The AXB and BXA set of recombinant inbred mouse strains

Marshall, Jan D.; Mu, Jian-Long; Cheah, Yin-Chai; Nesbitt, Muriel N.; Frankel, Wayne N.; Paigen, Beverly

doi:10.1007/bf00444361

Cited by 70 publications

(39 citation statements)

References 73 publications

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“…BXD strains are inbred lines derived from brother-sister matings starting from an F 2 cross (12,13). AXB͞BXA are based on reciprocal intercrosses between C57BL͞6J and A͞J (14). Animals were kept in conventional laboratory cages with standard food and access to food and water ad libitum.…”

Section: Methodsmentioning

confidence: 99%

“…Strains DBA͞2J and A͞J show particularly large differences in adult neurogenesis from the canonical mouse strain, C57BL͞6J (1). In this study, we explored natural variation in adult hippocampal neurogenesis in two complementary sets of recombinant inbred (RI) strains of mice (BXD and AXB͞BXD), which represent inbred progeny of F 2 crosses from C57BL͞6J and DBA͞2J (BXD), and C57BL͞6J and A͞J (AXB͞BXA) (12)(13)(14). On average, and in large panels, each RI strain shows an Ϸ50:50 pattern of genome inherited from the parental strains and is homologous at every locus.…”

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confidence: 99%

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Natural variation and genetic covariance in adult hippocampal neurogenesis

Kempermann

Chesler

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

179

162

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Adult hippocampal neurogenesis is highly variable and heritable among laboratory strains of mice. Adult neurogenesis is also remarkably plastic and can be modulated by environment and activity. Here, we provide a systematic quantitative analysis of adult hippocampal neurogenesis in two large genetic reference panels of recombinant inbred strains (BXD and AXB͞BXA, n ‫؍‬ 52 strains). We combined data on variation in neurogenesis with a new transcriptome database to extract a set of 190 genes with expression patterns that are also highly variable and that covary with rates of (i) cell proliferation, (ii) cell survival, or the numbers of surviving (iii) new neurons, and (iv) astrocytes. Expression of a subset of these neurogenesis-associated transcripts was controlled in cis across the BXD set. These self-modulating genes are particularly interesting candidates to control neurogenesis. Among these were musashi (Msi1h) and prominin1͞CD133 (Prom1), both of which are linked to stem-cell maintenance and division. Twelve neurogenesis-associated transcripts had significant cis-acting quantitative trait loci, and, of these, six had plausible biological association with adult neurogenesis (Prom1, Ssbp2, Kcnq2, Ndufs2, Camk4, and Kcnj9). Only one cis-acting candidate was linked to both neurogenesis and gliogenesis, Rapgef6, a downstream target of ras signaling. The use of genetic reference panels coupled with phenotyping and global transcriptome profiling thus allowed insight into the complexity of the genetic control of adult neurogenesis.gene array ͉ hippocampus ͉ precursor ͉ quantitative trait loci ͉ stem cell N eurogenesis in adult mammals is modulated by complex interactions among genetic and environmental factors. Our goal is to use a systems genetics approach to determine how the development of new neurons and glia is modulated by gene polymorphisms, activity, and environmental stimuli. A first step toward this goal is to analyze natural variation and genetic covariance among key neurogenesis parameters such as proliferation, survival, and differentiation of new cells. We have shown that natural variation is substantial among different strains of mice (1-3). The normal range of variation often exceeds the effects of single gene mutations in engineered lines of mice.In this study, we extended this analysis of normal variation and applied a systems genetics approach to study the covariance structure of four key parameters of adult hippocampal neurogenesis across two large genetic reference populations consisting of a total of 52 recombinant inbred strains. This approach allowed us to exploit covariance of diverse traits to demonstrate biological linkage and pleiotropy (4, 5). The analysis, however, extends beyond a correlative approach. Both of the genetic reference populations used, the BXD and AXB͞BXA sets, are standard mapping panels, making it possible to search for gene loci, so-called quantitative trait loci (QTL), that produce common variation and pleiotropy among traits linked to adult hippocampal neurogenesis.A...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Natural variation and genetic covariance in adult hippocampal neurogenesis

Kempermann

Chesler

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

179

162

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“…These advantages include the development of diverse and unique genetic resources, including completion of a detailed map of murine genomic sequence that is freely available through the internet, as well as Ͼ450 inbred strains of mice that have been generated over the past century, with each strain genetically being homogeneous and offering a unique array of phenotypes (8,9). The availability of murine embryonic stem cells has also provided the ability to disrupt the expression and function of specific preselected genes (10 -12).…”

