency but we also consistently observed highly significant transmission ratio distortion at specific loci across all three populations. On Chromosome 2 there is significant overrepresentation of WSB/EiJ alleles and on Chromosome X there is a large deficit of CC lines with CAST/EiJ alleles. Linkage disequilibrium decays as expected and there is no evidence of gametic disequilibrium in the CC population as a whole or in random subsets of the population. This is in marked contrast with the situation in a large panel of 4 classical inbred strains. Finally, we discuss access to the CC population and to data associated with it.