Inbred Strains Research Articles

Absence of Embigin accelerates hearing loss and causes sub-viability, brain and heart defects in C57BL/6N mice due to interaction with Cdh23ahl

Mouse studies continue to help elaborate upon the genetic landscape of mammalian disease and the underlying molecular mechanisms. Here, we have investigated an Embigintm1b allele maintained on a standard C57BL/6N background and on a co-isogenic C57BL/6N background in which the Cdh23ahl allele has been "repaired." The hypomorphic Cdh23ahl allele is present in several commonly used inbred mouse strains, predisposing them to progressive hearing loss, starting in high-frequency regions. Absence of the neural cell adhesion molecule Embigin on the standard C57BL/6N background leads to accelerated hearing loss and causes sub-viability, brain and cardiac defects. Contrastingly, Embigintm1b/tm1b mice maintained on the co-isogenic "repaired" C57BL/6N background exhibit normal hearing and viability. Thus Embigin genetically interacts with Cdh23. Importantly, our study is the first to demonstrate an effect of the common Cdh23ahl allele outside of the auditory system, which has important ramifications for genetic studies involving inbred strains carrying this allele.

Variation in the CENP-A sequence association landscape across diverse inbred mouse strains

Centromeres are crucial for chromosome segregation, but their underlying sequences evolve rapidly, imposing strong selection for compensatory changes in centromere-associated kinetochore proteins to assure the stability of genome transmission. While this co-evolution is well documented between species, it remains unknown whether population-level centromere diversity leads to functional differences in kinetochore protein association. Mice (Mus musculus) exhibit remarkable variation in centromere size and sequence, but the amino acid sequence of the kinetochore protein CENP-A is conserved. Here, we apply k-mer-based analyses to CENP-A chromatin profiling data from diverse inbred mouse strains to investigate the interplay between centromere variation and kinetochore protein sequence association. We show that centromere sequence diversity is associated with strain-level differences in both CENP-A positioning and sequence preference along the mouse core centromere satellite. Our findings reveal intraspecies sequence-dependent differences in CENP-A/centromere association and open additional perspectives for understanding centromere-mediated variation in genome stability.

Discrimination of cell-intrinsic and environment-dependent effects of natural genetic variation on Kupffer cell epigenomes and transcriptomes

Noncoding genetic variation drives phenotypic diversity, but underlying mechanisms and affected cell types are incompletely understood. Here, investigation of effects of natural genetic variation on the epigenomes and transcriptomes of Kupffer cells derived from inbred mouse strains identified strain-specific environmental factors influencing Kupffer cell phenotypes, including leptin signaling in Kupffer cells from a steatohepatitis-resistant strain. Cell-autonomous and non-cell-autonomous effects of genetic variation were resolved by analysis of F1 hybrid mice and cells engrafted into an immunodeficient host. During homeostasis, non-cell-autonomous trans effects of genetic variation dominated control of Kupffer cells, while strain-specific responses to acute lipopolysaccharide injection were dominated by actions of cis-acting effects modifying response elements for lineage-determining and signal-dependent transcription factors. These findings demonstrate that epigenetic landscapes report on trans effects of genetic variation and serve as a resource for deeper analyses into genetic control of transcription in Kupffer cells and macrophages in vitro.

Susceptibility to Zika virus in a Collaborative Cross mouse strain is induced by Irf3 deficiency in vitro but requires other variants in vivo.

