Mapping and Congenic Dissection of Genetic Loci Contributing to Hyperglycemia and Dyslipidemia in Mice

Background

Patients with dyslipidemia have an increased risk of developing type 2 diabetes, and diabetic patients often have dyslipidemia. Potential genetic connections of fasting plasma glucose with plasma lipid profile were evaluated using hyperlipidemic mice.

Methods

225 male F₂ mice were generated from BALB/cJ (BALB) and SM/J(SM) Apoe-deficient (Apoe^−/−) mice and fed a Western diet for 5 weeks. Fasting plasma glucose and lipid levels of F₂ mice were measured before and after 5 weeks of Western diet and quantitative trait locus (QTL) analysis was performed using data collected from these two time points. 144 SNP(single nucleotide polymorphism) markers across the entire genome were typed.

Results

One major QTL (logarithm of odds ratio (LOD): 6.46) peaked at 12.7 cM on chromosome 9,Bglu16, and 3 suggestive QTLs on chromosomes 15, 18 and X were identified for fasting glucose, and over 10 loci identified for lipid traits. Bglu16 was adjacent to a major QTL, Hdlq17, for high-density lipoprotein (HDL) cholesterol (LOD: 6.31, peak: 19.1 cM). A congenic strain with a donor chromosomal region harboring Bglu16 and Hdlq17 on the Apoe^−/− background showed elevations in plasma glucose and HDL levels. Fasting glucose levels were significantly correlated with non-HDL cholesterol and triglyceride levels, especially on the Western diet, but only marginally correlated with HDL levels in F₂ mice.

Conclusions

We have demonstrated a correlative relationship between fasting glucose and plasma lipids in a segregating F₂ population under hyperlipidemic conditions, and this correlation is partially due to genetic linkage between the two disorders.     

THERPA: A small molecule database related to prion protein regulation and prion diseases progression

Prion diseases are fatal neurodegenerative disorders that affect humans and animals. Although various small molecules have been evaluated for application in the treatment of prion diseases, none have been shown to be efficacious. Expanding our knowledge of these molecules is important for understanding of the complex mechanisms of prion diseases. To improve access to the scattered information on small molecules related to prion diseases, we built a database of therapeutic molecules associated with prion diseases (THERPA, therpa.pythonanywhere.com). THERPA includes 119 small molecules and their 283 relationships with prion diseases. THERPA is an interactive visual database and useful for improving search efficiency which can help researchers identify intrinsic small molecules that can be used for developing therapeutics for prion diseases.     

A case of interdigitating dendritic cell sarcoma studied by whole-exome sequencing

Interdigitating dendritic cell sarcoma (IDCS) is an aggressive neoplasm and is an extremely rare disease, with a challenging diagnosis. Etiology of IDCS is also unknown and most studies with only case reports. In our case, immunohistochemistry showed that the tumor cells were positive for S100, CD45, and CD68, but negative for CD1a and CD21. This study aimed to investigate the causative factors of IDCS by sequencing the protein-coding regions of IDCS. We performed whole-exome sequencing with genomic DNA from blood and sarcoma tissue of the IDCS patient using the Illumina Hiseq 2500 platform. After that, we conducted Sanger sequencing for validation of sarcoma-specific variants and gene ontology analysis using DAVID bioinformatics resources. Through comparing sequencing data of sarcoma with normal blood, we obtained 15 nonsynonymous single nucleotide polymorphisms (SNPs) as sarcoma-specific variants. Although the 15 SNPs were not validated by Sanger sequencing due to tumor heterogeneity and low sensitivity of Sanger sequencing, we examined the function of the genes in which each SNP is located. Based on previous studies and gene ontology database, we found that POLQ encoding DNA polymerase theta enzyme and FNIP1 encoding tumor suppressor folliculin-interacting protein might have contributed to the IDCS. Our study provides potential causative genetic factors of IDCS and plays a role in advancing the understanding of IDCS pathogenesis.     

