Complete overview of protein-inactivating sequence variations in 36 sequenced mouse inbred strains.

Mouse inbred strains remain essential in science. We have analyzed the publicly available genome sequences of 36 popular inbred strains and provide lists for each strain of protein-coding genes that acquired sequence variations that cause premature STOP codons, loss of STOP codons and single nucleotide polymorphisms, and short in-frame insertions and deletions. Our data give an overview of predicted defective proteins, including predicted impact scores, of all these strains compared with the reference mouse genome of C57BL/6J. These data can also be retrieved via a searchable website (mousepost.be) and allow a global, better interpretation of genetic background effects and a source of naturally defective alleles in these 36 sequenced classical and high-priority mouse inbred strains.

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

The house mouse is a powerful model to dissect the genetic basis of phenotypic variation, and serves as a model to study human diseases. Despite a wealth of discoveries, most classical laboratory strains have captured only a small fraction of genetic variation known to segregate in their wild progenitors, and existing strains are often related to each other in complex ways. Inbred strains of mice independently derived from natural populations have the potential to increase power in genetic studies with the addition of novel genetic variation. Here, we perform exome-enrichment and high-throughput sequencing (~8× coverage) of 26 wild-derived strains known in the mouse research community as the "Montpellier strains." We identified 1.46 million SNPs in our dataset, approximately 19% of which have not been detected from other inbred strains. This novel genetic variation is expected to contribute to phenotypic variation, as they include 18,496 nonsynonymous variants and 262 early stop codons. Simulations demonstrate that the higher density of genetic variation in the Montpellier strains provides increased power for quantitative genetic studies. Inasmuch as the power to connect genotype to phenotype depends on genetic variation, it is important to incorporate these additional genetic strains into future research programs.

Translating Mouse Models.

Mice and humans branched from a common ancestor approximately 80 million years ago. Despite this, mice are routinely utilized as animal models of human disease and in drug development because they are inexpensive, easy to handle, and relatively straightforward to genetically manipulate. While this has led to breakthroughs in the understanding of genotype-phenotype relationships and in the identification of therapeutic targets, translation of beneficial responses to therapeutics from mice to humans has not always been successful. In a large part, these differences may be attributed to variations in the alignment of protein expression and signaling in the immune systems between mice and humans. Well-established inbred strains of "The Laboratory Mouse" vary in their immune response patterns as a result of genetic mutations and polymorphisms arising from intentional selection for research relevant traits, and even closely related substrains vary in their immune response patterns as a result of genetic mutations and polymorphisms arising from genetic drift. This article reviews some of the differences between the mouse and human immune system and between inbred mouse strains and shares examples of how these differences can impact the usefulness of mouse models of disease.

Mechanistic basis of infertility of mouse intersubspecific hybrids.

According to the Dobzhansky-Muller model, hybrid sterility is a consequence of the independent evolution of related taxa resulting in incompatible genomic interactions of their hybrids. The model implies that the incompatibilities evolve randomly, unless a particular gene or nongenic sequence diverges much faster than the rest of the genome. Here we propose that asynapsis of heterospecific chromosomes in meiotic prophase provides a recurrently evolving trigger for the meiotic arrest of interspecific F1 hybrids. We observed extensive asynapsis of chromosomes and disturbance of the sex body in >95% of pachynemas of Mus m. musculus × Mus m. domesticus sterile F1 males. Asynapsis was not preceded by a failure of double-strand break induction, and the rate of meiotic crossing over was not affected in synapsed chromosomes. DNA double-strand break repair was delayed or failed in unsynapsed autosomes, and misexpression of chromosome X and chromosome Y genes was detected in single pachynemas and by genome-wide expression profiling. Oocytes of F1 hybrid females showed the same kind of synaptic problems but with the incidence reduced to half. Most of the oocytes with pachytene asynapsis were eliminated before birth. We propose the heterospecific pairing of homologous chromosomes as a preexisting condition of asynapsis in interspecific hybrids. The asynapsis may represent a universal mechanistic basis of F1 hybrid sterility manifested by pachytene arrest. It is tempting to speculate that a fast-evolving subset of the noncoding genomic sequence important for chromosome pairing and synapsis may be the culprit.

