Recombinant Inbred Strains Research Articles

A Suite of Tools for Biologists That Improve Accessibility and Visualization of Large Systems Genetics Datasets: Applications to the Hybrid Mouse Diversity Panel.

In this chapter we address the recent explosion in large multilevel population studies such as the METSIM study in humans as well as large panels of animal models such as the Hybrid Mouse Diversity Panel or the BXD set of recombinant inbred strains. These studies have harnessed the increasing affordability of large-scale high-throughput profiling to gather massive quantities of data. These datasets, spread across different -omics levels (genome, transcriptome, etc.), different tissues (e.g. heart, plasma, bone) and different environmental factors (e.g. diet, drugs) each individually have led to a number of novel findings relevant to a variety of complex diseases and other phenotypes. The analysis of these results, however, is often limited to individuals with a comprehensive understanding of database languages such as SQL. In this chapter, we describe the development of a GUI-based database analysis suite, using the Hybrid Mouse Diversity Panel as an example to lay out a series of methods for visualization and integration of large systems genetics datasets. The database is based on the Shiny suite of tools in R, and is transferrable to other SQL-based datasets.

Complex Genetics of Behavior: BXDs in the Automated Home-Cage.

This chapter describes a use case for the genetic dissection and automated analysis of complex behavioral traits using the genetically diverse panel of BXD mouse recombinant inbred strains. Strains of the BXD resource differ widely in terms of gene and protein expression in the brain, as well as in their behavioral repertoire. A large mouse resource opens the possibility for gene finding studies underlying distinct behavioral phenotypes, however, such a resource poses a challenge in behavioral phenotyping. To address the specifics of large-scale screening we describe how to investigate: (1) how to assess mouse behavior systematically in addressing a large genetic cohort, (2) how to dissect automation-derived longitudinal mouse behavior into quantitative parameters, and (3) how to map these quantitative traits to the genome, deriving loci underlying aspects of behavior.

Sex difference in EGFR pathways in mouse kidney-potential impact on the immune system.

BackgroundEpidermal growth factor receptor (Egfr) has been the target of several drugs for cancers. The potential gender differences in genes in the Egfr axis have been suggested in humans and in animal models. Female and male mice from the same recombinant inbred (RI) strain have the same genomic components except the sex difference. A population of different RI mouse strains allows to conduct precise analysis of molecular pathways and regulation of Egfr between female and male mice.MethodsThe whole genome expression profiles of 70 genetically diverse RI strains of mice were used to compare three major molecular aspects of Egfr gene: the relative expression levels, gene network and expression quantitative trait loci (eQTL) that regulate the expression of Egfr between female and male mice.ResultsOur data showed that there is a significant sex difference in the expression levels in kidney. A considerable number of genes in the gene network of Egfr are sex differentially expressed. The expression levels of Egfr in mice are statistical significant different between C57BL/6 J (B6) and DBA/2 J (D2) genotypes in male while no difference in female mice. The eQTLs that regulate the expression levels of Egfr between female and male mice are also different. Furthermore, the differential expression levels of Egfr showed significantly different correlations with two known biological traits between male and female mice.ConclusionOverall there is a substantial sex difference in the Egfr pathways in mice. These data may have significant impact on drug target design, development, formulation, and dosage determinant for women and men in clinical trials.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0449-3) contains supplementary material, which is available to authorized users.

A Mouse Model of Chronic West Nile Virus Disease.

Infection with West Nile virus (WNV) leads to a range of disease outcomes, including chronic infection, though lack of a robust mouse model of chronic WNV infection has precluded identification of the immune events contributing to persistent infection. Using the Collaborative Cross, a population of recombinant inbred mouse strains with high levels of standing genetic variation, we have identified a mouse model of persistent WNV disease, with persistence of viral loads within the brain. Compared to lines exhibiting no disease or marked disease, the F1 cross CC(032x013)F1 displays a strong immunoregulatory signature upon infection that correlates with restraint of the WNV-directed cytolytic response. We hypothesize that this regulatory T cell response sufficiently restrains the immune response such that a chronic infection can be maintained in the CNS. Use of this new mouse model of chronic neuroinvasive virus will be critical in developing improved strategies to prevent prolonged disease in humans.

