The Collaborative Cross at Oak Ridge National Laboratory: developing a powerful resource for systems genetics

Chesler, Elissa J.; Miller, Darla R.; Branstetter, Lisa R.; Galloway, Leslie; Jackson, Barbara L.; Philip, Vivek M.; Voy, Brynn H.; Culiat, Cymbeline T.; Threadgill, David W.; Williams, Robert W.; Churchill, Gary A.; Johnson, Dabney K.; Manly, Kenneth F.

doi:10.1007/s00335-008-9135-8

Cited by 250 publications

(270 citation statements)

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“…The CC will encompass a large number of inbred strains resulting from systematic crossing of eight genetically diverse founder strains that capture B90% of the known mouse genetic variability (Roberts et al, 2007). The CC was initiated at several research institutions including Oak Ridge National Laboratory (ORNL) (Chesler et al, 2008;Philip et al, 2011) and recently has been employed in quantitative trait analysis of a wide range of phenotypes (Aylor et al, 2011;Philip et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Host genetic and environmental effects on mouse intestinal microbiota

et al. 2012

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The mammalian gut harbors complex and variable microbial communities, across both host phylogenetic space and conspecific individuals. A synergy of host genetic and environmental factors shape these communities and account for their variability, but their individual contributions and the selective pressures involved are still not well understood. We employed barcoded pyrosequencing of V1-2 and V4 regions of bacterial small subunit ribosomal RNA genes to characterize the effects of host genetics and environment on cecum assemblages in 10 genetically distinct, inbred mouse strains. Eight of these strains are the foundation of the Collaborative Cross (CC), a panel of mice derived from a genetically diverse set of inbred founder strains, designed specifically for complex trait analysis. Diversity of gut microbiota was characterized by complementing phylogenetic and distance-based, sequence-clustering approaches. Significant correlations were found between the mouse strains and their gut microbiota, reflected by distinct bacterial communities. Cohabitation and litter had a reduced, although detectable effect, and the microbiota response to these factors varied by strain. We identified bacterial phylotypes that appear to be discriminative and strainspecific to each mouse line used. Cohabitation of different strains of mice revealed an interaction of host genetic and environmental factors in shaping gut bacterial consortia, in which bacterial communities became more similar but retained strain specificity. This study provides a baseline analysis of intestinal bacterial communities in the eight CC progenitor strains and will be linked to integrated host genotype, phenotype and microbiota research on the resulting CC panel.

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Section: Introductionmentioning

confidence: 99%

Host genetic and environmental effects on mouse intestinal microbiota

et al. 2012

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“…Furthermore, as this archive is a freely accessible, expanding resource, appreciation for how SERT and 5-HT-linked gene variants impact physiology can be increasingly enriched as additional phenotypes are registered. This integrative approach to reverse genetics of identified polymorphisms should also be applicable to more powerful genetic reference populations (13,16,17).Our report initiates with an analysis of the distribution among laboratory mouse strains, followed by neurochemical analyses of SERT function in synaptosomes from several standard inbred lines. Subsequently, we confirm reduced 5-HT transport mSERT phenotype associated with the GK variant in a heterologous expression system.…”