On the subspecific origin of the laboratory mouse.

The genome of the laboratory mouse is thought to be a mosaic of regions with distinct subspecific origins. We have developed a high-resolution map of the origin of the laboratory mouse by generating 25,400 phylogenetic trees at 100-kb intervals spanning the genome. On average, 92% of the genome is of Mus musculus domesticus origin, and the distribution of diversity is markedly nonrandom among the chromosomes. There are large regions of extremely low diversity, which represent blind spots for studies of natural variation and complex traits, and hot spots of diversity. In contrast with the mosaic model, we found that most of the genome has intermediate levels of variation of intrasubspecific origin. Finally, mouse strains derived from the wild that are supposed to represent different mouse subspecies show substantial intersubspecific introgression, which has strong implications for evolutionary studies that assume these are pure representatives of a given subspecies.

The International Mouse Strain Resource (IMSR): cataloging worldwide mouse and ES cell line resources.

The availability of and access to quality genetically defined, health-status known mouse resources is critical for biomedical research. By ensuring that mice used in research experiments are biologically, genetically, and health-status equivalent, we enable knowledge transfer, hypothesis building based on multiple data streams, and experimental reproducibility based on common mouse resources (reagents). Major repositories for mouse resources have developed over time and each has significant unique resources to offer. Here we (a) describe The International Mouse Strain Resource that offers users a combined catalog of worldwide mouse resources (live, cryopreserved, embryonic stem cells), with direct access to repository sites holding resources of interest and (b) discuss the commitment to nomenclature standards among resources that remain a challenge in unifying mouse resource catalogs.

An integrated genomics approach to identify genetic regions associated with neonatal growth trait in mice.

Neonatal growth during the early post-partum period is closely associated with lactation performance. Neonatal growth reflects milk output and is a complex variable trait among inbred mouse strains, but few studies have compared this trait systematically across more than a few strains. In the present study, 11 inbred strains of mice were measured for a neonatal growth phenotype during the first eight days of lactation. Significant differences in neonatal growth trait were observed with QSi5 (3.71±0.05 g) and DBA/1J (2.67±0.06 g) strains defining the two extremes of the phenotype. In silico association analysis was performed for trait variability using the high density SNP information on inbred strains of mice. We found strong evidence to refine a previously identified large neonatal growth QTL on mouse chromosome 9, Neogq1. When an integrated strategy that combined fine mapping and analysis of mammary transcriptome expression profiles of lactating mice with divergent phenotypes was applied, we identified neogenin (Neo1), a gene important for mammary gland morphogenesis, as a likely quantitative trait gene (QTG) underlying the Neogq1 QTL in mice.

Divergent physiological characteristics and responses to endurance training among inbred mouse strains.

Both baseline values and adaptive changes in mice can vary depending on the genetic background. We aimed to assess variation in a battery of variables and their adaptations to endurance training in six inbred mouse strains. Males, n = 184, from A/J, BALB/cByJ, C3H/HeJ, C57BL/6J, DBA/2J, and PWD/PhJ strains were assigned to a control or an endurance group (5 weeks swimming exercise). Enzyme activity, histology of soleus (SOL) muscle, swimming endurance, cardiac ventricular and hind limb muscle weight, and femur length were examined. Endurance capacity, morphological and histological variables, and enzyme activity substantially differed among strains. For example, SOL weight was twofold higher and cross-sectional area (CSA) of fibers was ≈ 30% greater in C57BL/6J than in PWD/PhJ strain. The CSA of type 1 fibers were larger than type 2A in PWD/PhJ (P < 0.01); however, the reverse was true in DBA/2J and BALB/cByJ strains (P < 0.05). Swimming endurance in DBA/2J strain was ≈ 9 times better than in BALB/cByJ. Endurance training increased the activity of citrate synthase in gastrocnemius across strains (P < 0.01), however, changes in endurance were strain-specific; the C57BL/6J and DBA/2J strains improved substantially, whereas A/J and BALB/cByJ strains did not. In conclusion, genetic background is a potent determinant of the physiological characteristics and adaptations to training in mice.