C57BL/6J mouse apolipoprotein A2 gene is deterministic for apnea

RationaleBrainstem apolipoprotein AII (apoa2) mRNA expression correlates with apnea in breathing present in the adult C57Bl/6J (B6) sleep apnea model. ObjectivesTo test the hypothesis that the B6 apoa2 gene contributes to the trait, we performed plethysmographic testing in apoa2 knock out (KO: −/-) mice, an in situ brainstem-spinal cord preparation comparing KO to WT (+/+) mice, and B6xDBA recombinant inbred strains (RISs). Measurements and main resultsApoa2 WT do, but KO and heterozygote (+/−) mice do not exhibit apnea during post-hypoxic breathing, measured in vivo. In the in situ model, pauses and instability in fictive phrenic bursting are substantially reduced in KO vs. WT preparations. In 24 RISs, apnea number in vivo was higher in strains with B6 apoa2 than with DBA apoa2 alleles. ConclusionsThe B6 apoa2 polymorphism is directly involved in breath production, and its identification suggests a novel pathway influencing risk for adult sleep apnea

Genetic Networks in Mouse Retinal Ganglion Cells.

Retinal ganglion cells (RGCs) are the output neuron of the eye, transmitting visual information from the retina through the optic nerve to the brain. The importance of RGCs for vision is demonstrated in blinding diseases where RGCs are lost, such as in glaucoma or after optic nerve injury. In the present study, we hypothesize that normal RGC function is transcriptionally regulated. To test our hypothesis, we examine large retinal expression microarray datasets from recombinant inbred mouse strains in GeneNetwork and define transcriptional networks of RGCs and their subtypes. Two major and functionally distinct transcriptional networks centering around Thy1 and Tubb3 (Class III beta-tubulin) were identified. Each network is independently regulated and modulated by unique genomic loci. Meta-analysis of publically available data confirms that RGC subtypes are differentially susceptible to death, with alpha-RGCs and intrinsically photosensitive RGCs (ipRGCs) being less sensitive to cell death than other RGC subtypes in a mouse model of glaucoma.

Early changes in the knee of healer and non-healer mice following non-invasive mechanical injury.

In this study, we examined early time-dependent changes in articular cartilage and synovium in response to tibial compression and sought the plausible origin of cells that respond to compression in the healer (LGXSM-6) and non-healer (LGXSM-33) recombinant inbred mouse strains. The right knee of 13-week old male mice was subjected to tibial compression using 9N axial loading. The contralateral left knee served as a control. Knees were harvested at 5, 9, and 14 days post-injury. Histological changes in cartilage and synovium, immunofluorescence pattern of CD44, aggrecan, type-II collagen, cartilage oligomeric matrix protein and the aggrecan neo-epitope NITEGE, and cell apoptosis (by TUNEL) were examined. We used a double nucleoside analog cell-labeling strategy to trace cells responsive to injury. We showed that tibial compression resulted in rupture of anterior cruciate ligament, cartilage matrix loss and chondrocyte apoptosis at the injury site. LGXSM-33 showed higher synovitis and ectopic synovial chondrogenesis than LGXSM-6 with no differences for articular cartilage lesions. With loading, an altered pattern of CD44 and NITEGE was observed: cells in the impacted area underwent apoptosis, cells closely surrounding the injured area expressed CD44, and cells in the intact area expressed NITEGE. Cells responding to injury were found in the synovium, subchondral bone marrow and the Groove of Ranvier. Taken together, we found no strain differences in chondrocytes in the early response to injury. However, the synovial response was greater in LGXSM-33 indicating that, at early time points, there is a genetic difference in synovial cell reaction to injury. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:524-536, 2017.

The abundance of cis-acting loci leading to differential allele expression in F1 mice and their relationship to loci harboring genes affecting complex traits.