Zika virus (ZIKV) is a Flavivirus responsible for recent epidemics in Pacific Islands and in the Americas. In humans, the consequences of ZIKV infection range from asymptomatic infection to severe neurological disease such as Guillain-Barré syndrome or fetal neurodevelopmental defects, suggesting, among other factors, the influence of host genetic variants. We previously reported similar diverse outcomes of ZIKV infection in mice of the Collaborative Cross (CC), a collection of inbred strains with large genetic diversity. CC071/TauUnc (CC071) was the most susceptible CC strain with severe symptoms and lethality. Notably, CC071 has been recently reported to be also susceptible to other flaviviruses including dengue virus, Powassan virus, West Nile virus, and to Rift Valley fever virus. To identify the genetic origin of this broad susceptibility, we investigated ZIKV replication in mouse embryonic fibroblasts (MEFs) from CC071 and two resistant strains. CC071 showed uncontrolled ZIKV replication associated with delayed induction of type-I interferons (IFN-I). Genetic analysis identified a mutation in the Irf3 gene specific to the CC071 strain which prevents the protein phosphorylation required to activate interferon beta transcription. We demonstrated that this mutation induces the same defective IFN-I response and uncontrolled viral replication in MEFs as an Irf3 knock-out allele. By contrast, we also showed that Irf3 deficiency did not induce the high plasma viral load and clinical severity observed in CC071 mice and that susceptibility alleles at other genes, not associated with the IFN-I response, are required. Our results provide new insight into the in vitro and in vivo roles of Irf3, and into the genetic complexity of host responses to flaviviruses.

Difference in immune responses to Candida albicans in two inbred strains of male rats

ObjectiveTo investigate the influence of strain differences in immune response on the pathogenesis of oral candidiasis in Dark Agouti (DA) and Albino Oxford (AO) inbred strains of rats. DesignSeventy male 8-weeks old DA and AO rats were inoculated with Candida albicans to induce three different experimental models of oral candidiasis, one immunocompetent and two immunocompromised models. The animals were sacrificed after 16 days from the beginning of the experiment followed by collecting the samples of the tongue dorsum and blood for histopathological (PAS and H&E staining), immunohistochemical, qRT-PCR, and oxidative stress analyses. ResultsHistopathological and immunohistochemical analyses revealed lower levels of epithelial colonization, epithelial damage, and inflammatory infiltration in DA compared to AO strain of rats. DA rats had fewer CD45, CD68, and CD3 positive cells but more HIS 48 positive cells than AO rats. The expressions of IL-1β, TNFα, IFN-γ, IL-10 and TGF-β1 were consistently higher in DA strain across all experimental models. However, the expressions of IL-4 and IL-17 differed inconsistently between DA and AO strain in various experimental models. Strain differences were observed in levels of prooxidative hydrogen peroxide and lipid peroxidation, with higher levels presented in AO rats compared to DA rats, while antioxidative parameters presented little yet inconsistent difference between strains. ConclusionDA strain of rats consistently presented lower susceptibility to oral infection with C. albicans compared to AO strain with robust Th1/Th17 immune response indicating the importance of the genetic background on the development of oral candidiasis.

Low prepulse inhibition predicts lower social interaction, impaired spatial working memory, reference memory and cognitive flexibility in genetically heterogeneous rats

The “Genetically Heterogeneous National Institutes of Health (NIHHS)” stock rat (hereafter HS) shows a wide phenotypic variation, as a result of having been derived from eight inbred rat strains. Thus, these rats may be a conceivable parallel model of a healthy human sample. In order to evaluate whether HS rats have face validity as an animal model of schizophrenia-relevant features, it should be demonstrated that they present behavioural traits that may model negative and cognitive symptoms of the disorder. Previous studies on HS rats have shown that prepulse inhibition (PPI, a measure of sensorimotor gating processes), which is impaired in schizophrenic patients, is correlated with their working memory performance. In this study, we evaluated whether low PPI in the HS stock rat predicts impairments of spatial working memory (SWM), spatial reference memory and cognitive flexibility in the Morris water maze (MWM) test, and we evaluated HS rats for social interaction (SI) in a social investigation task. HS rats were stratified into 2 different groups according to their PPI scores, i.e. low- and high-PPI. In the SI task, low-PPI rats showed decreased social behaviour compared to high-PPI rats. In addition, relative to high-PPI HS rats, the low-PPI group displayed poorer SWM performance, impaired cognitive flexibility (in a reversal task) and worsened long-term spatial memory. Such differential behaviours in social and cognitive paradigms provide evidence on the face validity of low-PPI HS rats as a model of negative-like and cognitive schizophrenia-relevant traits.

