The Complexity of Skeletal Transverse Dimension: From Diagnosis, Management, and Treatment Strategies to the Application of Collaborative Cross (CC) Mouse Model.

This study investigates the significance of skeletal transverse dimension (STD) in orthodontic therapy and its impact on occlusal relationships. The primary goal is to enhance understanding and promote the integration of transverse skeletal diagnostics into routine orthodontic assessments. To achieve this aim, the study employs a comprehensive approach, utilizing model analysis, clinical assessments, radiographic measurements, and occlusograms. The initial step involves a meticulous assessment of deficiencies in the maxilla, mainly focusing on transverse dimension issues. Various successful diagnostic methods are employed to ascertain the type and presence of these deficiencies. Furthermore, the study compares surgically assisted maxillary expansion (SARME) and orthopedic maxillary expansion (OME) in addressing skeletal transverse issues. Stability assessments and efficacy analyses are conducted to provide valuable insights into the superiority of SARME over OME. The findings reveal that proper evaluation of STD is crucial in orthodontic diagnosis, as overlooking transverse dimension issues can lead to complications such as increased masticatory muscle activity, occlusal interferences, and an elevated risk of gingival recession. Surgically assisted maxillary expansion emerges as a more stable solution than orthopedic methods. In conclusion, incorporating skeletal transverse diagnostics into routine orthodontic assessments is imperative for achieving optimal occlusal relationships and minimizing negative consequences on dentition, periodontium, and joints. The study emphasizes the significance of accurate three-dimensional assessments and recommends the consideration of SARME over OME for addressing skeletal transverse deficiencies. Finally, the Collaborative Cross (CC) mouse model is also a novel mouse model for studying complex traits. Exploring the Collaborative Cross mouse model opens avenues for future research, promising further insights into transverse skeletal issues in orthodontics.

Identifying genetic susceptibility to Aspergillus fumigatus infection using collaborative cross mice and RNA-Seq approach.

BACKGROUND: Aspergillus fumigatus (Af) is one of the most ubiquitous fungi and its infection potency is suggested to be strongly controlled by the host genetic background. The aim of this study was to search for candidate genes associated with host susceptibility to Aspergillus fumigatus (Af) using an RNAseq approach in CC lines and hepatic gene expression. METHODS: We studied 31 male mice from 25 CC lines at 8 weeks old; the mice were infected with Af. Liver tissues were extracted from these mice 5 days post-infection, and next-generation RNA-sequencing (RNAseq) was performed. The GENE-E analysis platform was used to generate a clustered heat map matrix. RESULTS: Significant variation in body weight changes between CC lines was observed. Hepatic gene expression revealed 12 top prioritized candidate genes differentially expressed in resistant versus susceptible mice based on body weight changes. Interestingly, three candidate genes are located within genomic intervals of the previously mapped quantitative trait loci (QTL), including Gm16270 and Stox1 on chromosome 10 and Gm11033 on chromosome 8. CONCLUSIONS: Our findings emphasize the CC mouse model's power in fine mapping the genetic components underlying susceptibility towards Af. As a next step, eQTL analysis will be performed for our RNA-Seq data. Suggested candidate genes from our study will be further assessed with a human cohort with aspergillosis.

Mapping novel QTL and fine mapping of previously identified QTL associated with glucose tolerance using the collaborative cross mice.

