Academic journal article Genetics

Genomes of the Mouse Collaborative Cross

Academic journal article Genetics

Genomes of the Mouse Collaborative Cross

Article excerpt

GENETIC reference populations derived from multiple parents, or multiparent populations (MPPs), have become popular in a wide variety ofmodel organisms (Churchill et al. 2004; Kover et al. 2009; Huang et al. 2011; King et al. 2012; Bouchet etai. 2017; Cubillos etai. 2017; King and Long 2017; Mangandi et al. 2017; Najarro et al. 2017; Raghavan et al. 2017: Stanley et al. 2017; Tisné et al. 2017). The Collaborative Cross (CC) (Supplemental Material, Table S1 lists all abbreviations used throughout this manuscript) is a mouse MPP derived from eight inbred strains that was initially conceived as a mapping population for complex traits and as a platform for integration of phenotypic data across a reproducible set of variable genotypes (our approach to infuse genetics into the field of systems biology) (Threadgill et al. 2002; Churchill et al. 2004). The CC project first had to overcome an assortment of logistic and financial hurdles (Chesler et al. 2008; Iraqi et al. 2008; Morahan et al. 2008; Collaborative Cross Consortium 2012). More importantly, our goals had to face the unrelenting resistance of biology that led to an extraordinary rate of extinction among the hundreds of CC lines that were initially set up (Shorter et al 2017). Despite these challenges, the CC has been used successfully in both complex trait mapping and systems genetics (Aylor et al. 2011; Kelada et al. 2012; Ferris et al. 2013; Gralinski et al. 2015, 2017; Green et al. 2017). All of these studies point to the expansion of the phenotypic range previously described in laboratory mice and its continuous distribution for many traits. In addition, these studies reported the breakdown of phenotypic correlations previously thought to be hardwired. It has become evident that CC strains represent a rich source of murine models for human diseases that do not exist or are underrepresented in standard laboratory mice (Rogala et al 2014). A timely example of convergence of the main three uses of the CC is provided by a recent study on the effect of genetic variation on Ebola virus susceptibility (Rasmussen et al. 2014).

The CC has been a catalyst for the development of many new resources and tools for mouse genetics. For example, the Diversity Outbred (DO) population is a popular outbred MPP derived from a subset of incompletely inbred CC lines (Svenson et al. 2012). Tracking the inbreeding and founder contribution in the CC was the motivation behind the development of widely used genotyping platforms such as the Mouse Diversity Array (Yang et al. 2009) and the several iterations of the Mouse Universal Genotyping Array (MUGA) (Collaborative Cross Consortium 2012; Morgan et al. 2015). The CC was the seed for the development of a wide variety of analytic and informatics tools and methods from haplotype mosaic reconstruction, to improvement in the interpretation of genotyping arrays, to genotype imputation of mouse populations, and to new databases (Mott et al. 2000; Fu et al. 2012; Welshetal. 2013; Gattietal. 2014; Oreperetal. 2017). Finally, mouse MPPs in general and the CC and DO in particular were an impetus to sequencing, characterization, and de novo assembly of the genomes of an ever-expanding collection of mouse laboratory strains (Keane et al. 2011; Yalcin et al. 2011; Wong etal. 2012; Ananda etal. 2014; Doran etal. 2016; Morgan et al. 2016a). Collectively these contributions have opened new and exciting avenues to answer key long-standing biological questions (Chick etal. 2016; Morgan etal. 2017).

Previous studies have reported the genotypes of incompletely inbred CC lines, typically one mouse per line (Aylor et al. 2011; Kelada et al. 2012; Ferris et al. 2013; Gralinski et al. 2015). More importantly in 2012 a large collaborative study reported the CC genome architecture based on genotypes of a single mouse from >300 CC lines using the first iteration of the MUGA family of arrays (Collaborative Cross Consortium 2012). This study included CC lines from all three breeding sites that contributed to the CC population [Oak Ridge National Laboratory (ORNL), United States; Tel Aviv University (Tau), Israel; Geniad LLC (Geni), Australia]. …

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