Radiation cataract in Heterogeneous Stock mice after γ-ray or HZE ion exposure

Health effects of space radiation are a serious concern for astronauts on long-duration missions. The lens of the eye is one of the most radiosensitive tissues in the body and, therefore, ocular health risks for astronauts is a significant concern. Studies in humans and animals indicate that ionizing radiation exposure to the eye produces characteristic lens changes, termed “radiation cataract,” that can affect visual function. Animal models of radiation cataractogenesis have previously utilized inbred mouse or rat strains. These studies were essential for determining morphological changes and dose-response relationships between radiation exposure and cataract. However, the relevance of these studies to human radiosensitivity is limited by the narrow phenotypic range of genetically homogeneous animal models. To model radiation cataract in genetically diverse populations, longitudinal cataract phenotyping was nested within a lifetime carcinogenesis study in male and female heterogeneous stock (HS/Npt) mice exposed to 0.4 Gy HZE ions (n = 609) or 3.0 Gy γ-rays (n = 602) and in unirradiated controls (n = 603). Cataractous change was quantified in each eye for up to 2 years using Merriam-Focht grading criteria by dilated slit lamp examination. Virtual Optomotry™ measurement of visual acuity and contrast sensitivity was utilized to assess visual function in a subgroup of mice. Prevalence and severity of posterior lens opacifications were 2.6-fold higher in HZE ion and 2.3-fold higher in γ-ray irradiated mice compared to unirradiated controls. Male mice were at greater risk for spontaneous and radiation associated cataracts. Risk for cataractogenesis was associated with family structure, demonstrating that HS/Npt mice are well-suited to evaluate genetic determinants of ocular radiosensitivity. Last, mice were extensively evaluated for cataract and tumor formation, which revealed an overlap between individual susceptibility to both cancer and cataract.

The effect of chronic stress on the immunogenicity and immunoprotection of the M6-TT vaccine in female mice

Active vaccination is an effective therapeutic option to reduce the reinforcing effects of opioids. Several studies showed that chronic stress affects the immune system decreasing the efficiency of some vaccines. Heroin withdrawal is a stressor and it is a stage in which the patient who abuses heroin is vulnerable to stress affects the immune response and consequently its immunoprotective capacity, then, the objective was to determine the effect of heroin-withdrawal and heroin-withdrawal plus immobilization, on the immune (immunogenicity) and protective response (behavioral response) of morphine-6-hemisuccinate-tetanus toxoid (M6-TT) vaccine in animals of two inbred mice strains with different sensitivity to drug-opioid and stress.Female BALB/c and C57Bl/6 inbred mice were immunized with the M6-TT. A solid-phase antibody-capture ELISA was used to monitor antibody titer responses after each booster dose in vaccinated animals. During the vaccination period, the animals were subjected to two different stress conditions: drug-withdrawal (DW) and immobilization (IMM). The study used tail-flick testing to evaluate the heroin-induced antinociceptive effects. Additionally, heroin-induced locomotor activity was evaluated. Stress decreased the heroin-specific antibody titer generated by the M6-TT vaccine in the two inbred mouse strains evaluated. In the two stress conditions, the antibody titer was not able to decrease the heroin-induced antinociceptive effects and locomotor activity. These findings suggest that stress decreases the production of antibodies and the immunoprotective capacity of the M6-TT vaccine. This observation is important to determine the efficacy of active vaccination as a potential therapy for patients with opioid drug use disorder, since these patients during drug-withdrawal present stress disorders, which could affect the efficacy of therapy such as active vaccination.

Diazepam effects on anxiety-related defensive behavior of male and female high and low open‐field activity inbred mouse strains