Immunological variation between inbred laboratory mouse strains: points to consider in phenotyping genetically immunomodified mice.

Inbred laboratory mouse strains are highly divergent in their immune response patterns as a result of genetic mutations and polymorphisms. The generation of genetically engineered mice (GEM) has, in the past, used embryonic stem (ES) cells for gene targeting from various 129 substrains followed by backcrossing into more fecund mouse strains. Although common inbred mice are considered "immune competent," many have variations in their immune system-some of which have been described-that may affect the phenotype. Recognition of these immune variations among commonly used inbred mouse strains is essential for the accurate interpretation of expected phenotypes or those that may arise unexpectedly. In GEM developed to study specific components of the immune system, accurate evaluation of immune responses must take into consideration not only the gene of interest but also how the background strain and microbial milieu contribute to the manifestation of findings in these mice. This article discusses points to consider regarding immunological differences between the common inbred laboratory mouse strains, particularly in their use as background strains in GEM.

Mouse phenome database.

The Mouse Phenome Database (MPD; http://www.jax.org/phenome) is an open source, web-based repository of phenotypic and genotypic data on commonly used and genetically diverse inbred strains of mice and their derivatives. MPD is also a facility for query, analysis and in silico hypothesis testing. Currently MPD contains about 1400 phenotypic measurements contributed by research teams worldwide, including phenotypes relevant to human health such as cancer susceptibility, aging, obesity, susceptibility to infectious diseases, atherosclerosis, blood disorders and neurosensory disorders. Electronic access to centralized strain data enables investigators to select optimal strains for many systems-based research applications, including physiological studies, drug and toxicology testing, modeling disease processes and complex trait analysis. The ability to select strains for specific research applications by accessing existing phenotype data can bypass the need to (re)characterize strains, precluding major investments of time and resources. This functionality, in turn, accelerates research and leverages existing community resources. Since our last NAR reporting in 2007, MPD has added more community-contributed data covering more phenotypic domains and implemented several new tools and features, including a new interactive Tool Demo available through the MPD homepage (quick link: http://phenome.jax.org/phenome/trytools).

Immunoglobulin Light Chain Gene Rearrangements, Receptor Editing and the Development of a Self-Tolerant Antibody Repertoire.

Discussion of the antibody repertoire usually emphasizes diversity, but a conspicuous feature of the light chain repertoire is its lack of diversity. The diversity of reported allelic variants of germline light chain genes is also limited, even in well-studied species. In this review, the implications of this lack of diversity are considered. We explore germline and rearranged light chain genes in a variety of species, with a particular focus on human and mouse genes. The importance of the number, organization and orientation of the genes for the control of repertoire development is discussed, and we consider how primary rearrangements and receptor editing together shape the expressed light chain repertoire. The resulting repertoire is dominated by just a handful of IGKV and IGLV genes. It has been hypothesized that an important function of the light chain is to guard against self-reactivity, and the role of secondary rearrangements in this process could explain the genomic organization of the light chain genes. It could also explain why the light chain repertoire is so limited. Heavy and light chain genes may have co-evolved to ensure that suitable light chain partners are usually available for each heavy chain that forms early in B cell development. We suggest that the co-evolved loci of the house mouse often became separated during the inbreeding of laboratory mice, resulting in new pairings of loci that are derived from different sub-species of the house mouse. A resulting vulnerability to self-reactivity could explain at least some mouse models of autoimmune disease.

Sixteen diverse laboratory mouse reference genomes define strain-specific haplotypes and novel functional loci.

We report full-length draft de novo genome assemblies for 16 widely used inbred mouse strains and find extensive strain-specific haplotype variation. We identify and characterize 2,567 regions on the current mouse reference genome exhibiting the greatest sequence diversity. These regions are enriched for genes involved in pathogen defence and immunity and exhibit enrichment of transposable elements and signatures of recent retrotransposition events. Combinations of alleles and genes unique to an individual strain are commonly observed at these loci, reflecting distinct strain phenotypes. We used these genomes to improve the mouse reference genome, resulting in the completion of 10 new gene structures. Also, 62 new coding loci were added to the reference genome annotation. These genomes identified a large, previously unannotated, gene (Efcab3-like) encoding 5,874 amino acids. Mutant Efcab3-like mice display anomalies in multiple brain regions, suggesting a possible role for this gene in the regulation of brain development.