A chronic metabolic illness, type 2 diabetes (T2D) is a polygenic and multifactorial complicated disease. With an estimated 463 million persons aged 20 to 79 having diabetes, the number is expected to rise to 700 million by 2045, creating a significant worldwide health burden. Polygenic variants of diabetes are influenced by environmental variables. T2D is regarded as a silent illness that can advance for years before being diagnosed. Finding genetic markers for T2D and metabolic syndrome in groups with similar environmental exposure is therefore essential to understanding the mechanism of such complex characteristic illnesses. So herein, we demonstrated the exclusive use of the collaborative cross (CC) mouse reference population to identify novel quantitative trait loci (QTL) and, subsequently, suggested genes associated with host glucose tolerance in response to a high-fat diet. In this study, we used 539 mice from 60 different CC lines. The diabetogenic effect in response to high-fat dietary challenge was measured by the three-hour intraperitoneal glucose tolerance test (IPGTT) test after 12 weeks of dietary challenge. Data analysis was performed using a statistical software package IBM SPSS Statistic 23. Afterward, blood glucose concentration at the specific and between different time points during the IPGTT assay and the total area under the curve (AUC0-180) of the glucose clearance was computed and utilized as a marker for the presence and severity of diabetes. The observed AUC0-180 averages for males and females were 51,267.5 and 36,537.5 mg/dL, respectively, representing a 1.4-fold difference in favor of females with lower AUC0-180 indicating adequate glucose clearance. The AUC0-180 mean differences between the sexes within each specific CC line varied widely within the CC population. A total of 46 QTL associated with the different studied phenotypes, designated as T2DSL and its number, for Type 2 Diabetes Specific Locus and its number, were identified during our study, among which 19 QTL were not previously mapped. The genomic interval of the remaining 27 QTL previously reported, were fine mapped in our study. The genomic positions of 40 of the mapped QTL overlapped (clustered) on 11 different peaks or close genomic positions, while the remaining 6 QTL were unique. Further, our study showed a complex pattern of haplotype effects of the founders, with the wild-derived strains (mainly PWK) playing a significant role in the increase of AUC values.

Towards system genetics analysis of head and neck squamous cell carcinoma using the mouse model, cellular platform, and clinical human data.

Head and neck squamous cell cancer (HNSCC) is a leading global malignancy. Every year, More than 830 000 people are diagnosed with HNSCC globally, with more than 430 000 fatalities. HNSCC is a deadly diverse malignancy with many tumor locations and biological characteristics. It originates from the squamous epithelium of the oral cavity, oropharynx, nasopharynx, larynx, and hypopharynx. The most frequently impacted regions are the tongue and larynx. Previous investigations have demonstrated the critical role of host genetic susceptibility in the progression of HNSCC. Despite the advances in our knowledge, the improved survival rate of HNSCC patients over the last 40 years has been limited. Failure to identify the molecular origins of development of HNSCC and the genetic basis of the disease and its biological heterogeneity impedes the development of new therapeutic methods. These results indicate a need to identify more genetic factors underlying this complex disease, which can be better used in early detection and prevention strategies. The lack of reliable animal models to investigate the underlying molecular processes is one of the most significant barriers to understanding HNSCC tumors. In this report, we explore and discuss potential research prospects utilizing the Collaborative Cross mouse model and crossing it to mice carrying single or double knockout genes (e.g. Smad4 and P53 genes) to identify genetic factors affecting the development of this complex disease using genome-wide association studies, epigenetics, microRNA, long noncoding RNA, lncRNA, histone modifications, methylation, phosphorylation, and proteomics.

Host Genetic Background Effect on Body Weight Changes Influenced by Heterozygous Smad4 Knockout Using Collaborative Cross Mouse Population.

Obesity and its attendant conditions have become major health problems worldwide, and obesity is currently ranked as the fifth most common cause of death globally. Complex environmental and genetic factors are causes of the current obesity epidemic. Diet, lifestyle, chemical exposure, and other confounding factors are difficult to manage in humans. The mice model is helpful in researching genetic BW gain because genetic and environmental risk factors can be controlled in mice. Studies in mouse strains with various genetic backgrounds and established genetic structures provide unparalleled opportunities to find and analyze trait-related genomic loci. In this study, we used the Collaborative Cross (CC), a large panel of recombinant inbred mouse strains, to present a predictive study using heterozygous Smad4 knockout profiles of CC mice to understand and effectively identify predispositions to body weight gain. Male C57Bl/6J Smad4+/- mice were mated with female mice from 10 different CC lines to create F1 mice (Smad4+/-x CC). Body weight (BW) was measured weekly until week 16 and then monthly until the end of the study (week 48). The heritability (H2) of the assessed traits was estimated and presented. Comparative analysis of various machine learning algorithms for predicting the BW changes and genotype of mice was conducted. Our data showed that the body weight records of F1 mice with different CC lines differed between wild-type and mutant Smad4 mice during the experiment. Genetic background affects weight gain and some lines gained more weight in the presence of heterozygous Smad4 knockout, while others gained less, but, in general, the mutation caused overweight mice, except for a few lines. In both control and mutant groups, female %BW had a higher heritability (H2) value than males. Additionally, both sexes with wild-type genotypes showed higher heritability values than the mutant group. Logistic regression provides the most accurate mouse genotype predictions using machine learning. We plan to validate the proposed method on more CC lines and mice per line to expand the literature on machine learning for BW prediction.