Open-field activity is a commonly used measure of anxiety-related behavior in rodents. The inbred High and Low Activity strains of mice, selected for extreme differences in open-field activity, have been used as a genetic model of anxiety-related behaviors. These selected strains have been thoroughly studied through extensive behavioral testing, quantitative trait locus (QTL) mapping, whole-genome sequencing, and RNA sequencing, to uncover phenotypic and genotypic differences related to anxiety-related behavior. However, the effects of anxiolytic drugs on anxiety-related behavior in these strains have not been studied previously. This study allowed us to expand on previous findings to further characterize the anxiety-related behavior of these unique strains, using an anxiolytic drug. The goal of this study was to determine whether the treatment of adult male and female High Activity (low anxiety) and Low Activity (high anxiety) mice with diazepam, an agonist at the benzodiazepine allosteric site on the GABAA receptor and a drug commonly prescribed to treat anxiety disorders in humans, led to decreases in anxiety-like defensive behavioral responses as assessed in the open-field test (OFT) and elevated plus-maze (EPM). We tested the effects of three doses of diazepam (0, 0.5, 1.0, 3.0 mg/kg, i.p.), given 30 min before behavioral testing to one High Activity strain (H2) and two Low Activity strains (L1 and L2). There was an anxiolytic effect of diazepam observed in the High Activity strain, with more entries into the open arms of the elevated plus-maze, an effect similar to that seen in common mouse strains. However, the only anxiolytic effect of diazepam seen in the Low Activity strains was a reduction in stretch attend posture (SAP). Low Activity strains also displayed freezing behavior in both the OFT and EPM. The combination of the observed freezing behavior, that was not reduced by diazepam, and the reduction in SAP seen with diazepam, suggests a more complex phenotype that includes a component of innate fear in addition to anxiety-related risk assessment behaviors. Since fear and anxiety are distinguishable traits, and both contribute to human anxiety disorders, these results provide novel insight about interpretation of previous genetic and phenotypic differences observed between the High and Low Activity strains.

Metabolic profile of blood serum in experimental arterial hypertension.

The etiology of essential hypertension is intricate, since it employs simultaneously various body systems related to the regulation of blood pressure in one way or another: the sympathetic nervous system, renin-angiotensin-aldosterone and hypothalamic-pituitary-adrenal systems, renal and endothelial mechanisms. The pathogenesis of hypertension is influenced by a variety of both genetic and environmental factors, which determines the heterogeneity of the disease in human population. Hence, there is a need to perform research on experimental models - inbred animal strains, one of them being ISIAH rat strain, which is designed to simulate inherited stress-induced arterial hypertension as close as possible to primary (or essential) hypertension in humans. To determine specific markers of diseases, various omics technologies are applied, including metabolomics, which makes it possible to evaluate the content of low-molecular compounds - amino acids, lipids, carbohydrates, nucleic acids fragments - in biological samples available for clinical analysis (blood and urine). We analyzed the metabolic profile of the blood serum of male ISIAH rats with a genetic stress-dependent form of arterial hypertension in comparison with the normotensive WAG rats. Using the method of nuclear magnetic resonance spectroscopy (NMR spectroscopy), 56 metabolites in blood serum samples were identified, 18 of which were shown to have significant interstrain differences in serum concentrations. Statistical analysis of the data obtained showed that the hypertensive status of ISIAH rats is characterized by increased concentrations of leucine, isoleucine, valine, myo-inositol, isobutyrate, glutamate, glutamine, ornithine and creatine phosphate, and reduced concentrations of 2-hydroxyisobutyrate, betaine, tyrosine and tryptophan. Such a ratio of the metabolite concentrations is associated with changes in the regulation of glucose metabolism (metabolic markers - leucine, isoleucine, valine, myo-inositol), of nitric oxide synthesis (ornithine) and catecholamine pathway (tyrosine), and with inflammatory processes (metabolic markers - betaine, tryptophan), all of these changes being typical for hypertensive status. Thus, metabolic profiling of the stress-dependent form of arterial hypertension seems to be an important result for a personalized approach to the prevention and treatment of hypertensive disease.

Adaptor protein complex 2 in the orbitofrontal cortex predicts alcohol use disorder.