Section: Iabetic Nephropathy (Dn) Is the Major Single Cause Of Esrdmentioning

confidence: 99%

Mouse Models of Diabetic Nephropathy

Breyer¹,

Böttinger²,

Brosius³

et al. 2005

Journal of the American Society of Nephrology

483

516

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Mice provide an experimental model of unparalleled flexibility for studying mammalian diseases. Inbred strains of mice exhibit substantial differences in their susceptibility to the renal complications of diabetes. Much remains to be established regarding the course of diabetic nephropathy (DN) in mice as well as defining those strains and/or mutants that are most susceptible to renal injury from diabetes. Through the use of the unique genetic reagents available in mice (including knockouts and transgenics), the validation of a mouse model reproducing human DN should significantly facilitate the understanding of the underlying genetic mechanisms that contribute to the development of DN. Establishment of an authentic mouse model of DN will undoubtedly facilitate testing of translational diagnostic and therapeutic interventions in mice before testing in humans.J (1), with costs for care of these patients projected to be $12 billion/yr by 2010 (1). Despite the high prevalence of DN, only 20 to 40% of all diabetic patients are prone to developing kidney failure, and family-based studies suggest that a significant genetic component confers risk for DN (2-4). Studies of diabetic mice suggest that, like people, mice exhibit differential susceptibility to diabetes and renal and cardiovascular diseases (5-7). In mice, identification of a strain that is prone to disease provides the relevant discriminator rather than identification of an individual who is at risk for diabetic complications. However, in contrast to people, each inbred mouse strain represents a genetically homogeneous and readily replenished resource that is amenable to repeated experimental study.Biomedical experimentation in mice affords significant advantages over experimentation in other species. These advantages include the development of diverse and unique genetic resources, including completion of a detailed map of murine genomic sequence that is freely available through the internet, as well as Ͼ450 inbred strains of mice that have been generated over the past century, with each strain genetically being homogeneous and offering a unique array of phenotypes (8,9). The availability of murine embryonic stem cells has also provided the ability to disrupt the expression and function of specific preselected genes (10 -12). Finally, repositories of mice that bear multiple mutations that alter function in each known gene are gradually being assembled (13-15). These unique resources have the potential to significantly facilitate studies into the pathogenesis of disease in mice. Through the use of the unique genetic reagents that are available in mice (including knockouts and transgenics), the identification of a robust mouse model of DN should significantly facilitate understanding of the underlying genetic mechanisms that contribute to the development of DN in people as well as in mice. Establishment of a valid mouse model of DN should also facilitate testing of translational diagnostic and therapeutic interventions in mice before testing in humans. Workin...

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“…This artificial introgression of genetic heterogeneity in inbred mouse populations must not be considered more than an involuntary human error, although with relevant consequences if the resulting abnormal mice are used for research. Several studies have revealed contamination in experimental breeding stocks of mice (West et al, 1985;Marshall et al, 1992;Nandakumar and Holmdahl, 2005;Nitzky et al, 2007), leading to an additional source of allogenicity.…”

Section: Contaminationmentioning

confidence: 99%

Inbred mouse strains and genetic stability: a review

Casellas

2011

Animal

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Inbred mice were essential animal models for scientific research during the 20th century and will contribute decisive results in the current and next centuries. Far from becoming an obsolete research tool, the generation of new inbred strains is continuing and such strains are being used in many research fields. However, their genetic properties have been overlooked for decades, although recent research has revealed new insights into their genetic fragility and relative instability. Contrary to what we usually assume, inbred mice are far from being completely isogenic and both single-gene major mutations and polygenic mutational variability are continuously uploading into inbred populations as new sources of genetic polymorphisms. Note that several inbred strains from new major mutations are released every year, whereas small mutations can accumulate up to accounting for a significant percentage of the phenotypic variance (e.g. 4.5% in a recent study on C57BL/6J mice). Moreover, this genetic heterogeneity can be maintained for several generations by heterozygote selection and, if fixed instead of dropping off, genetic drift must be anticipated. The contribution of accidental genetic contamination in inbred strains must also be considered, although its incidence in current breeding stocks should be minimal, or even negligible. This review revisits several relevant topics for current inbred strains, discussing the latest cutting-edge results within the context of the genetic homogeneity and stability of laboratory mice. Inbred mice can no longer be considered as completely isogenic, but provide a remarkably homogeneous animal model with an inevitable moderate-to-low degree of genetic variability. Despite a certain degree of genetic heterogeneity becoming inescapable, inbred mice still provide very useful animal models with evident advantages when compared with outbred, that is, highly variable, populations.Keywords: heterozygote selection, inbred strain, isogenicity, mouse, mutation Implications Inbred mice are basic tools for multiple research fields. Despite their relevance, their genetic architecture was overlooked for decades and recent research evidenced their genetic fragility, and even instability. Within this context, this review revisits several hot topics for current inbred strains, discussing the latest cutting-edge results on mutation and genetic drift, and characterizing other sources of genetic heterogeneity such as heterozygote selection or contamination. Far from invalidating the usefulness of inbred mice in research, this review was an attempt to describe the different sources of allogenicity and warns about potential consequences on the genetic stability of mice.

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The AXB and BXA set of recombinant inbred mouse strains

Cited by 70 publications

References 73 publications

Natural variation and genetic covariance in adult hippocampal neurogenesis

Natural variation and genetic covariance in adult hippocampal neurogenesis

Mouse Models of Diabetic Nephropathy

Inbred mouse strains and genetic stability: a review

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