BackgroundGenome-wide surveys have detected cis-acting quantitative trait loci altering levels of RNA transcripts (RNA-eQTLs) by associating SNV alleles to transcript levels. However, the sensitivity and specificity of detection of cis- expression quantitative trait loci (eQTLs) by genetic approaches, reliant as it is on measurements of transcript levels in recombinant inbred strains or offspring from arranged crosses, is unknown, as is their relationship to QTL’s for complex phenotypes.ResultsWe used transcriptome-wide differential allele expression (DAE) to detect cis-eQTLs in forebrain and kidney from reciprocal crosses between three mouse inbred strains, 129S1/SvlmJ, DBA/2J, and CAST/EiJ and C57BL/6 J. Two of these crosses were previously characterized for cis-eQTLs and QTLs for various complex phenotypes by genetic analysis of recombinant inbred (RI) strains. 5.4 %, 1.9 % and 1.5 % of genes assayed in forebrain of B6/129SF1, B6/DBAF1, and B6/CASTF1 mice, respectively, showed differential allelic expression, indicative of cis-acting alleles at these genes. Moreover, the majority of DAE QTLs were observed to be tissue-specific with only a small fraction showing cis-effects in both tissues. Comparing DAE QTLs in F1 mice to cis-eQTLs previously mapped in RI strains we observed that many of the cis-eQTLs were not confirmed by DAE. Additionally several novel DAE-QTLs not identified as cis-eQTLs were identified suggesting that there are differences in sensitivity and specificity for QTL detection between the two methodologies. Strain specific DAE QTLs in B6/DBAF1 mice were located in excess at candidate genes for alcohol use disorders, seizures, and angiogenesis previously implicated by genetic linkage in C57BL/6J × DBA/2JF2 mice or BXD RI strains.ConclusionsVia a survey for differential allele expression in F1 mice, a substantial proportion of genes were found to have alleles altering expression in cis-acting fashion. Comparing forebrain and kidney, many or most of these alleles were tissue-specific in action. The identification of strain specific DAE QTLs, can assist in assessment of candidate genes located within the large intervals associated with trait QTLs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2922-9) contains supplementary material, which is available to authorized users.

Transomics: Mitochondrial Systems Analyses Get Supercomplex

New "omics" tools are accelerating our ability to connect genomic variation to complex traits. Williams etal. (2016) reveal the power of layering quantitative proteomics and metabolomics measurements into a "systems genetics" analysis of recombinant inbred mouse strains to unravel new aspects of mitochondrial metabolism.

Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking.

Alcohol (ethanol) dependence is a chronic relapsing brain disorder partially influenced by genetics and characterized by an inability to regulate harmful levels of drinking. Emerging evidence has linked genes that encode KV7, KIR, and KCa2 K+ channels with variation in alcohol-related behaviors in rodents and humans. This led us to experimentally test relations between K+ channel genes and escalation of drinking in a chronic-intermittent ethanol (CIE) exposure model of dependence in BXD recombinant inbred strains of mice. Transcript levels for K+ channel genes in the prefrontal cortex (PFC) and nucleus accumbens (NAc) covary with voluntary ethanol drinking in a non-dependent cohort. Transcripts that encode KV7 channels covary negatively with drinking in non-dependent BXD strains. Using a pharmacological approach to validate the genetic findings, C57BL/6J mice were allowed intermittent access to ethanol to establish baseline consumption before they were treated with retigabine, an FDA-approved KV7 channel positive modulator. Systemic administration significantly reduced drinking, and consistent with previous evidence, retigabine was more effective at reducing voluntary consumption in high-drinking than low-drinking subjects. We evaluated the specific K+ channel genes that were most sensitive to CIE exposure and identified a gene subset in the NAc and PFC that were dysregulated in the alcohol-dependent BXD cohort. CIE-induced modulation of nine genes in the NAc and six genes in the PFC covaried well with the changes in drinking induced by ethanol dependence. Here we identified novel candidate genes in the NAc and PFC that are regulated by ethanol dependence and correlate with voluntary drinking in non-dependent and dependent BXD mice. The findings that Kcnq expression correlates with drinking and that retigabine reduces consumption suggest that KV7 channels could be pharmacogenetic targets to treat individuals with alcohol addiction.

Self-Confirmation and Ascertainment of the Candidate Genomic Regions of Complex Trait Loci - A None-Experimental Solution.

Over the past half century, thousands of quantitative trait loci (QTL) have been identified by using animal models and plant populations. However, the none-reliability and imprecision of the genomic regions of these loci have remained the major hurdle for the identification of the causal genes for the correspondent traits. We used a none-experimental strategy of strain number reduction for testing accuracy and ascertainment of the candidate region for QTL. We tested the strategy in over 400 analyses with data from 47 studies. These studies include: 1) studies with recombinant inbred (RI) strains of mice. We first tested two previously mapped QTL with well-defined genomic regions; We then tested additional four studies with known QTL regions; and finally we examined the reliability of QTL in 38 sets of data which are produced from relatively large numbers of RI strains, derived from C57BL/6J (B6) X DBA/2J (D2), known as BXD RI mouse strains; 2) studies with RI strains of rats and plants; and 3) studies using F2 populations in mice, rats and plants. In these cases, our method identified the reliability of mapped QTL and localized the candidate genes into the defined genomic regions. Our data also suggests that LRS score produced by permutation tests does not necessarily confirm the reliability of the QTL. Number of strains are not the reliable indicators for the accuracy of QTL either. Our strategy determines the reliability and accuracy of the genomic region of a QTL without any additional experimental study such as congenic breeding.