Alcohol use disorder (AUD) is a life-threatening disease characterized by compulsive drinking, cognitive deficits, and social impairment that continue despite negative consequences. The inability of individuals with AUD to regulate drinking may involve functional deficits in cortical areas that normally balance actions that have aspects of both reward and risk. Among these, the orbitofrontal cortex (OFC) is critically involved in goal-directed behavior and is thought to maintain a representation of reward value that guides decision making. In the present study, we analyzed post-mortem OFC brain samples collected from age- and sex-matched control subjects and those with AUD using proteomics, bioinformatics, machine learning, and reverse genetics approaches. Of the 4,500+ total unique proteins identified in the proteomics screen, there were 47 proteins that differed significantly by sex that were enriched in processes regulating extracellular matrix and axonal structure. Gene ontology enrichment analysis revealed that proteins differentially expressed in AUD cases were involved in synaptic and mitochondrial function, as well as transmembrane transporter activity. Alcohol-sensitive OFC proteins also mapped to abnormal social behaviors and social interactions. Machine learning analysis of the post-mortem OFC proteome revealed dysregulation of presynaptic (e.g., AP2A1) and mitochondrial proteins that predicted the occurrence and severity of AUD. Using a reverse genetics approach to validate a target protein, we found that prefrontal Ap2a1 expression significantly correlated with voluntary alcohol drinking in male and female genetically diverse mouse strains. Moreover, recombinant inbred strains that inherited the C57BL/6J allele at the Ap2a1 interval consumed higher amounts of alcohol than those that inherited the DBA/2J allele. Together, these findings highlight the impact of excessive alcohol consumption on the human OFC proteome and identify important cross-species cortical mechanisms and proteins that control drinking in individuals with AUD.

The Wistar Kyoto Rat: A Model of Depression Traits.

There is an ongoing debate about the value of animal research in psychiatry with valid lines of reasoning stating the limits of individual animal models compared to human psychiatric illnesses. Human depression is not a homogenous disorder; therefore, one cannot expect a single animal model to reflect depression heterogeneity. This limited review presents arguments that the Wistar Kyoto (WKY) rats show intrinsic depression traits. The phenotypes of WKY do not completely mirror those of human depression but clearly indicate characteristics that are common with it. WKYs present despair- like behavior, passive coping with stress, comorbid anxiety, and enhanced drug use compared to other routinely used inbred or outbred strains of rats. The commonly used tests identifying these phenotypes reflect exploratory, escape-oriented, and withdrawal-like behaviors. The WKYs consistently choose withdrawal or avoidance in novel environments and freezing behaviors in response to a challenge in these tests. The physiological response to a stressful environment is exaggerated in WKYs. Selective breeding generated two WKY substrains that are nearly isogenic but show clear behavioral differences, including that of depression-like behavior. WKY and its substrains may share characteristics of subgroups of depressed individuals with social withdrawal, low energy, weight loss, sleep disturbances, and specific cognitive dysfunction. The genomes of the WKY and WKY substrains contain variations that impact the function of many genes identified in recent human genetic studies of depression. Thus, these strains of rats share characteristics of human depression at both phenotypic and genetic levels, making them a model of depression traits.

Cognitive comorbidities of experimental absence seizures are independent of anxiety

Typical absence seizures (ASs) are brief periods of lack of consciousness, associated with 2.5–4 Hz spike-wave discharges (SWDs) in the EEG, which are highly prevalent in children and teenagers. The majority of probands in these young epileptic cohorts show neuropsychological comorbidities, including cognitive, memory and mood impairments, even after the seizures are pharmacologically controlled. Similar cognition and memory deficits have been reported in different, but not all, genetic animal models of ASs. However, since these impairments are subtle and highly task-specific their presence may be confounded by an anxiety-like phenotype and no study has tested anxiety and memory in the same animals. Moreover, the majority of studies used non-epileptic inbred animals as the only control strain and this may have contributed to a misinterpretation of these behavioural results. To overcome these issues, here we used a battery of behavioural tests to compare anxiety and memory in the same animals from the well-established inbred model of Genetic Absence Epilepsy Rats from Strasbourg (GAERS), their inbred strain of Non-Epileptic Control (NEC) strain (that lack ASs) and normal outbred Wistar rats. We found that GAERS do not exhibit increased anxiety-like behavior and neophobia compared to both NEC and Wistar rats. In contrast, GAERS show decreased spontaneous alternation, spatial working memory and cross-modal object recognition compared to both NEC and Wistar rats. Furthermore, GAERS preferentially used egocentric strategies to perform spatial memory tasks. In summary, these results provide solid evidence of memory deficits in GAERS rats that do not depend on an anxiety or neophobic phenotype. Moreover, the presence of differences between NEC and Wistar rats stresses the need of using both outbred and inbred control rats in behavioural studies involving genetic models of ASs.

