An in silico analysis of deleterious single nucleotide polymorphisms and molecular dynamics simulation of disease linked mutations in genes responsible for neurodegenerative disorder

Abstract

Mutation in two genes deglycase gene (DJ-1) and retromer complex component gene (VPS35) are linked with neurodegenerative disorder such as Parkinson's disease, Huntington's disease, and Alzheimer's disease. DJ-1 gene located at 1p36 chromosomal position and involved in PD pathogenesis through many pathways including mitochondrial dysfunction and oxidative injury. VPS35 gene located at 16q13-q21 chromosomal position and the two pathways, the Wnt signaling pathway, and retromer-mediated DMT1 missorting are proposed for basis of VPS35 related PD. The study focuses on identifying most deleterious SNPs through computational analysis. Result obtained from various bioinformatics tools shows that D149A is most deleterious in DJ-1 and A54W, R365H, and V717M are most deleterious in VPS35. To understand the functionality of protein comparative modeling of DJ-1 and VPS35 native and mutants was done by MODELLER. The generated structures are validated by two web servers–ProSa and RAMPAGE. Molecular dynamic simulation (MDS) analysis done for the most validated structures to know the functional and structural nature of native and mutants protein of DJ-1 and VPS35. Native structure of DJ-1 and VPS35 show more flexibility through MDS analysis. DJ-1 D149A mutant structures become more compact which shows the structural perturbation and loss of DJ-1 protein function which in turn are probable cause for PD. A54W, R365H, and V717M mutant protein of VPS35 also shows compactness which cause structure perturbation and absence of retromer function which likely to be linked to PD pathogenesis. This in silico study may provide a new insight for fundamental molecular mechanism involved in Parkinson’s disease.

Communicated by Ramaswamy H. Sarma     

IGFBP3 gene promoter methylation analysis and its association with clinicopathological characteristics of colorectal carcinoma

Molecular Biology Reports - Promoter methylation mediated silencing of tumor suppressor genes plays an important role in the tumorigenesis of colorectal carcinoma (CRC). Tumor suppressor gene,...     

Zebrafish AID is capable of deaminating methylated deoxycytidines

Activation-induced cytidine deaminase (AID) deaminates deoxycytidine (dC) to deoxyuracil (dU) at immunoglobulin loci in B lymphocytes to mediate secondary antibody diversification. Recently, AID has been proposed to also mediate epigenetic reprogramming by demethylating methylated cytidines (mC) possibly through deamination. AID overexpression in zebrafish embryos was shown to promote genome demethylation through G:T lesions, implicating a deamination-dependent mechanism. We and others have previously shown that mC is a poor substrate for human AID. Here, we examined the ability of bony fish AID to deaminate mC. We report that zebrafish AID was unique among all orthologs in that it efficiently deaminates mC. Analysis of domain-swapped and mutant AID revealed that mC specificity is independent of the overall high-catalytic efficiency of zebrafish AID. Structural modeling with or without bound DNA suggests that efficient deamination of mC by zebrafish AID is likely not due to a larger catalytic pocket allowing for better fit of mC, but rather because of subtle differences in the flexibility of its structure.     

Chemical activators: A novel and sustainable management approach for Meloidogyne incognita (Kofoid and White) Chitwood in Chamomilla recutita L

Use of chemical activator for the management of root-knot disease in medicinal and aromatic plants can become an attractive alternative to traditionally used nematicides. Large numbers of chemical molecules are present in the plants and are involved in the induction of different types of proteins. The purpose of our research study is to explore the possibilities of resistance factors that are inherent in the plant by treating them with few chemical activators to activate against root-knot nematode infection. Efforts were made to achieve a satisfactory suppression of root-knot nematode, Meloidogyne incognita, a serious menace to successful cultivation of chamomile, Matricaria recutita L. Rauch (syn. Matricaria chamomilla L. Fain. Asteraceae) causing root-knot disease through use of different chemical activators. Here we examined selected groups of resistance activator viz. Isonicotinamide, 2-chloronicotinic acid, 5-nitrosalicylic acid, 4-chlorosalicylic acid, DL-2 aminobutyric acid, 2-aminobutyric acid, O-acetylsalicylic acid, 4-amino salicylic acid, salicylic acid and these were used as soil drench using 3 week old seedlings transplanted to root-knot nematode infested pots. Maximum reduction in root-knot severity and nematode population occurred with 4-chlorosalicylic acid, O-acetyl salicylic acid, 2-chloronicotinic acid and gave significant flower yield advantages. Present experiment suggests a strong possibility of these activators in integrated management for protection against plant parasitic nematodes.     