MPTP neurotoxicity is highly concordant between the sexes among BXD recombinant inbred mouse strains

Continuing our previous work in which we showed wide-ranging strain differences in MPTP neurotoxicity in male mice among ten BXD recombinant inbred strains, we replicated our work in females from nine of the same strains. Mice received a single s.c. injection of 12.5mg/kg MPTP or saline. Forty-eight hours later the striatum was dissected for neurochemical analysis. Striatal dopamine (DA) and its metabolites, DOPAC and HVA, striatal serotonin (5-HT) and its metabolite, 5-HIAA, were analyzed using HPLC. Tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP), an astrocytic protein that increases during the astroglial response to neural injury, were measured using ELISA. There were wide genetic variations in the DA, DOPAC, HVA, TH and GFAP responses to MPTP. We also performed principal component analysis (PCA) on the difference values, saline minus MPTP, for DA, DOPAC, HVA and TH and mapped the dominant principal component to a suggestive QTL on chromosome 1 at the same location that we observed previously for males. Moreover, there were significant correlations between the sexes for the effect of MPTP on DA, HVA, and TH. Our findings suggest that the systems genetic approach as utilized here can help researchers understand the role of sex in individual differences. The same approach can pave the way to understand and pinpoint the genetic bases for individual differences in pathology attributable to toxicants. Such systems genetics approach has broad implications for elucidating gene-environment contributions to neurodegenerative diseases.

The influence of genetic diversity on neonatal respiratory syncytial virus disease

Abstract Respiratory syncytial virus (RSV) is the number one cause of lower respiratory infections in children. Although most children are infected with RSV in their first year of life, 40% have severe disease suggesting a genetic component in addition to age. This collaborative project aims to identify genetic determinants associated with RSV infectivity during the neonatal period. Recombinant inbred strains of mice such as the BXD family have been extensively typed for both genetic polymorphisms (5 million variants) and a wide range of phenotypes, including influenza and other pathogens. Here, we infected different BXD strains with RSV at five days of age and evaluated pulmonary viral load. We show a difference in viral burden in the lungs of neonatal mice between different BXD strains, suggesting a role for genetic variation in RSV infectivity. Therefore, we have a novel system to identify genetic loci involved in the development of RSV disease. These results will be critical in the development of specific antivirals and vaccines against RSV.

Mouse and Human Genetic Analyses Associate Kalirin with Ventral Striatal Activation during Impulsivity and with Alcohol Misuse.

Impulsivity is associated with a spectrum of psychiatric disorders including drug addiction. To investigate genetic associations with impulsivity and initiation of drug taking, we took a two-step approach. First, we identified genes whose expression level in prefrontal cortex, striatum and accumbens were associated with impulsive behavior in the 5-choice serial reaction time task across 10 BXD recombinant inbred (BXD RI) mouse strains and their progenitor C57BL/6J and DBA2/J strains. Behavioral data were correlated with regional gene expression using GeneNetwork (www.genenetwork.org), to identify 44 genes whose probability of association with impulsivity exceeded a false discovery rate of < 0.05. We then interrogated the IMAGEN database of 1423 adolescents for potential associations of SNPs in human homologs of those genes identified in the mouse study, with brain activation during impulsive performance in the Monetary Incentive Delay task, and with novelty seeking scores from the Temperament and Character Inventory, as well as alcohol experience. There was a significant overall association between the human homologs of impulsivity-related genes and percentage of premature responses in the MID task and with fMRI BOLD-response in ventral striatum (VS) during reward anticipation. In contrast, no significant association was found between the polygenic scores and anterior cingulate cortex activation. Univariate association analyses revealed that the G allele (major) of the intronic SNP rs6438839 in the KALRN gene was significantly associated with increased VS activation. Additionally, the A-allele (minor) of KALRN intronic SNP rs4634050, belonging to the same haplotype block, was associated with increased frequency of binge drinking.

Identification of quantitative trait loci and candidate genes for an anxiolytic-like response to ethanol in BXD recombinant inbred strains.