A universal method for generating knockout mice in multiple genetic backgrounds using zygote electroporation.

Genetically engineered mouse models are essential tools for understanding mammalian gene functions and disease pathogenesis. Genome editing allows the generation of these models in multiple inbred strains of mice without backcrossing. Zygote electroporation dramatically removed the barrier for introducing the CRISPR-Cas9 complex in terms of cost and labour. Here, we demonstrate that the generalised zygote electroporation method is also effective for generating knockout mice in multiple inbred strains. By combining in vitro fertilisation and electroporation, we obtained founders for knockout alleles in eight common inbred strains. Long-read sequencing analysis detected not only intended mutant alleles but also differences in read frequency of intended and unintended alleles among strains. Successful germline transmission of knockout alleles demonstrated that our approach can establish mutant mice targeting the same locus in multiple inbred strains for phenotyping analysis, contributing to reverse genetics and human disease research.

Comparative study between phenotypic and genomic analyses aimed at choosing parents for hybridization purposes

The development of superior cultivars involves parents with superiority for the traits of interest and wide genetic variability. Efficient plant breeding and selection strategies that allow for the identification of superior genotypes are essential in breeding programs. This work aims to carry out a comparative study between several strategies for choosing parents, for hybridization purposes, based on phenotypic analysis and molecular information. To obtain the phenotypic and genotypic information of the parents, data simulation was used. For genotyping, 2000 single nucleotide polymorphism markers were used, and from all possible gametes to be formed (22000), 5000 were randomly sampled to form each of the 100 individuals of the population of recombinant inbred strains. To obtain the phenotypic information, five characteristics with different levels of complexity were simulated. The comparative study was carried out using data referring to simulated genotypic values of hybrids and parents. Then, aiming to choose the parents destined for hybridization, different traditional selection strategies based on phenotypic analysis and the genome-wide selection methodology were approached. The genomic information resulted in the choice of the best lines and in obtaining superior hybrids when compared with traditional methodologies. The inclusion of the genomic genetic values of the parents in determining the crosses to be carried out increases the probability of generating phenotypically superior hybrids. Thus, the traditional methods of choosing parents for hybridization purposes are effective, but when incorporating the information from genome-wide selection, the choice of parents provides superior and promising results.

A mouse model of the 3-hit effects of stress: Genotype controls the effects of life adversities in females

Helplessness is a dysfunctional coping response to stressors associated with different psychiatric conditions. The present study tested the hypothesis that early and adult adversities cumulate to produce helplessness depending on the genotype (3-hit hypothesis of psychopathology). To this aim, we evaluated whether Chronic Unpredictable Stress (CUS) differently affected coping and mesoaccumbens dopamine (DA) responses to stress challenge by adult mice of the C57BL/6J (B6) and DBA/2J (D2) inbred strains depending on early life experience (Repeated Cross Fostering, RCF). Three weeks of CUS increased the helplessness expressed in the Forced Swimming Test (FST) and the Tail Suspension Test by RCF-exposed female mice of the D2 strain. Moreover, female D2 mice with both RCF and CUS experiences showed inhibition of the stress-induced extracellular DA outflow in the Nucleus Accumbens, as measured by in vivo microdialysis, during and after FST. RCF-exposed B6 mice, instead, showed reduced helplessness and increased mesoaccumbens DA release. The present results support genotype-dependent additive effects of early experiences and adult adversities on behavioral and neural responses to stress by female mice. To our knowledge, this is the first report of a 3-hit effect in an animal model. Finally, the comparative analyses of behavioral and neural phenotypes expressed by B6 and D2 mice suggest some translationally relevant hypotheses of genetic risk factors for psychiatric disorders.

Mating compatibility and offspring traits evaluation among different strains of Tenebrio molitor.

