Genetic analysis in the Collaborative Cross breeding population

Abstract

Genetic reference populations in model organisms are critical resources for systems genetic analysis of disease related phenotypes. The breeding history of these inbred panels may influence detectable allelic and phenotypic diversity. The existing panel of common inbred strains reflects historical selection biases, and existing recombinant inbred panels have low allelic diversity. All such populations may be subject to consequences of inbreeding depression. The Collaborative Cross (CC) is a mouse reference population with high allelic diversity that is being constructed using a randomized breeding design that systematically outcrosses eight founder strains, followed by inbreeding to obtain new recombinant inbred strains. Five of the eight founders are common laboratory strains, and three are wild-derived. Since its inception, the partially inbred CC has been characterized for physiological, morphological, and behavioral traits. The construction of this population provided a unique opportunity to observe phenotypic variation as new allelic combinations arose through intercrossing and inbreeding to create new stable genetic combinations. Processes including inbreeding depression and its impact on allelic and phenotypic diversity were assessed. Phenotypic variation in the CC breeding population exceeds that of existing mouse genetic reference populations due to both high founder genetic diversity and novel epistatic combinations. However, some focal evidence of allele purging was detected including a suggestive QTL for litter size in a location of changing allele frequency. Despite these inescapable pressures, high diversity and precision for genetic mapping remain. These results demonstrate the potential of the CC population once completed and highlight implications for development of related populations.

The need for mouse models in osteoporosis genetics research

“…29 Some very interesting studies have now been completed using mice from the early stages of inbreeding the CC lines (so called ' pre-CC ' mice). These studies demonstrate that the breadth of values for a given phenotype measured in the pre-CC is greater than observed in the founder strains alone 31,32 ( Figure 1 ). Moreover, these traits display greater breadth of phenotypic variation than is observed when measured in a genetic mapping panel derived from two progenitor strains.…”

“…Moreover, these traits display greater breadth of phenotypic variation than is observed when measured in a genetic mapping panel derived from two progenitor strains. 32 The first CC genetic loci have also now been mapped. 31 -33 As predicted from the computer simulations, 34 QTL mapped in the pre-CC are an order of magnitude narrower than QTL mapped using an intercross mapping population.…”

“…31 -33 As predicted from the computer simulations, 34 QTL mapped in the pre-CC are an order of magnitude narrower than QTL mapped using an intercross mapping population. 31,32 For example, a QTL for periosteal circumference mapped to chromosome 19 had a confidence interval width of only 0.96 Mb containing five candidate genes. 32 The average confidence interval size of BMD QTL mapped using a traditional intercross population is ~ 32 cM.…”

“…31,32 For example, a QTL for periosteal circumference mapped to chromosome 19 had a confidence interval width of only 0.96 Mb containing five candidate genes. 32 The average confidence interval size of BMD QTL mapped using a traditional intercross population is ~ 32 cM. 20 Assuming that on average 1 cM equals 2 Mb and that there are on average 10 genes per Mb, 35 this equals ~ 640 candidate genes per QTL.…”

Mouse Genome Database: From sequence to phenotypes and disease models

“…Genetic engineering methodologies including CRISPR/Cas (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated sequences) engineering (Wang et al ., 2013) and elegant, technologies that allow spatiotemporal control of gene ablation and regulation are providing new insight into gene function through the use of conditional mutagenesis (Murray et al ., 2012). Other new resources for complex traits and QTL (Quantitative Trait Loci), including the Collaborative Cross (Collaborative Cross Consortium, 2012; Threadgill and Churchill, 2012) and Diversity Outbred mice (Churchill et al ., 2012; Svenson et al ., 2012), are beginning to bear fruit in analysis of complex and multigenic diseases (Philip et al ., 2011; Logan et al ., 2013; Chesler, 2014). …”