Genetic differences in acute behavioral responses to ethanol contribute to the susceptibility to alcohol use disorder and the reduction of anxiety is a commonly reported motive underlying ethanol consumption among alcoholics. Therefore, we studied the genetic variance in anxiolytic-like responses to ethanol across the BXD recombinant inbred (RI) mouse panel using the light-dark transition model of anxiety. Strain-mean genetic mapping and a mixed-model quantitative trait loci (QTL) analysis replicated several previously published QTL for locomotor activity and identified several novel anxiety-related loci. Significant loci included a chromosome 11 saline anxiety-like QTL (Salanq1) and a chromosome 12 locus (Etanq1) influencing the anxiolytic-like response to ethanol. Etanq1 was successfully validated by studies with BXD advanced intercross strains and fine-mapped to a region comprising less than 3.5 Mb. Through integration of genome-wide mRNA expression profiles of the mesocorticolimbic reward circuit (prefrontal cortex, nucleus accumbens and ventral midbrain) across the BXD RI panel, we identified high priority candidate genes within Etanq1, the strongest of which was Ninein (Nin), a Gsk3β-interacting protein that is highly expressed in the brain.

Genetic Polymorphisms Affect Mouse and Human Trace Amine-Associated Receptor 1 Function.

Methamphetamine (MA) and neurotransmitter precursors and metabolites such as tyramine, octopamine, and β-phenethylamine stimulate the G protein-coupled trace amine-associated receptor 1 (TAAR1). TAAR1 has been implicated in human conditions including obesity, schizophrenia, depression, fibromyalgia, migraine, and addiction. Additionally TAAR1 is expressed on lymphocytes and astrocytes involved in inflammation and response to infection. In brain, TAAR1 stimulation reduces synaptic dopamine availability and alters glutamatergic function. TAAR1 is also expressed at low levels in heart, and may regulate cardiovascular tone. Taar1 knockout mice orally self-administer more MA than wild type and are insensitive to its aversive effects. DBA/2J (D2) mice express a non-synonymous single nucleotide polymorphism (SNP) in Taar1 that does not respond to MA, and D2 mice are predisposed to high MA intake, compared to C57BL/6 (B6) mice. Here we demonstrate that endogenous agonists stimulate the recombinant B6 mouse TAAR1, but do not activate the D2 mouse receptor. Progeny of the B6XD2 (BxD) family of recombinant inbred (RI) strains have been used to characterize the genetic etiology of diseases, but contrary to expectations, BXDs derived 30–40 years ago express only the functional B6 Taar1 allele whereas some more recently derived BXD RI strains express the D2 allele. Data indicate that the D2 mutation arose subsequent to derivation of the original RIs. Finally, we demonstrate that SNPs in human TAAR1 alter its function, resulting in expressed, but functional, sub-functional and non-functional receptors. Our findings are important for identifying a predisposition to human diseases, as well as for developing personalized treatment options.

QTL Mapping of Endocochlear Potential Differences between C57BL/6J and BALB/cJ mice.

We reported earlier that the endocochlear potential (EP) differs between C57BL/6J (B6) and BALB/cJ (BALB) mice, being lower in BALBs by about 10mV (Ohlemiller et al. Hear Res 220: 10-26, 2006). This difference corresponds to strain differences with respect to the density of marginal cells in cochlear stria vascularis. After about 1year of age, BALB mice also tend toward EP reduction that correlates with further marginal cell loss. We therefore suggested that early sub-clinical features of the BALB stria vascularis may predispose these mice to a condition modeling Schuknecht's strial presbycusis. We further reported (Ohlemiller et al. J Assoc Res Otolaryngol 12: 45-58, 2011) that the acute effects of a 2-h 110 dB SPL noise exposure differ between B6 and BALB mice, such that the EP remains unchanged in B6 mice, but is reduced by 40-50mV in BALBs. In about 25% of BALBs, the EP does not completely recover, so that permanent EP reduction may contribute to noise-induced permanent threshold shifts in BALBs. To identify genes and alleles that may promote natural EP variation as well as noise-related EP reduction in BALB mice, we have mapped related quantitative trait loci (QTLs) using 12 recombinant inbred (RI) strains formed from B6 and BALB (CxB1-CxB12). EP and strial marginal cell density were measured in B6 mice, BALB mice, their F1 hybrids, and RI mice without noise exposure, and 1-3 h after broadband noise (4-45 kHz, 110 dB SPL, 2 h). For unexposed mice, the strain distribution patterns for EP and marginal cell density were used to generate preliminary QTL maps for both EP and marginal cell density. Six QTL regions were at least statistically suggestive, including a significant QTL for marginal cell density on chromosome 12 that overlapped a weak QTL for EP variation. This region, termed Maced (Marginal cell density QTL) supports the notion of marginal cell density as a genetically influenced contributor to natural EP variation. Candidate genes for Maced notably include Foxg1, Foxa1, Akap6, Nkx2-1, and Pax9. Noise exposure produced significant EP reductions in two RI strains as well as significant EP increases in two RI strains. QTL mapping of the EP in noise-exposed RI mice yielded four suggestive regions. Two of these overlapped with QTL regions we previously identified for noise-related EP reduction in CBA/J mice (Ohlemiller et al. Hear Res 260: 47-53, 2010) on chromosomes 5 and 18 (Nirep). The present map may narrow the Nirep interval to a ~10-Mb region of proximal Chr. 18 that includes Zeb1, Arhgap12, Mpp7, and Gjd4. This study marks the first exploration of natural gene variants that modulate the EP. Their orthologs may underlie some human hearing loss that originates in the lateral wall.