The fast-growing sector of insects for food and feed stimulates researchers and the industry to explore uncharted territories, such as insect breeding, to improve economically important insect fitness traits. The yellow mealworm, Tenebrio molitor L., is one of the most thoroughly studied insect species as food and feed. However, data on mating compatibility and the effect of cross-breeding between different strains on the performance and fitness of the hybrids are scarce. In the present study, we comparatively evaluated the mating compatibility between two T. molitor inbred strains (Greek and Italian) and their outbred strains, i.e., Italian (♀)-Greek (♂) and Greek (♀)-Italian (♂), as well as the performance of their hybrid offspring. Based on the results, there is good mating compatibility among adults of the strains tested. Offspring performance, quantified as larval survival and final larval weight, followed a similar pattern among the crossings examined. Even though differences were insignificant, the outbreeding of females of the Italian strain resulted in a higher cumulative number of eggs and hatching rate and higher offspring weight. The present study sheds light on the mating compatibility of different T. molitor strains and their hybrids' economically important life table characteristics to take the mass production of insects one step further.

Mouse phenome database: curated data repository with interactive multi-population and multi-trait analyses.

The Mouse Phenome Database continues to serve as a curated repository and analysis suite for measured attributes of members of diverse mouse populations. The repository includes annotation to community standard ontologies and guidelines, a database of allelic states for 657 mouse strains, a collection of protocols, and analysis tools for flexible, interactive, user directed analyses that increasingly integrates data across traits and populations. The database has grown from its initial focus on a standard set of inbred strains to include heterogeneous mouse populations such as the Diversity Outbred and mapping crosses and well as Collaborative Cross, Hybrid Mouse Diversity Panel, and recombinant inbred strains. Most recently the system has expanded to include data from the International Mouse Phenotyping Consortium. Collectively these data are accessible by API and provided with an interactive tool suite that enables users' persistent selection, storage, and operation on collections of measures. The tool suite allows basic analyses, advanced functions with dynamic visualization including multi-population meta-analysis, multivariate outlier detection, trait pattern matching, correlation analyses and other functions. The data resources and analysis suite provide users a flexible environment in which to explore the basis of phenotypic variation in health and disease across the lifespan.

Response to selection for growth in an inbred strain of the Pacific oyster Crassostrea gigas

Response to selection for growth in an inbred strain of the Pacific oyster Crassostrea gigas

Large differences in collateral blood vessel abundance among individuals arise from multiple genetic variants

Collateral blood flow varies greatly among humans for reasons that remain unclear, resulting in significant differences in ischemic tissue damage. A similarly large variation has also been found in mice that is caused by genetic background-dependent differences in the extent of collateral formation, termed collaterogenesis—a unique angiogenic process that occurs during development and determines collateral number and diameter in the adult. Previous studies have identified several quantitative trait loci (QTL) linked to this variation. However, understanding has been hampered by the use of closely related inbred strains that do not model the wide genetic variation present in the “outbred” human population. The Collaborative Cross (CC) multiparent mouse genetic reference panel was developed to address this limitation. Herein we measured the number and average diameter of cerebral collaterals in 60 CC strains, their 8 founder strains, 8 F1 crosses of CC strains selected for abundant versus sparse collaterals, and 2 intercross populations created from the latter. Collateral number evidenced 47-fold variation among the 60 CC strains, with 14% having poor, 25% poor-to-intermediate, 47% intermediate-to-good, and 13% good collateral abundance, that was associated with large differences in post-stroke infarct volume. Collateral number in skeletal muscle and intestine of selected high- and low-collateral strains evidenced the same relative abundance as in brain. Genome-wide mapping demonstrated that collateral abundance is a highly polymorphic trait. Subsequent analysis identified: 6 novel QTL circumscribing 28 high-priority candidate genes harboring putative loss-of-function polymorphisms (SNPs) associated with low collateral number; 335 predicted-deleterious SNPs present in their human orthologs; and 32 genes associated with vascular development but lacking protein coding variants. Six additional suggestive QTL (LOD > 4.5) were also identified in CC-wide QTL mapping. This study provides a comprehensive set of candidate genes for future investigations aimed at identifying signaling proteins within the collaterogenesis pathway whose variants potentially underlie genetic-dependent collateral insufficiency in brain and other tissues.