Anterior Open Bite Malocclusion: From Clinical Treatment Strategies towards the Dissection of the Genetic Bases of the Disease Using Human and Collaborative Cross Mice Cohorts.

Anterior open bite malocclusion is a complex dental condition characterized by a lack of contact or overlap between the upper and lower front teeth. It can lead to difficulties with speech, chewing, and biting. Its etiology is multifactorial, involving a combination of genetic, environmental, and developmental factors. Genetic studies have identified specific genes and signaling pathways involved in jaw growth, tooth eruption, and dental occlusion that may contribute to open bite development. Understanding the genetic and epigenetic factors contributing to skeletal open bite is crucial for developing effective prevention and treatment strategies. A thorough manual search was undertaken along with searches on PubMed, Scopus, Science Direct, and Web of Science for relevant studies published before June 2022. RCTs (clinical trials) and subsequent observational studies comprised the included studies. Orthodontic treatment is the primary approach for managing open bites, often involving braces, clear aligners, or other orthodontic appliances. In addition to orthodontic interventions, adjuvant therapies such as speech therapy and/or physiotherapy may be necessary. In some cases, surgical interventions may be necessary to correct underlying skeletal issues. Advancements in technology, such as 3D printing and computer-assisted design and manufacturing, have improved treatment precision and efficiency. Genetic research using animal models, such as the Collaborative Cross mouse population, offers insights into the genetic components of open bite and potential therapeutic targets. Identifying the underlying genetic factors and understanding their mechanisms can lead to the development of more precise treatments and preventive strategies for open bite. Here, we propose to perform human research using mouse models to generate debatable results. We anticipate that a genome-wide association study (GWAS) search for significant genes and their modifiers, an epigenetics-wide association study (EWAS), RNA-seq analysis, the integration of GWAS and expression-quantitative trait loci (eQTL), and micro-, small-, and long noncoding RNA analysis in tissues associated with open bite in humans and mice will uncover novel genes and genetic factors influencing this phenotype.

Narrating the Genetic Landscape of Human Class I Occlusion: A Perspective-Infused Review.

This review examines a prevalent condition with multifaceted etiology encompassing genetic, environmental, and oral behavioral factors. It stands as a significant ailment impacting oral functionality, aesthetics, and quality of life. Longitudinal studies indicate that malocclusion in primary dentition may progress to permanent malocclusion. Recognizing and managing malocclusion in primary dentition is gaining prominence. The World Health Organization ranks malocclusions as the third most widespread oral health issue globally. Angle's classification system is widely used to categorize malocclusions, with Class I occlusion considered the norm. However, its prevalence varies across populations due to genetic and examination disparities. Genetic factors, including variants in genes like MSX1, PAX9, and AXIN2, have been associated with an increased risk of Class I occlusion. This review aims to provide a comprehensive overview of clinical strategies for managing Class I occlusion and consolidate genetic insights from both human and murine populations. Additionally, genomic relationships among craniofacial genes will be assessed in individuals with Class I occlusion, along with a murine model, shedding light on phenotype-genotype associations of clinical relevance. The prevalence of Class I occlusion, its impact, and treatment approaches will be discussed, emphasizing the importance of early intervention. Additionally, the role of RNA alterations in skeletal Class I occlusion will be explored, focusing on variations in expression or structure that influence craniofacial development. Mouse models will be highlighted as crucial tools for investigating mandible size and prognathism and conducting QTL analysis to gain deeper genetic insights. This review amalgamates cellular, molecular, and clinical trait data to unravel correlations between malocclusion and Class I phenotypes.

Comprehensive Deciphering the Complexity of the Deep Bite: Insight from Animal Model to Human Subjects.