Genetic Regulation of Gelsolin in Lung in Mouse Model and its Potential Broad Spectrum of Biological Functions

Considerable studies have been done on the potential biological function of gelsolin and its connection to human immune system, diseases and other disorders. The objective of our study was to identify genetic factors that regulate gelsolin in mouse lung and analyze its function immune system using well defined recombinant inbred strains. For this purpose we chose the BXD recombinant inbred (RI) strains derived from progeny of the C57BL/6J (B6) and DBA/2J (D2) progenitor strains. Whole genome gene expression in lung was used for the eQTL mapping. Bioinformatics tools and genotyping data were used for the candidate gene analysis. Gene network and correlation processes were used to assess the association between gelsolin and biological traits. Data indicated that an eQTL on chromosome 9 covering a genomic area between 21Mb and 30Mb is a major play in regulation of the gelsolin expression level. Analysis of genetic elements within this region revealed that Ncapd3 is the most favorite candidate gene. Its expression level is highly associated to that of gelsolin. The expression level of gelsolin between mouse strains with two genotype of SNP (rs13480109) in a regulatory region of the Ncapd3 showed a significant difference. Additional association analysis suggest that gelsolin may has a broad spectrum of biological function. The expression level of gelsolin has very high correlation with genes in a variety of biological function. These highly associated genes are mainly for protein binding. The expression of gelsolin is also correlated to multiple known immune phenotypes. These data contribute significantly to our current knowledge on the biological function of gelsolin.

Sex Difference of Egfr Expression and Molecular Pathway in the Liver: Impact on Drug Design and Cancer Treatments?

Epidermal growth factor receptor (EGFR) has been used as the target in drug design for cancer treatment including the liver cancer. Men and women have different levels of EGFR expression during the life. The whole genome expression profiles of livers of recombinant inbred (RI) strains derived from C57BL/6J (B6) X DBA/2J (D2) were used to compare three major molecular aspects of Egfr gene: the relative expression levels, gene network and eQTLs that regulate the expression of Egfr between female and male mice. Our data suggest that there is a significant difference in the expression levels in the liver between female and male mice. Several important genes in the gene network of Egfr are differentially expressed between female and male mice. The regulatory elements for the expression levels of Egfr between female and male mice are also different. In summary, our data reveals an important sex difference in the Egfr pathways in the liver of the mice. These data may have substantial impact on drug development and dosage determinant for women and men in the clinical trials.

Sex Difference in the Expression and Gene Network of Epidermal Growth Factor Receptor in Pituitary Gland in Mice

Background: Epidermal growth factor receptor (EGFR) involves in diverse cellular functions and plays an important role in the pathogenesis of many malignancies in the human population. The pituitary gland is a target of epidermal growth factor (EGF) and it is well known that EGFR plays a role in pituitary tumor as well as other tumors formation and progression. Methods: In this study, we have screened expression profiles for the whole genome of pituitary genes of both sexes from multiple mouse recombinant inbred strains. In addition, using Network Graph, we have constructed the gene network in combination with the correlation matrix. To determine the chromosomal locations that regulate the expression of Egfr in females and males, the transcriptome mapping was conducted using Gene Network mapping tool. Furthermore, we conducted bioinformatics analysis to identify genes that have been reported to regulate or functionally connect to Egfr. Results: Statistical analysis of Egfr expression levels between female and male mice produced a P value of 1.56442E-09. The R value obtained from the correlation analysis is 0.22. A considerable number of genes in the gene network of Egfr showed sex difference. These genes are known important in caner pathways. The eQTLs that regulate the expression levels of Egfr also showed sex difference. Gender difference of the correlations between Egfr expression levels and the T cell growth is also observed. Conclusion: Our data suggest that sex difference in the expression levels of Egfr may have a significant impact on immunological disorders.