Strain-specific differential expression of astrocytes and microglia in the mouse hippocampus.

Introduction: Genetic background influences neurotransmitter expression and function of the hippocampus. Genetic background influences the phenotype of the hippocampus, but expression of neuroglia in hippocampus has not been well established dependent on various mouse strains. Objectives: In this study, we investigated the effects of genetic background on cell population of astrocytes and microglia in eight widely used inbred strains (C57BL/6J, A/J, BALB/c, C3H/HeJ, FVB, 129/SvJ, DBA/1, and DBA/2) and one outbred strain (ICR). Methods: In all mouse strains, glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes and ionized calcium-binding adaptor molecule 1 (Iba-1)-immunoreactive microglia were found in almost all layers of hippocampal CA1-4 regions and the dentate gyrus. Results: We observed significant differences in the number of astrocytes and microglia. In the CA1 and CA3 regions, the number of GFAP-immunoreactive astrocytes was highest in the C3H/HeJ strain, and lowest in the 129/SvJ and FVB strains. In the polymorphic layer of the dentate gyrus, the number was highest in the DBA/1 strain and lowest in the 129/SvJ strain. Among the nine mouse strains, the number of Iba-1-immunoreactive microglia was highest in the CA1 and CA3 regions in the ICR and in the dentate gyrus of the C57BL/6 strain. The CA1 region of the FVB strain and the CA3 region and dentate gyrus of DBA/2 had the lowest number of Iba-1-immunoreactive microglia. Conclusion: These results suggest that the numbers of astrocytes and microglia differ depending on the mouse strain and these differences may be related to strain-dependent function of astrocytes.

Strain-dependent acute lung injury after intra-tracheal administration of a 'refined' aniline-denatured rapeseed oil: a murine model of the toxic oil syndrome?

Most attempts to reproduce the toxic oil syndrome in animals, either with case-related oils or with refined rapeseed oils, have been unsuccessful. An aniline-denatured rapeseed oil that was subsequently refined according to a protocol yielding relevant markers of "toxic oil" (oil RSO160401) had led to possibly relevant lesions following oral administration in mice. Therefore, in the present study, RSO160401 was subjected to a more extended in vivo testing. To try and maximize the response, BALB/c, DBA/2, A/J, and C57BL/6 mice were administered RSO160401 oil by a single intra-tracheal instillation (1ml/kg), with sacrifice 2 or 7 days post-exposure. Intra-tracheal administration led to a strain-dependent acute response: acute pulmonary damage in DBA/2 and A/J mice, and increases in blood eosinophilia in DBA/2 mice (6.5% vs 3.1% in controls). The pulmonary lesions regressed with time after exposure, being more complete in A/J than in DBA/2 mice. The observation of strain-dependent effects suggests that genetic susceptibility is an important factor in disease induction by the RSO160401 oil.

Genetic influence on neurogenesis in the dentate gyrus of two strains of adult mice.

Previous studies have suggested that there is a genetic influence on the regulation of cell proliferation and survival within the hippocampus. However, the links between perturbations in neurogenesis and genomic control remain unclear. Here, we examined the impact of mouse strain on four parameters of the neurogenic program, proliferation, migration, differentiation and survival in the dentate gyrus of the hippocampus as a means of determining whether allelic variation of two independently derived mouse strains, FVB/NJ and C57BL/6J, modulates basal adult murine dentate gyrus neurogenesis. New cells were labeled with the thymidine analogue 5-bromo-2'-deoxyuridine (BrdU) and their identity was determined immunocytochemically with various phenotypic markers. Consistent with previous studies in other strains of mice, we observed a strain-dependent difference in hippocampal proliferation. Hippocampal cell proliferation in FVB/NJ mice was reduced as compared to animals of the C57BL/6J strain. In contrast, the number of surviving cells in C57BL/6J mice was not significantly different from FVB/NJ mice. Regardless of mouse strain, the majority of surviving BrdU-labeled cells migrated into the granule cell layer and was of a neuronal phenotype. However, fewer surviving cells were located within the granule cell layer of FVB/NJ mice as compared to C57BL/6J mice. Overall, regardless of strain, no significant differences in the relative ratio of neurogenesis versus gliagenesis were observed. These results suggest that genetic background primarily influences newborn cell proliferation and migration, but not differentiation or survival.

