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

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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.

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Acknowledgments

We are grateful to Ping Fu for preparing Supplementary Fig. 6 and to Jeremy Wang and Leonard McMillan for contributing to Box 1. We also thank François Bonhomme and an anonymous reviewer for their comments on an earlier version of the manuscript. JPD is supported by grants from the National Institutes of Health (P50MH090338 and P50HG006582 (to FPMV)). National Institute of General Medical Sciences Centers of Excellence supported critical work reviewed here in the Systems Biology program (Grant GM-076468).

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Authors and Affiliations

  1. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    John P. Didion & Fernando Pardo-Manuel de Villena

  2. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    John P. Didion & Fernando Pardo-Manuel de Villena

  3. Carolina Center for Genome Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    John P. Didion & Fernando Pardo-Manuel de Villena

Authors
  1. John P. Didion
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  2. Fernando Pardo-Manuel de Villena
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Corresponding authors

Correspondence to John P. Didion or Fernando Pardo-Manuel de Villena.

Additional information

Dedicated to Kenneth and Beverly Paigen and François Bonhomme for their outstanding contributions to the field of mouse genetics.

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335_2012_9441_MOESM2_ESM.xlsx

Table S1 Strains that have been genotyped at high-density or whole genome sequenced. Providers correspond to labeled circles in Figure 3. Trapping locations are shown for wild-derived strains. References: 1) Yang et al. 2011; 2) Keane et al. 2011; 3) Frazer et al. 2007; 4) Didion et al. 2012; 5) Zhang et al. 2012; 6) Yalcin et al. 2010; 7) Yazbek et al. 2010; 8) The Jackson Laboratory (http://www.jax.org). (XLSX 63 kb)

Glossary of terms

Ancestral polymorphism

A polymorphic locus known to be segregating in the most recent common ancestor of multiple lineages rather than having arisen following their divergence. Note that gene flow may lead to the appearance of ancestral polymorphism

Ascertainment bias

Systematic deviations from an expected theoretical result attributable to the sampling processes used to find (ascertain) SNPs and estimate their population-specific allele frequencies

Classical strain

An inbred laboratory strain derived from a small population of “fancy” mice beginning in the early 20th century

Commensal

A form of symbiosis in which one organism derives a benefit while the other is unaffected. House mice are traditionally called a commensal of humans however their status as economic pest and carriers of disease arguably classifies them as parasites

De novo assembly

Assembling a new genome without using an existing reference genome as a guide. De novo assembly is computationally difficult, but it has the benefit of assembling sequences that reference-guided alignment may miss due to their absence from the reference sequence

Diagnostic marker

A polymorphic marker for which one allele is present in only one population. In human studies, these are often referred to as ancestry-informative markers (AIMs). Alleles that are diagnostic for a single house mouse subspecies are used to assign subspecific origin to regions of the genome

Effective population size

The minimum size of a population that would be required to observe the same dispersion of allele frequencies under random genetic drift or the same amount of inbreeding as the population under consideration

Fancy mice

Mice bred as pets. The breeding of fancy mice selects for traits that are attractive to enthusiasts rather than researchers, such as interesting coat colors and behaviors. Fancy mice comprised the founder population of classical inbred strains

Haplotype

A collection of co-occurring, contiguous alleles. May be used to refer to the alleles at a specific locus or across the entire genome

House mouse

Common name for Mus musculus species. Includes three distinct subspecies: domesticus (Western Europe), musculus (Eastern Europe and North Asia), and castaneus (Southeast Asia). Laboratory mice are of house mouse origin but are a mixture of multiple subspecific origins

Hybrid zone

A boundary between two distinct interbreeding populations. The best-known example is the ~2,500-km-long European transect where M. m. domesticus and M. m. musculus meet

Imputation

A statistical method of deriving the complete sequence of a large number of samples using genotype information to identify matching haplotypes in a small number of reference sequences

Inbred strain

A mouse strain created by successive generations of sibling–sibling or parent–offspring mating, which results in a completely homozygous genome. Until the availability of high-density arrays, the consensus was to declare a strain homozygous after 20 generations of inbreeding

Introgression

The transmission of a novel allele into a population by hybridization followed by backcrossing to one of the parental populations

Monophyly

When a taxon forms a single clade in a phylogeny, meaning that it contains all descendants of the most recent common ancestor of all members of the group

Mosaic genome

A genome derived from multiple distinct ancestries. Mosaicism is identified by haplotype blocks that contain diagnostic alleles. The house mouse is a mosaic of the three M. musculus subspecies, although most of its genome is M. m. domesticus in origin

Mouse

In both colloquial and taxonomic usage the name “mouse” is applied to many different species of small mammals. We use the term strictly to refer to an animal belonging to genus Mus

Nucleotide diversity

The degree of polymorphism within a population. Calculated as the average number of nucleotide differences per site between any two DNA sequences chosen randomly from the sample population

Outbred stock

A heterogeneous strain typically maintained in a colony and allowed to random-mate. Outbred strains are primarily derived from intercrossing classical strains, including fancy mice of Swiss origin

Pan-genome

A consensus reference sequence created by aligning sequences from multiple individuals. Polymorphic sites may be annotated as heterozygous, or the most common allele may be assigned to that position in the consensus sequence

Pseudo-genome

A synthetic genome created by imputation. A new sample is genotyped and compared to multiple, fully assembled reference genomes. In each region, the most similar reference genome is identified, and those regions are concatenated

Reference genome

A whole-genome sequence that is agreed upon as the index for a species. The genome must be fully assembled and given positional annotations. This enables researchers to associate a physical position with genes and other genomic features. A reference genome may be created from a single individual or it may be a consensus of multiple individuals

Single nucleotide polymorphism (SNP)

A site in the genome that is polymorphic within a population

SNP discovery

Comparison of sequence from multiple individuals to identify polymorphic loci

Structural variation

A polymorphism that alters the structure rather than just the content, of the ancestral genome. Insertion and deletion (indels) of bases, ranging from single bases to entire genes, are the most common structural variation. Copy number variation is a special class of indel in which the number of copies of a short tandem repeat increases or decreases between generations

VINO

A type of genotypic marker that represents previously uncharacterized variation. Useful for counteracting ascertainment bias in phylogenetic studies (Didion et al. 2012)

Wild-derived strain

Generally, any laboratory strain that is not descended from the same common genetic pool as classical strains. Most wild-derived strains have been derived from wild-caught mice

Wild mouse

A mouse trapped in nature and not a product of any genetic manipulation or selective breeding

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Didion, J.P., de Villena, F.PM. Deconstructing Mus gemischus: advances in understanding ancestry, structure, and variation in the genome of the laboratory mouse. Mamm Genome 24, 1–20 (2013). https://doi.org/10.1007/s00335-012-9441-z

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