Mouse consomic strains: Exploiting genetic divergence between Mus m. musculus and Mus m. domesticus subspecies

Abstract

Consomic (chromosome substitution) strains (CSs) represent the most recent addition to the mouse genetic resources aimed to geneticaly analyze complex trait loci (QTLs). In this study, we report the development of a set of 28 mouse intersubspecific CSs. In each CS, we replaced a single chromosome of the C57BL/6J (B6) inbred strain (mostly Mus m. domesticus) with its homolog from the PWD/Ph inbred strain of the Mus m. musculus subspecies. These two progenitor subspecies diverged less than 1 million years ago and accumulated a large number of genetic differences that constitute a rich resource of genetic variation for QTL analyses. Altogether, the 18 consomic, nine subconsomic, and one conplastic strain covered all 19 autosomes, X and Y sex chromosomes, and mitochondrial DNA. Most CSs had significantly lower reproductive fitness compared with the progenitor strains. CSs homosomic for chromosomes 10 and 11, and the C57BL/6J-Chr X males, failed to reproduce and were substituted by less affected subconsomics carrying either a proximal, central, or distal part of the respective chromosome. A genome-wide scan of 965 DNA markers revealed 99.87% purity of the B6 genetic background. Thirty-three nonsynonymous substitutions were uncovered in the protein-coding regions of the mitochondrial DNA of the B6.PWD-mt conplastic strain. A pilot-phenotyping experiment project revealed a high number of variations among B6.PWD consomics.[Supplemental material is available online at www.genome.org. The sequence data from this study have been submitted to GenBank under accession no. DQ874614.]Consomic strains (CSs), also known as chromosome (chr) substitution strains, represent the newest addition to the mouse genetic resources aimed at a genetic analysis of complex traits. To construct a CS, the genomes of two inbred strains are combined so that one chromosome pair of the host strain is replaced by the corresponding chromosome pair of the donor strain (Nadeau et al. 2000). Since the mouse genome is composed of 19 pairs of autosomes, and X and Y gonosomes, 21 CSs constitute the complete set.Nadeau, Lander, and coworkers developed the first set of mouse CSs with the A/J strain as a chromosome donor and C57BL/6J (hereafter B6) as the recipient strain ). Another series of 65 genome-wide congenic (subconsomic) strains was created by transferring segments of individual autosomes of the DBA/2J strain on the background of B6 (Davis et al. 2005) that covered 95% of the autosomal genome. The transfer of sex chromosomes was not reported. Most recently, the same laboratory reported the construction of ∼40 congenic (subconsomic) strains from a CAST/Ei inbred strain of Mus m. castaneus origin (Davis et al. 2007). These strains cover ∼80% of CAST/Ei autosomes. The transfer of sex chromosomes and mitochondrial DNA was not reported. In the accompanying paper in this issue of Genome Research, Takada et al. (2008) describe a full set of consomic strains, using B6 as a background strain and the MSM/ Ms of Mus m. molossinus origin as the chromosome donor....

Genetic Dissection of a Key Reproductive Barrier Between Nascent Species of House Mice

“…In hybrid males, sterility is more common when M. m. musculus is the mother (Britton-Davidian et al 2005;Good et al 2008b;Vyskočilová et al 2009). The role for the M. m. musculus X chromosome suggested by these observations has been confirmed through backcrosses (Storchová et al 2004) and chromosomal introgression studies (Good et al 2008a;Gregorová et al 2008). Reduced gene flow of X-linked loci across the hybrid zone (Tucker et al 1992;Dod et al 1993;Munclinger et al 2002;Payseur et al 2004;Dod et al 2005;Macholán et al 2007) raises the possibility that this chromosome also confers hybrid male sterility in natural populations.…”

“…In addition, chromosome substitution lines that carry either chromosome 10 or 11 from M. m. musculus PWD on the genomic background of a classical inbred strain derived primarily from M. m. domesticus (C57BL/6J) show reduced fertility (Gregorová et al 2008).…”

“…Backcrosses between M. m. domesticus and Mus musculus molossinus (a hybrid between M. m. musculus and Mus musculus castaneus) have identified several autosomal QTL that affect hybrid sterility when the entire M. m. molossinus X chromosome is present on the M. m. domesticus genetic background (Oka et al 2007). Substituting M. m. musculus chromosomes 10 or 11 onto a mostly M. m. domesticus background (C57BL/6J inbred line) strongly reduces litter size (Gregorová et al 2008). Finally, some autosomal loci show reduced introgression across the European hybrid zone (Macholán et al 2007;Teeter et al 2008Teeter et al , 2010.…”

A Complex Genetic Basis to X-Linked Hybrid Male Sterility Between Two Species of House Mice

“…It is important to bear in mind, however, that a large X effect has not yet been demonstrated in mice, and this calculation is thus very rough. Two recent studies constructed large sets of consomic lines substituting individual chromosomes from M. m. molossinus (MSM/Ms; Takada et al 2008) or M. musculus (PWK/Ph; Gregorová et al 2008) on the background of the classic laboratory strain C57BL/6J. Both experiments uncovered putative incompatibilities involving most autosomes, with deleterious effects on strain reproduction and viability.…”

Mouse inter-subspecific consomic strains for genetic dissection of quantitative complex traits

“…Recently, Forejt and colleagues constructed another set of inter-subspecific consomic strains, using M. m. musculusderived PWD/Ph strain as the donor and B6 as the host strain (Gregorová et al 2008). Phenotyping of these consomic strains also detected a number of QTLs.…”