Deep bite is a malocclusion phenotype, defined as the misalignment in the vertical dimension of teeth and jaws and characterized by excessive overlap of the upper front teeth over the lower front teeth. Numerous factors, including genetics, environmental factors, and behavioral ones, might contribute to deep bite. In this study, we discuss the current clinical treatment strategies for deep bite, summarize the already published findings of genetic analysis associated with this complex phenotype, and their constraints. Finally, we propose a comprehensive roadmap to facilitate investigations for determining the genetic bases of this complex phenotype development. Initially, human deep bite phenotype, genetics of human deep bite, the prevalence of human deep bite, diagnosis, and treatment of human deep bite were the search terms for published publications. Here, we discuss these findings and their limitations and our view on future strategies for studying the genetic bases of this complex phenotype. New preventative and treatment methods for this widespread dental issue can be developed with the help of an understanding of the genetic and epigenetic variables that influence malocclusion. Additionally, malocclusion treatment may benefit from technological developments like 3D printing and computer-aided design and manufacture (CAD/CAM). These technologies enable the development of personalized surgical and orthodontic guidelines, enhancing the accuracy and effectiveness of treatment. Overall, the most significant results for the patient can only be achieved with a customized treatment plan created by an experienced orthodontic professional. To design a plan that meets the patient's specific requirements and expectations, open communication between the patient and the orthodontist is essential. Here, we propose to conduct a genome-wide association study (GWAS), RNAseq analysis, integrating GWAS and expression quantitative trait loci (eQTL), micro and small RNA, and long noncoding RNA analysis in tissues associated with deep bite malocclusion in human, and complement it by the same approaches in the collaborative cross (CC) mouse model which offer a novel platform for identifying genetic factors as a cause of deep bite in mice, and subsequently can then be translated to humans. An additional direct outcome of this study is discovering novel genetic elements to advance our knowledge of how this malocclusion phenotype develops and open the venue for early identification of patients carrying the susceptible genetic factors so that we can offer early prevention and treatment strategies, a step towards applying a personalized medicine approach.

Skeletal Class II Malocclusion: From Clinical Treatment Strategies to the Roadmap in Identifying the Genetic Bases of Development in Humans with the Support of the Collaborative Cross Mouse Population.

Depending on how severe it is, malocclusion, which may involve misaligned teeth, jaws, or a combination of the two, can hurt a person's overall facial aesthetics. The maxillary molar develops before the mandibular molar in class II malocclusion, which affects 15% of the population in the United States. With a retrusive mandible, patients typically have a convex profile. The goal of this study is to classify the skeletal and dental variability present in class II malocclusion, to reduce heterogeneity, present the current clinical treatment strategies, to summarize the previously published findings of genetic analysis, discuss these findings and their constraints, and finally, propose a comprehensive roadmap to facilitate investigations aimed at determining the genetic bases of malocclusion development using a variety of genomic approaches. To further comprehend the hereditary components involved in the onset and progression of class II malocclusion, a novel animal model for class II malocclusion should be developed while considering the variety of the human population. To overcome the constraints of the previous studies, here, we propose to conduct novel research on humans with the support of mouse models to produce contentious findings. We believe that carrying out a genome-wide association study (GWAS) on a large human cohort to search for significant genes and their modifiers; an epigenetics-wide association study (EWAS); RNA-seq analysis; integrating GWAS and the expression of quantitative trait loci (eQTL); and the testing of microRNAs, small RNAs, and long noncoding RNAs in tissues related to the skeletal class II malocclusion (SCIIMO) phenotype, such as mandibular bone, gum, and jaw in humans and the collaborative cross (CC) mouse model, will identify novel genes and genetic factors affecting this phenotype. We anticipate discovering novel genetic elements to advance our knowledge of how this malocclusion phenotype develops and open the venue for the early identification of patients carrying the susceptible genetic factors so that we can offer early prevention treatment strategies.

A study of the influence of genetic variance and sex on the density and thickness of the calvarial bone in collaborative cross mice.

