Deconstructing Mus gemischus: advances in understanding ancestry, structure, and variation in the genome of the laboratory mouse

Abstract

The laboratory mouse is an artificial construct with a complex relationship to its natural ancestors. In 2002, the mouse became the first mammalian model organism with a reference genome. Importantly, the mouse genome sequence was assembled from data on a single inbred laboratory strain, C57BL/6. Several large-scale genetic variant discovery efforts have been conducted, resulting in a catalog of tens of millions of SNPs and structural variants. High-density genotyping arrays covering a subset of those variants have been used to produce hundreds of millions of genotypes in laboratory stocks and a small number of wild mice. These landmark resources now enable us to determine relationships among laboratory mice, assign local ancestry at fine scale, resolve important controversies, and identify a new set of challenges—most importantly, the troubling scarcity of genetic data on the very natural populations from which the laboratory mouse was derived. Our aim with this review is to provide the reader with an historical context for the mouse as a model organism and to explain how practical decisions made in the past have influenced both the architecture of the laboratory mouse genome and the design and execution of current large-scale resources. We also provide examples on how the accomplishments of the past decade can be used by researchers to streamline the use of mice in their experiments and correctly interpret results. Finally, we propose future steps that will enable the mouse community to extend its successes in the decade to come.

“Drinking in the Dark” (DID): A Simple Mouse Model of Binge‐Like Alcohol Intake

“…C57BL/6J have become the ‘reference genome” for mouse studies, but they have many idiosyncracies that distinguish them from most murine genotypes (Didion and de Villena, 2013). Genetic contributions are important determinants of DID avidity.…”

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

“…Wild derived inbred strains represent independent derivations from particular geographic areas. In contrast, classical inbred strains derive from a small pool of founders whose origins trace to Japanese and European mouse fanciers (Beck et al 2000; Frazer et al 2007; Moriwaki 1994; Morse 1978; Morse 2007; Silver 1995; Wade and Daly 2005; Wade et al 2002), who likely crossed strains from different geographic or species origins prior to inbreeding (Didion and Villena 2013; Keane et al 2011; Yang et al 2007; Yang et al 2011). As a result, 97% of the genome of classical inbred strains can be traced to 10 different haplotypes (Yang et al 2011).…”

PWD/PhJ mice have a genetically determined increase in nutrient-stimulated insulin secretion

“…However, many of the routinely studied strains have common ancestors (Didion and de Villena 2013;Mott 2007), limiting their genetic and phenotypic variability. To overcome this problem, new inbred strains were created from wild-caught mice.…”

“…To overcome this problem, new inbred strains were created from wild-caught mice. These wild-derived inbred strains are unrelated to the commonly studied strains (Didion and de Villena 2013;Keane et al 2011;Petkov et al 2004). As such, they are genetically very different to the common strains.…”