Epidemiology and prediction of brown leaf rust of mulberry caused by Peridiopsora mori

Brown leaf rust (BLR) caused by Peridiopsora mori is one of the major foliar diseases of mulberry (Morus sp.) in the subtropical hills of eastern India. The disease appeared in first week of August and continued up to September with maximum severity in second and third week of September. The disease symptoms appeared at atmospheric temperature (27.00–20.07°C), relative humidity (92.14–82.43%), rainfall (11.20 cm) and rainy days (7) of the preceding week. Disease severity (>50 PDI) was observed at temperature (26.29–19.29°C), relative humidity (94.14–80.14%), rainfall (4.12 cm) and number of rainy days (2–3 days). Apparent rate of infection was found high at temperature (27.00–19.83°C), relative humidity (94.67–85.00%), rainfall (4.6 cm) and rainy days (2) of the preceding week. The correlation coefficient between disease severity and average meteorological factors of the preceding 7 days revealed that BLR disease severity showed significant negative correlation with minimum temperature. It was also revealed that contribution of maximum and minimum temperature 42.23% and 35.21%, maximum and minimum relative humidity (RH) 11.23% and 10.69% and rainfall and number of rainy days 0.11% and 0.50%, respectively towards development of BLR disease severity. Multiple regression analysis revealed that average of maximum and minimum temperatures and minimum RH of preceding 7 days were found to maximally influence BLR disease severity.     

Determination of biotic aetiology of tapping panel dryness (TPD) syndrome of rubber tree (Hevea brasiliensis) by return-polyacrylamide gel electrophoresis (R-PAGE) technique

Tapping panel dryness (TPD) syndrome affecting rubber tree (Hevea brasiliensis) is known to reduce natural latex production. Its aetiology remains ambiguous despite long years of research. A low molecular weight RNA similar to viroid RNA was isolated from TPD-affected samples of rubber trees. In the present study, a modified return-polyacrylamide gel electrophoresis procedure was standardised. The viroid-like low molecular weight (LMW) RNA was found associated with leaf, bark and root tissues and rubber seedlings. The technique was employed to detect LMW RNA in different clones of rubber planted in different locations and in bud-grafted plants. The LMW RNA isolated from TPD-affected trees was found infectious on seedlings of tomato cv Pusa Ruby. The LMW RNA was reisolated from symptomatic tomato leaves but not from control plants. This is for the first time that a biotic agent, a viroid RNA, is found consistently associated with the syndrome. The technology developed can be useful to demonstrate the onset of TPD in untapped trees in the absence of other methods such as nucleic acid hybridisation.     

Association of peroxisome proliferator activated receptor-γ gene with non-alcoholic fatty liver disease in Asian Indians residing in north India

Background

Genetics of non-alcoholic fatty liver (NAFLD) in Asian Indians has been inadequately studied. We investigated the association of polymorphisms C161T and Pro12Ala of peroxisome proliferator-activated receptor gamma (PPARγ) with clinical and biochemical parameters in Asian Indians with NAFLD.

Methods

In this case–control study, 162 NAFLD cases and 173 controls were recruited. Abdominal ultrasound, clinical and biochemical profiles, fasting insulin levels and value of homeostasis model assessment of insulin resistance were determined. Polymerase chain reaction–restriction fragment length polymorphisms of two polymorphisms were performed. The association of these polymorphisms with clinical and biochemical parameters was analysed.

Results

Higher frequency of Ala and T alleles of PPARγ was obtained in cases. Ala/Ala genotype of PPARγ (Pro12Ala) was associated with significantly higher serum triglycerides (TG), alkaline phosphatase (ALK) and waist–hip ratio in cases as compared to controls. In C161T polymorphism, TT genotype was significantly increased TG (p = 0.04), total cholesterol (p = 0.01), ALK (p = 0.04) and gamma-glutamyl transpeptidase (p = 0.007) in cases. The linkage disequilibrium for these two single-nucleotide polymorphisms of PPARγ was differed in cases (D1 = 0.1; p = 0.006) and controls (D1 = 0.07; p = 0.1). Using a multivariate analysis after adjusting for age, sex and body mass index, the presence of NAFLD was linked to these two polymorphisms (odds ratio 1.64 (95% CI: 1.09–2.45, p = 0.05)].

Conclusion

Asian Indians in north India carrying the alleles Ala and T of PPARγ (Pro12Ala and C161T) polymorphisms are predisposed to develop NAFLD.     

Seasonal variations in the mating-related traits of Drosophila melanogaster

The Indian subcontinent shows high levels of seasonal weather variation, but the extent to which mating-related traits (mating latency, copulation duration and number of progeny produced) are being affected by such variations in Drosophila species remain poorly understood. In the present study, we analyzed the effects of seasonal change (humidity and temperature) on mating-related traits of Drosophila melanogaster by mimicking natural conditions in the laboratory. The light body color phenotype is collected in large numbers during the rainy season, while the dark phenotype is prevalent in the winter. We found that a short-term stress, in the form of reduced humidity or temperature, causes a strong climatic selection pressure, which leads to assortative mating and longer copulation duration of the dark phenotype. By contrast, the light phenotype shows higher assortative mating and longer copulation duration after short-term high humidity or high temperature stress. Higher assortative mating and increased copulation duration results in high progeny numbers which may be a cause for the high prevalence of the dark phenotype in winter and the light phenotype in the rainy season. Thus, besides plasticity, seasonal changes in mating propensity can be a potential cause of the change in the frequency of the dark and light phenotypes of D. melanogaster during different seasons.