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confidence: 99%

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confidence: 99%

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

Carneiro¹,

Airey²,

Thompson³

et al. 2009

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

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The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology and treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism, and obsessive-compulsive disorder (OCD). Here, we use naturally occurring polymorphisms in recombinant inbred (RI) lines to identify multiple phenotypes associated with altered SERT function. The widely used mouse strain C57BL/ 6J, harbors a SERT haplotype defined by 2 nonsynonymous coding variants [Gly-39 and Lys-152 (GK)]. At these positions, many other mouse lines, including DBA/2J, encode, respectively, Glu-39 and Arg-152 (ER haplotype), amino acids found also in hSERT. Ex vivo synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant, a finding confirmed by in vitro heterologous expression studies. Experimental and in silico approaches using RI lines (C57BL/6J ؋ DBA/2J ‫؍‬ BXD) identify multiple anatomical, biochemical, and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are several traits associated with alcohol consumption and multiple traits associated with dopamine signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates iron-regulated DA phenotypes. Our studies provide an example of the power of coordinated in vitro, in vivo, and in silico approaches using mouse RI lines to elucidate and quantify the system-level impact of gene variation.A complex set of phylogentically conserved traits relies upon the production, secretion, and inactivation of the biogenic amine 5-HT (1). A critical and conserved mechanism to regulate 5-HT signaling involves the action of the presynaptic 5-HT transporter, SERT (2). SERTs are not only responsible for the clearance of 5-HT after release, but also recycle synaptic 5-HT to sustain adequate stores for 5-HT release (3).The recognition of the central role played by SERT in 5-HT inactivation has been reinforced by studies where mouse SERT (mSERT) has been eliminated (4), suppressed (5, 6), or enhanced (7). Although investigations with these models provide critical support for a role of SERT in presynaptic 5-HT clearance and homeostasis, inferences linking SERT to neural signaling and behavior are complicated by significant compensatory changes in other genes (8). Conversely, a lack of recognition for background genetic diversity in mouse strains likely limits the full elaboration of phenotypes associated with SERT genetic variation (9). Indeed, SERT knockout mice display different phenotypes depending on their genetic background (10).An alternative approach is the identification of traits that are sensitive to naturally occurring polymorphisms using genetic reference populations, such as BXD recombinant inbred (RI) lines (11). BXD RI lines are isogenic, homozygous mosaics of C57BL/6J and DBA/2J inbred strains, previ...

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“…The generation of this panel has been undertaken to create a large enough population of mice with enough genetic diversity to allow for systems biology analyses of complex traits. 29 The eight founder strains are five classical inbred strains: C57BL / 6J, A / J, 129S1 / SvImJ, NZO / H1LtJ and NOD / LtJ, and three wild-derived strains: WSB / EiJ, PWK / PhJ and CAST / EiJ. 30 In short, offspring from a two strain mating (G1 generation) were mated with other G1 mice to produced G2 generation animals (descended from four strains).…”

Section: Genetic Loci Mapping In Micementioning

confidence: 99%

“…These G2:F1 mice were then, and continue to be, interbred such that fully inbred RI lines are established. 29 Some very interesting studies have now been completed using mice from the early stages of inbreeding the CC lines (so called ' pre-CC ' mice). These studies demonstrate that the breadth of values for a given phenotype measured in the pre-CC is greater than observed in the founder strains alone 31,32 ( Figure 1 ).…”

Section: Genetic Loci Mapping In Micementioning

confidence: 99%

The need for mouse models in osteoporosis genetics research

Ackert‐Bicknell¹,

Hibbs²

2012

BoneKEy Reports

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Osteoporosis, the progressive loss of bone mass resulting in fragility fractures, affects ~ 75 million people in the United States, Europe and Japan. Bone mineral density (BMD) correlates with fracture risk and is widely used in clinical settings to predict fracture. Numerous studies have demonstrated that peak bone mass is highly heritable and consequently a number of genome-wide association studies (GWASs) have been conducted to identify the genes that regulate BMD. Traditional intercross mapping in the mouse has met with limited successes in the field of skeletal biology. With the advent of human GWAS, questions have arisen about the continued need for mouse models in genetics research. However, significant advances have been made in the field of mouse genetics, including new genetics resource populations and loci mapping techniques, which enable gene-level mapping resolution. In this review, we discuss the need for mouse models to help understand the skeletal biology underlying novel human GWAS findings, how loci discovered in the mouse can be used to complement GWAS analysis and highlight the recent advances made in the field of skeletal biology from the use of these new and developing resources. We conclude this paper with a discussion of the need for systems-level approaches in the skeletal biology field, with an emphasis on the need for pathway and network analyses.

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The Collaborative Cross at Oak Ridge National Laboratory: developing a powerful resource for systems genetics

Cited by 250 publications

References 10 publications

Host genetic and environmental effects on mouse intestinal microbiota

Host genetic and environmental effects on mouse intestinal microbiota

Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes

The need for mouse models in osteoporosis genetics research

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