BACKGROUND: Bone microarchitecture is affected by multiple genes, each having a small effect on the external appearance. It is thus challenging to characterize the genes and their specific effect on bone thickness and porosity. The purpose of this study was to assess the heritability and the genetic variation effect, as well as the sex effect on the calvarial bone thickness (Ca.Th) and calvarial porosity (%PoV) using the Collaborative Cross (CC) mouse population. METHODS: In the study we examined the parietal bones of 56 mice from 9 lines of CC mice. Morphometric parameters were evaluated using microcomputed tomography (µCT) and included Ca.Th and %PoV. We then evaluated heritability, genetic versus environmental variance and the sex effect for these parameters. RESULTS: Our morphometric analysis showed that Ca.Th and %PoV are both significantly different among the CC lines with a broad sense heritability of 0.78 and 0.90, respectively. The sex effect within the lines was significant in line IL111 and showed higher values of Ca.Th and %PoV in females compared to males. In line IL19 there was a borderline sex effect in Ca.Th in which males showed higher values than females. CONCLUSIONS: These results stress the complexity of sex and genotype interactions controlling Ca.Th and %PoV, as the skeletal sexual dimorphism was dependent on the genetic background. This study also shows that the CC population is a powerful tool for establishing the genetic effect on these traits.

Unraveling the Host Genetic Background Effect on Internal Organ Weight Influenced by Obesity and Diabetes Using Collaborative Cross Mice.

Type 2 diabetes mellitus (T2DM) is a severe chronic epidemic that results from the body's improper usage of the hormone insulin. Globally, 700 million people are expected to have received a diabetes diagnosis by 2045, according to the International Diabetes Federation (IDF). Cancer and macro- and microvascular illnesses are only a few immediate and long-term issues it could lead to. T2DM accelerates the effect of organ weights by triggering a hyperinflammatory response in the body's organs, inhibiting tissue repair and resolving inflammation. Understanding how genetic variation translates into different clinical presentations may highlight the mechanisms through which dietary elements may initiate or accelerate inflammatory disease processes and suggest potential disease-prevention techniques. To address the host genetic background effect on the organ weight by utilizing the newly developed mouse model, the Collaborative Cross mice (CC). The study was conducted on 207 genetically different CC mice from 8 CC lines of both sexes. The experiment started with 8-week-old mice for 12 weeks. During this period, one group maintained a standard chow diet (CHD), while the other group maintained a high-fat diet (HFD). In addition, body weight was recorded bi-weekly, and at the end of the study, a glucose tolerance test, as well as tissue collection (liver, spleen, heart), were conducted. Our study observed a strong effect of HFD on blood glucose clearance among different CC lines. The HFD decreased the blood glucose clearance displayed by the significant Area Under Curve (AUC) values in both populations. In addition, variation in body weight changes among the different CC lines in response to HFD. The female liver weight significantly increased compared to males in the overall population when exposed to HFD. Moreover, males showed higher heritability values than females on the same diet. Regardless of the dietary challenge, the liver weight in the overall male population correlated positively with the final body weight. The liver weight results revealed that three different CC lines perform well under classification models. The regression results also varied among organs. Accordingly, the differences among these lines correspond to the genetic variance, and we suspect that some genetic factors invoke different body responses to HFD. Further investigations, such as quantitative trait loci (QTL) analysis and genomic studies, could find these genetic elements. These findings would prove critical factors for developing personalized medicine, as they could indicate future body responses to numerous situations early, thus preventing the development of complex diseases.

Towards Genetic Dissection of Skeletal Class III Malocclusion: A Review of Genetic Variations Underlying the Phenotype in Humans and Future Directions.

