Genomes of the Mouse Collaborative Cross

Abstract

The Collaborative Cross (CC) is a multiparent panel of recombinant inbred (RI) mouse strains derived from eight founder laboratory strains. RI panels are popular because of their long-term genetic stability, which enhances reproducibility and integration of data collected across time and conditions. Characterization of their genomes can be a community effort, reducing the burden on individual users. Here we present the genomes of the CC strains using two complementary approaches as a resource to improve power and interpretation of genetic experiments. Our study also provides a cautionary tale regarding the limitations imposed by such basic biological processes as mutation and selection. A distinct advantage of inbred panels is that genotyping only needs to be performed on the panel, not on each individual mouse. The initial CC genome data were haplotype reconstructions based on dense genotyping of the most recent common ancestors (MRCAs) of each strain followed by imputation from the genome sequence of the corresponding founder inbred strain. The MRCA resource captured segregating regions in strains that were not fully inbred, but it had limited resolution in the transition regions between founder haplotypes, and there was uncertainty about founder assignment in regions of limited diversity. Here we report the whole genome sequence of 69 CC strains generated by paired-end short reads at 30× coverage of a single male per strain. Sequencing leads to a substantial improvement in the fine structure and completeness of the genomes of the CC. Both MRCAs and sequenced samples show a significant reduction in the genome-wide haplotype frequencies from two wild-derived strains, CAST/EiJ and PWK/PhJ. In addition, analysis of the evolution of the patterns of heterozygosity indicates that selection against three wild-derived founder strains played a significant role in shaping the genomes of the CC. The sequencing resource provides the first description of tens of thousands of new genetic variants introduced by mutation and drift in the CC genomes. We estimate that new SNP mutations are accumulating in each CC strain at a rate of 2.4 ± 0.4 per gigabase per generation. The fixation of new mutations by genetic drift has introduced thousands of new variants into the CC strains. The majority of these mutations are novel compared to currently sequenced laboratory stocks and wild mice, and some are predicted to alter gene function. Approximately one-third of the CC inbred strains have acquired large deletions (>10 kb) many of which overlap known coding genes and functional elements. The sequence of these mice is a critical resource to CC users, increases threefold the number of mouse inbred strain genomes available publicly, and provides insight into the effect of mutation and drift on common resources.

Quantitative trait mapping in Diversity Outbred mice identifies two genomic regions associated with heart size

“…The breeding scheme for the DO is specifically designed to minimize the impact of genetic drift and new mutations; however, the use of partially inbred CC lines to seed the DO may have introduced new variants not present in the sequenced genome of the founder strains (Chesler et al 2016). Every CC strain has accumulated unique variation, primarily due to genetic drift, which is not present in the eight founder strains (Srivastava et al 2017; Shorter et al 2017). The frequency of these mutations is low; however, in functional mutations, there is an increase in phenotypic variance within a haplotype.Whole genomic sequencing studies will exploit this variation when sequencing costs decline.…”

Sex Differences in Early Embryogenesis: Inter‐Chromosomal Regulation Sets the Stage for Sex‐Biased Gene Networks

“…Some genes involved in polygenic traits may be expressed at equivalent levels but have different effects in each sex. [119] Future work should focus on connecting dimorphisms during development to adult phenotypes. Biases in alternative splice forms have not been fully investigated, although our data suggests that they exist and can change the structure of the proteins they encode.…”

Whole exome sequencing of wild-derived inbred strains of mice improves power to link phenotype and genotype

“…Several important features contribute to their utility, including a high quality reference genome with more than a decade’s worth of improved assembly and annotation (Church et al 2009; Waterston et al 2002), multiple complete genomes from distinct genetic strains (Keane et al 2011; Nikolskiy et al 2015; Srivastava et al 2017; Wang et al 2016; Waterston et al 2002; Wong et al 2012) and wild individuals (Harr et al 2016), and dense genotyping of commonly used laboratory strains (Laurie et al 2007; Lindblad-Toh et al 2000; Petkov et al 2004; Wade et al 2002; Yang et al 2007; Yang et al 2009; Yang et al 2011). Thousands of phenotypes have been gathered from hundreds of inbred mouse strains (Grubb et al 2004; Wang et al 2016; White et al 2013), many of which are commercially available through institutions like The Jackson Laboratory.…”