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. 2012 Feb;190(2):389-401.
doi: 10.1534/genetics.111.132639.

The Genome Architecture of the Collaborative Cross Mouse Genetic Reference Population

Collaborators
Free PMC article

The Genome Architecture of the Collaborative Cross Mouse Genetic Reference Population

Collaborative Cross Consortium. Genetics. .
Free PMC article

Abstract

The Collaborative Cross Consortium reports here on the development of a unique genetic resource population. The Collaborative Cross (CC) is a multiparental recombinant inbred panel derived from eight laboratory mouse inbred strains. Breeding of the CC lines was initiated at multiple international sites using mice from The Jackson Laboratory. Currently, this innovative project is 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 publicly available the completed CC lines and their genotypes and sequence information. We genotyped, and report here, results from 458 extant lines from UNC, TAU, and GND using a custom genotyping array with 7500 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 generated by splitting incipient lines into two or more cousin lines at early generations of inbreeding. We then characterized the genome architecture of 350 genetically independent CC lines. Results showed that founder haplotypes are inherited at the expected frequency, although 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 we saw no evidence of gametic disequilibrium in the CC population as a whole or in random subsets of the population. Gametic equilibrium in the CC population is in marked contrast to the gametic disequilibrium present in a large panel of classical inbred strains. Finally, we discuss access to the CC population and to the associated raw data describing the genetic structure of individual lines. Integration of rich phenotypic and genomic data over time and across a wide variety of fields will be vital to delivering on one of the key attributes of the CC, a common genetic reference platform for identifying causative variants and genetic networks determining traits in mammals.

Figures

Figure 1
Figure 1
Breeding scheme of CC lines. The figure shows the breeding scheme for three independent CC lines. Each line has a funnel section followed by an inbreeding section. The eight founder strains are arranged in different positions (1–8) in each line, and this order determines the funnel code on the basis of a single letter code for each line. Founder order is randomized and not repeated across lines. The colors used for founder strains are seen throughout this article. Each mouse is represented by a pair of homologous autosomes and a symbol denoting its sex.
Figure 2
Figure 2
Overall contribution of the eight CC founder strains to the autosomes of the CC lines. The stacked columns show the founder contribution to the overall CC, CC-UNC, CC-TAU, and CC-GND populations.
Figure 3
Figure 3
Local founder strain contribution along the autosomes. (A) The CC population, (B) CC-UNC population, (C) CC-TAU population, and (D) CC-GND population. The percentage contribution from each founder is represented as a continuous line using the color schema shown in Figure 1. The dotted lines represent the threshold for TRD at P = 0.05 adjusted for genome-wide significance.
Figure 4
Figure 4
Local founder strain contribution on chromosome X. (A) Final CC population, (B) CC-UNC population, (C) CC-TAU, and (D) CC-GND population. The percentage contribution from each founder is represented as a continuous line using the color schema shown in Figure 1. The dotted lines represent the threshold for TRD at P = 0.05 adjusted for genome-wide significance.
Figure 5
Figure 5
Subspecific contribution to the genome of the CC lines. Each pie chart depicts the fraction of the genome that has a given pattern of subspecific contribution in each set of lines. (A) Subspecific contribution in the five CC founder strains that are classified as classical (A/J, 129S1SvImJ, C57BL/6J, NOD/ShiLtJ, and NZO/HILtJ). (B) Subspecific contribution in the eight CC founders. (C) Subspecific contribution in the 308 lines that represent the combined CC-UNC and CC-TAU populations. Blue represents M. m. domesticus, red represents M. m. musculus, and green represents M. m. castaneus. A scale in percentage is provided in B.
Figure 6
Figure 6
Linkage and gametic disequilibrium in mouse GRPs. Chromosomes are arranged in sequential order in the horizontal axis and the color of each pixel represents the maximum level of LD at that pair. The tick boxes denote the maximum level of gametic disequilibrium found genome-wide for each 500-kb window. (A) Mean level of maximum LD in 100 random sets of 88 CC lines. (B) A panel of 88 mouse inbred strains. The additional box at the bottom of the panel represents the cumulative contribution of the subspecies to the panel 88 of inbred strains. Blue represents M. m. domesticus, red represents M. m. musculus, and green represents M. m. castaneus.

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