INTRODUCTION: Skeletal abnormalities and malocclusions have varied features that impact populations globally, impairing aesthetics and lowering life quality. The prevalence of the Skeletal Class III disease is the lowest among all angle malocclusions, with varied prevalence across nations. Environmental, genetic, and societal factors play a role in its numerous etiologies. In this study, we conducted a thorough search across the published data relating to quantitative trait loci (QTL) and the genes associated with Class III progression in humans, discussed these findings and their limitations, and proposed future directions and strategies for studying this phenotype. METHODS: An inclusive search of published papers in the PubMed and Google Scholar search engines using the following terms: 1. Human skeletal Class III; 2. Genetics of Human skeletal Class III; 3. QTL mapping and gene associated with human skeletal Class III; 4. enriched skeletal Class-III-malocclusion-associated pathways. RESULTS: Our search has found 53 genes linked with skeletal Class III malocclusion reported in humans, genes associated with epigenetics and phenomena, and the top 20 enriched pathways associated with skeletal Class III malocclusion. CONCLUSIONS: The human investigations yielded some contentious conclusions. We conducted a genome-wide association study (GWAS), an epigenetics-wide association study (EWAS), RNA-seq analysis, integrating GWAS and expression quantitative trait loci (eQTL), micro- and small-RNA, and long non-coding RNA analysis in tissues connected to skeletal Class III malocclusion phenotype in tissues connected with the skeletal phenotype. Finally, we invite regional, national, and international orthodontists and surgeons to join this effort by contributing human samples with skeletal Class III malocclusion following the accepted Helsinki ethical protocol to challenge these phenomena jointly.

High-fat diet and oral infection induced type 2 diabetes and obesity development under different genetic backgrounds.

BACKGROUND: Type 2 diabetes (T2D) is an adult-onset and obese form of diabetes caused by an interplay between genetic, epigenetic, and environmental components. Here, we have assessed a cohort of 11 genetically different collaborative cross (CC) mouse lines comprised of both sexes for T2D and obesity developments in response to oral infection and high-fat diet (HFD) challenges. METHODS: Mice were fed with either the HFD or the standard chow diet (control group) for 12 weeks starting at the age of 8 weeks. At week 5 of the experiment, half of the mice of each diet group were infected with Porphyromonas gingivalis and Fusobacterium nucleatum bacteria strains. Throughout the 12-week experimental period, body weight (BW) was recorded biweekly, and intraperitoneal glucose tolerance tests were performed at weeks 6 and 12 of the experiment to evaluate the glucose tolerance status of mice. RESULTS: Statistical analysis has shown the significance of phenotypic variations between the CC lines, which have different genetic backgrounds and sex effects in different experimental groups. The heritability of the studied phenotypes was estimated and ranged between 0.45 and 0.85. We applied machine learning methods to make an early call for T2D and its prognosis. The results showed that classification with random forest could reach the highest accuracy classification (ACC = 0.91) when all the attributes were used. CONCLUSION: Using sex, diet, infection status, initial BW, and area under the curve (AUC) at week 6, we could classify the final phenotypes/outcomes at the end stage of the experiment (at 12 weeks).

Intestinal cancer development in response to oral infection with high-fat diet-induced Type 2 diabetes (T2D) in collaborative cross mice under different host genetic background effects.

Type 2 diabetes (T2D) is a metabolic disease with an imbalance in blood glucose concentration. There are significant studies currently showing association between T2D and intestinal cancer developments. High-fat diet (HFD) plays part in the disease development of T2D, intestinal cancer and infectious diseases through many biological mechanisms, including but not limited to inflammation. Understanding the system genetics of the multimorbidity of these diseases will provide an important knowledge and platform for dissecting the complexity of these diseases. Furthermore, in this study we used some machine learning (ML) models to explore more aspects of diabetes mellitus. The ultimate aim of this project is to study the genetic factors, which underline T2D development, associated with intestinal cancer in response to a HFD consumption and oral coinfection, jointly or separately, on the same host genetic background. A cohort of 307 mice of eight different CC mouse lines in the four experimental groups was assessed. The mice were maintained on either HFD or chow diet (CHD) for 12-week period, while half of each dietary group was either coinfected with oral bacteria or uninfected. Host response to a glucose load and clearance was assessed using intraperitoneal glucose tolerance test (IPGTT) at two time points (weeks 6 and 12) during the experiment period and, subsequently, was translated to area under curve (AUC) values. At week 5 of the experiment, mice of group two and four were coinfected with Porphyromonas gingivalis (Pg) and Fusobacterium nucleatum (Fn) strains, three times a week, while keeping the other uninfected mice as a control group. At week 12, mice were killed, small intestines and colon were extracted, and subsequently, the polyp counts were assessed; as well, the intestine lengths and size were measured. Our results have shown that there is a significant variation in polyp's number in different CC lines, with a spectrum between 2.5 and 12.8 total polyps on average. There was a significant correlation between area under curve (AUC) and intestine measurements, including polyp counts, length and size. In addition, our results have shown a significant sex effect on polyp development and glucose tolerance ability with males more susceptible to HFD than females by showing higher AUC in the glucose tolerance test. The ML results showed that classification with random forest could reach the highest accuracy when all the attributes were used. These results provide an excellent platform for proceeding toward understanding the nature of the genes involved in resistance and rate of development of intestinal cancer and T2D induced by HFD and oral coinfection. Once obtained, such data can be used to predict individual risk for developing these diseases and to establish the genetically based strategy for their prevention and treatment.