Standardized nomenclature for inbred strains of mice: seventh listing for the International Committee on Standardized Genetic Nomenclature for Mice.

This paper presents a list of inbred strains of mice with their origins and characteristics, a table of the strain distribution of alleles at polymorphic loci, and a list of standard subline designations.

Accessing Data Resources in the Mouse Phenome Database for Genetic Analysis of Murine Life Span and Health Span.

Understanding the source of genetic variation in aging and using this variation to define the molecular mechanisms of healthy aging require deep and broad quantification of a host of physiological, morphological, and behavioral endpoints. The murine model is a powerful system in which to understand the relations across age-related phenotypes and to identify research models with variation in life span and health span. The Jackson Laboratory Nathan Shock Center of Excellence in the Basic Biology of Aging has performed broad characterization of aging in genetically diverse laboratory mice and has placed these data, along with data from several other major aging initiatives, into the interactive Mouse Phenome Database. The data may be accessed and analyzed by researchers interested in finding mouse models for specific aging processes, age-related health and disease states, and for genetic analysis of aging variation and trait covariation. We expect that by placing these data in the hands of the aging community that there will be (a) accelerated genetic analyses of aging processes, (b) discovery of genetic loci regulating life span, (c) identification of compelling correlations between life span and susceptibility for age-related disorders, and (d) discovery of concordant genomic loci influencing life span and aging phenotypes between mouse and humans.

Whole Genome Sequence of Two Wild-Derived Mus musculus domesticus Inbred Strains, LEWES/EiJ and ZALENDE/EiJ, with Different Diploid Numbers.

Wild-derived mouse inbred strains are becoming increasingly popular for complex traits analysis, evolutionary studies, and systems genetics. Here, we report the whole-genome sequencing of two wild-derived mouse inbred strains, LEWES/EiJ and ZALENDE/EiJ, of Mus musculus domesticus origin. These two inbred strains were selected based on their geographic origin, karyotype, and use in ongoing research. We generated 14× and 18× coverage sequence, respectively, and discovered over 1.1 million novel variants, most of which are private to one of these strains. This report expands the number of wild-derived inbred genomes in the Mus genus from six to eight. The sequence variation can be accessed via an online query tool; variant calls (VCF format) and alignments (BAM format) are available for download from a dedicated ftp site. Finally, the sequencing data have also been stored in a lossless, compressed, and indexed format using the multi-string Burrows-Wheeler transform. All data can be used without restriction.

Strain differences in toxicity of oral cadmium intake in rats.

Influence of genetic background on toxicity of oral cadmium (Cd) administration (30 days, in drinking water; 5 ppm and 50 ppm of cadmium) was examined in Albino Oxford (AO) and Dark Agouti (DA) rats. Similar cadmium deposition was noted in gut and draining mesenteric lymph nodes (MLN) of both strains but intensity and/or the pattern of responses to cadmium in these tissues differ. Less intense intestinal damage and leukocyte infiltration was observed in gut of cadmium-exposed AO rats. While gut-associated lymph node cells of DA rats responded to cadmium with an increase of cell proliferation, oxidative activity, IFN-γ, IL-17 production and expression, no changes of these activities of MLN cells of cadmium-treated AO rats were observed. Spleen, which accumulated cadmium comparable to MLN, responded to metal by drop in cell viability and by reduced responsiveness of proliferation and cytokine production to stimulation in DA rats solely, which suggest tissue dependence of cadmium effects. More pronounced cadmium effects on MLN and spleen cells of DA rats (which accumulated similar cadmium doses as AO rats), showed greater susceptibility of this strain to cadmium. The results presented, for the first time, depict the influence of genetic background to effects of oral cadmium administration.