Mouse Genome Mapping and Genomics

Abstract

Mice probably first became associated with humans after the domestication of grasses, about 10,000–12,000 years ago. More recently, mice have become the most widely used mammalian laboratory animal, in particular because of the extensive genetic “tool-box” available to manipulate the mouse genome. Mice are prolific, have short generation times, and can be inbred successfully, traits that have contributed to their use in genetics. One of the most versatile genetic “tools” in the mouse is the ability to modify almost any sequence in embryonic stem cells and for the altered allele to be inherited. The resulting “knockout” mice have been used to model many human diseases. The first mouse genome map was constructed by linkage analysis of mutations that caused visible traits and is still of immense value, but the development of rapid genome sequencing has accelerated the task of identifying underlying causative variants. The mouse genome, composed of 20 pairs of nuclear chromosomes and a mitochondrial chromosome, contains about 22,000 protein-coding genes. By comparison with the human genome sequence, it is clear that there has been both expansion and contraction of specific protein coding gene families in the mouse. Genes that encode functional RNAs, rather than proteins, are also abundant in the mouse; a notable example is the XIST long noncoding RNA, which plays a key role in equalizing transcript levels for X-linked genes between the sexes. The mouse has been the subject of intense functional analysis, using not only gene knockouts, but also conditional mutagenesis, RNAi knockdowns, and random mutagenesis producing point mutations, deletions, and rearrangements. Systematic phenotyping is being applied to these mutant lines and also to genetic reference populations (GRP) to better capture novel traits. The genetic and functional genomic tool-box in the mouse has grown extensively in the last two decades and we are ever closer to achieving the goal of determining function(s) for every mouse gene and so, by inference, for their human equivalent.

Glossary

Congenic strains

In which selected chromosomal regions from one inbred strain have been introgressed onto the genetic background of a distinct strain.

Conplastic strains

Strains in which the mitochondrial genome from one strain has been transferred onto the nuclear genome of another.

Consomic strains

Special case of congenic strain, in which a whole chromosome from one inbred strain has been bred onto the genetic background of a distinct strain.

Heterogeneous stocks

Genetically heterogeneous stock of mice descended from a few, e.g., eight, inbred progenitor strains and derived from a pseudorandom breeding scheme over a large (~50) number of generations.

Inbred strains

Produced under a strict regime of at least 20 generations of sister–brother or equivalent matings—these mice will have minimal or no heterozygous loci.

Mutant stocks/strains

A mouse stock or inbred strain in which any permanent alteration in the DNA sequence, including chromosomal rearrangement or point mutation, has occurred.

Recombinant congenic strains

Strains produced by intercrossing two inbred strains, then back-crossing to one of the parental strains for a few generations (typically ~2–3 generations), then inbred, without any selection.

Recombinant inbred strains

A set of strains derived by the mating of individuals from the F2 generation of a cross of two inbred strains and from each subsequent generation in accordance with a strict routine of inbreeding.

Wild-derived strains

Inbred strains derived from wild-caught mice, e.g., MSM/Ms, which is derived from a Japanese wild mouse, Mus musculus molossinus.