Dissecting the Complexity of Skeletal-Malocclusion-Associated Phenotypes: Mouse for the Rescue.

Skeletal deformities and malocclusions being heterogeneous traits, affect populations worldwide, resulting in compromised esthetics and function and reduced quality of life. Skeletal Class III prevalence is the least common of all angle malocclusion classes, with a frequency of 7.2%, while Class II prevalence is approximately 27% on average, varying in different countries and between ethnic groups. Orthodontic malocclusions and skeletal deformities have multiple etiologies, often affected and underlined by environmental, genetic and social aspects. Here, we have conducted a comprehensive search throughout the published data until the time of writing this review for already reported quantitative trait loci (QTL) and genes associated with the development of skeletal deformation-associated phenotypes in different mouse models. Our search has found 72 significant QTL associated with the size of the mandible, the character, shape, centroid size and facial shape in mouse models. We propose that using the collaborative cross (CC), a highly diverse mouse reference genetic population, may offer a novel venue for identifying genetic factors as a cause for skeletal deformations, which may help to better understand Class III malocclusion-associated phenotype development in mice, which can be subsequently translated to humans. We suggest that by performing a genome-wide association study (GWAS), an epigenetics-wide association study (EWAS), RNAseq analysis, integrating GWAS and expression quantitative trait loci (eQTL), micro and small RNA, and long noncoding RNA analysis in tissues associated with skeletal deformation and Class III malocclusion characterization/phenotypes, including mandibular basic bone, gum, and jaw, in the CC mouse population, we expect to better identify genetic factors and better understand the development of this disease.

Lowering fasting blood glucose with non-dialyzable material of cranberry extract is dependent on host genetic background, sex and diet.

BACKGROUND: Type 2 diabetes (T2D) is a polygenic metabolic disease, characterized by high fasting blood glucose (FBG). The ability of cranberry (CRN) fruit to regulate glycemia in T2D patients is well known. Here, a cohort of 13 lines of the genetically diverse Collaborative Cross (CC) mouse model was assessed for the effect of non-dialyzable material (NDM) of cranberry extract in lowering fasting blood glucose. METHODS: Eight-week-old mice were maintained on either a standard chow diet (control group) or a high-fat diet (HFD) for 12 weeks, followed by injections of intraperitoneal (IP) NDM (50 mg/kg) per mouse, three times a week for the next 6 weeks. Absolute FBG (mg/dl) was measured bi-weekly and percentage changes in FBG (%FBG) between weeks 0 and 12 were calculated. RESULTS: Statistical analysis showed a significant decrease in FBG between weeks 0 and 12 in male and female mice maintained on CHD. However, a non-significant increase in FBG values was observed in male and female mice maintained on HFD during the same period. Following administration of NDM during the following 6 weeks, the results show a variation in significant levels of FBG lowering between lines, male and female mice and under the different diets. CONCLUSION: The results suggest that the efficacy of NDM treatment in lowering FGB depends on host genetic background (pharmacogenetics), sex of the mouse (pharmacosex), and diet (pharmacodiet). All these results support the need for follow-up research to better understand and implement a personalized medicine approach/utilization of NDM for reducing FBG.

The Collaborative Cross-Mouse Population for Studying Genetic Determinants Underlying Alveolar Bone Loss Due to Polymicrobial Synergy and Dysbiosis.