The role of YKL-40 in the pathogenesis of autoimmune diseases: a comprehensive review

YKL-40, a chitinase-3-like protein 1 (CHI3L1) or human cartilage glycoprotein 39 (HC gp-39), is expressed and secreted by various cell-types including macrophages, chondrocytes, fibroblast-like synovial cells and vascular smooth muscle cells. Its biological function is not well elucidated, but it is speculated to have some connection with inflammatory reactions and autoimmune diseases. Although having important biological roles in autoimmunity, there were only attempts to elucidate relationships of YKL-40 with a single or couple of diseases in the literature. Therefore, in order to analyze the relationship between YKL-40 and the overall diseases, we reviewed 51 articles that discussed the association of YKL-40 with rheumatoid arthritis, psoriasis, systemic lupus erythematosus, Behçet disease and inflammatory bowel disease. Several studies showed that YKL-40 could be assumed as a marker for disease diagnosis, prognosis, disease activity and severity. It is also shown to be involved in response to disease treatment. However, other studies showed controversial results particularly in the case of Behçet disease activity. Therefore, further studies are needed to elucidate the exact role of YKL-40 in autoimmunity and to investigate its potential in therapeutics.     

Time-calibrated phylogenomics of the porcine epidemic diarrhea virus: genome-wide insights into the spatio-temporal dynamics

Porcine epidemic diarrhea virus (PEDV), the causative agent of porcine epidemic diarrhea (PED), has led to tremendous economic losses in the global swine industry. Although the phylogeny of PEDV has been investigated extensively at the molecular level, there was no time-calibrated phylogenomic study on the virus. To improve insight into this topic, we analyzed 138 published genome sequences using the Bayesian coalescent analyses as well as Bayesian inferences and maximum likelihood methods. All of the global PEDV isolates were divided into six groups, except for one unclassified isolate. Of the six groups, Groups 1–5 comprised pandemic viruses while the remaining Group 6 contained classical isolates. Interestingly, the two clades, both pandemic and classical, consisted of clade-specific amino acid sequences in five genes: ORF1a, ORF1b, S, ORF3, and N. Within the pandemic clade, Group 1 and Group 2 originated from North America, whereas Group 3–Group 5 were derived from Asia. In Group 2, there was a common origin of S INDEL isolates. Within each group, there was no apparent association between temporal or geographic origin and heterogeneity of PEDVs. Our findings also showed that the PEDV virus evolved at a rate of 3.38?×?10^?4 substitutions/site/year, and the most recent common ancestor of the virus emerged 75.9 years ago. Our Bayesian skyline plot analysis indicated that the PEDV had maintained constant effective population size excluding only a short period, around 2012, when a valley shaped decline in the effective number of infections occurred.     

CD24 regulates cell proliferation and transforming growth factor β-induced epithelial to mesenchymal transition through modulation of integrin β1 stability

To determine the role of CD24 in breast cancer cells, we knocked down CD24 in MCF-7 human breast cancer cells by retroviral delivery of shRNA. MCF-7 cells with knocked down CD24 (MCF-7 hCD24 shRNA) exhibited decreased cell proliferation and cell adhesion as compared to control MCF-7 mCD24 shRNA cells. Decreased proliferation of MCF-7 hCD24 shRNA cells resulted from the inhibition of cell cycle progression from G1 to S phase. The specific inhibition of MEK/ERK signaling by CD24 ablation might be responsible for the inhibition of cell proliferation. Phosphorylation of Src/FAK and TGF-β1-mediated epithelial to mesenchymal transition was also down-regulated in MCF-7 hCD24 shRNA cells. Reduced Src/FAK activity was caused by a decrease in integrin β1 bound with CD24 and subsequent destabilization of integrin β1. Our results suggest that down-regulation of Raf/MEK/ERK signaling via Src/FAK may be dependent on integrin β1 function and that this mechanism is largely responsible for the CD24 ablation-induced decreases in cell proliferation and epithelial to mesenchymal transition.