Dysbiosis of oral microbiota is associated with the initiation and progression of periodontitis. The cause-and-effect relationship between genetics, periodontitis, and oral microbiome dysbiosis is poorly understood. Here, we demonstrate the power of the collaborative cross (CC) mice model to assess the effect of the genetic background on microbiome diversity shifts during periodontal infection and host suitability status. We examined the bacterial composition in plaque samples from seven different CC lines using 16s rRNA sequencing before and during periodontal infection. The susceptibility/resistance of the CC lines to alveolar bone loss was determined using the micro-CT technique. A total of 53 samples (7 lines) were collected before and after oral infection using oral swaps followed by DNA extraction and 16 s rRNA sequencing analysis. CC lines showed a significant variation in response to the co-infection (p < 0.05). Microbiome compositions were significantly different before and after infection and between resistant and susceptible lines to periodontitis (p < 0.05). Gram-positive taxa were significantly higher at the resistant lines compared to susceptible lines (p < 0.05). Gram-positive bacteria were reduced after infection, and gram-negative bacteria, specifically anaerobic groups, increased after infection. Our results demonstrate the utility of the CC mice in exploring the interrelationship between genetic background, microbiome composition, and periodontitis.

Distinct gene programs underpinning disease tolerance and resistance in influenza virus infection.

When challenged with an invading pathogen, the host-defense response is engaged to eliminate the pathogen (resistance) and to maintain health in the presence of the pathogen (disease tolerance). However, the identification of distinct molecular programs underpinning disease tolerance and resistance remained obscure. We exploited transcriptional and physiological monitoring across 33 mouse strains, during in vivo influenza virus infection, to identify two host-defense gene programs-one is associated with hallmarks of disease tolerance and the other with hallmarks of resistance. Both programs constitute generic responses in multiple mouse and human cell types. Our study describes the organizational principles of these programs and validates Arhgdia as a regulator of disease-tolerance states in epithelial cells. We further reveal that the baseline disease-tolerance state in peritoneal macrophages is associated with the pathophysiological response to injury and infection. Our framework provides a paradigm for the understanding of disease tolerance and resistance at the molecular level.

Genetics of murine type 2 diabetes and comorbidities.

Type 2 diabetes (T2D) is a polygenic and multifactorial complex disease, defined as chronic metabolic disorder. It's a major global health concern with an estimated 463 million adults aged 20-79 years with diabetes and projected to increase up to 700 million by 2045. T2D was reported to be one of the four leading causes of non-communicable disease (NCD) deaths in 2012. Environmental factors play a part in the development of polygenic forms of diabetes. Polygenic forms of diabetes often run-in families. Fortunately, T2D, which accounts for 90-95% of the entire four types of diabetes including, Type 1 diabetes (T1D), T2D, monogenic diabetes syndromes (MGDS), and Gestational diabetes mellitus, can be prevented or delayed through nutrition and lifestyle changes as well as through pharmacologic interventions. Typical symptom of the T2D is high blood glucose levels and comprehensive insulin resistance of the body, producing an impaired glucose tolerance. Impaired glucose tolerance of T2D is accompanied by extensive health complications, including cardiovascular diseases (CVD) that vary in morbidity and mortality among populations. The pathogenesis of T2D varies between populations and/or ethnic groupings and is known to be attributed extremely by genetic components and environmental factors. It is evident that genetic background plays a critical role in determining the host response toward certain environmental conditions, whether or not of developing T2D (susceptibility versus resistant). T2D is considered as a silent disease that can progress for years before its diagnosis. Once T2D is diagnosed, many metabolic malfunctions are observed whether as side effects or as independent comorbidity. Mouse models have been proven to be a powerful tool for mapping genetic factors that underline the susceptibility to T2D development as well its comorbidities. Here, we have conducted a comprehensive search throughout the published data covering the time span from early 1990s till the time of writing this review, for already reported quantitative trait locus (QTL) associated with murine T2D and comorbidities in different mouse models, which contain different genetic backgrounds. Our search has resulted in finding 54 QTLs associated with T2D in addition to 72 QTLs associated with comorbidities associated with the disease. We summarized the genomic locations of these mapped QTLs in graphical formats, so as to show the overlapping positions between of these mapped QTLs, which may suggest that some of these QTLs could be underlined by sharing gene/s. Finally, we reviewed and addressed published reports that show the success of translation of the identified mouse QTLs/genes associated with the disease in humans.