Identification of putative genetic variants in major depressive disorder patients in Pakistan.

BACKGROUND: Major depressive disorder (MDD) is a polygenic, and highly prevalent disorder affecting 322 million people globally. It results in several psychological changes which adversely affect different dimensions of life and may lead to suicide. METHODS: Whole exome sequencing of 15 MDD patients, enrolled at the Dr. A. Q. Khan Institute of Behavioral Sciences, Karachi, was performed using NextSeq500. Different bioinformatics tools and databases like ANNOVAR, ALoFT, and GWAS were used to identify both common and rare variants associated with the pathogenesis of MDD. RESULTS: A total of 1985 variations were identified in 479 MDD-related genes. Several SNPs including rs1079610, rs11750538, rs1799913, rs1801131, rs2230267, rs2231187, rs3819976, rs4314963, rs56265970, rs587780434, rs6330, rs75111588, rs7596487, and rs9624909 were prioritized due to their deleteriousness and frequency difference between the patients and the South Asian population. A non-synonymous variation rs56265970 (BCR) had 26% frequency in patients and was not found in the South Asian population; a multiallelic UTR-5' insertion rs587780434 (RELN) was present with an allelic frequency of 70% in patients whereas 22% in the SAS population. Genetic alterations in PABPC1 genes, a stress-associated gene also had higher allele frequency in the cases than in the normal population. CONCLUSION: This present study identifies both common and rare variants in the genes associated with the pathogenesis of MDD in Pakistani patients. Genetic variations in BCR, RELN, and stress-associated PABPC1 suggest potential roles in the pathogenesis of MDD.

Prediction of post translation modifications at the contact site between Anaplasma phagocytophilum and human host during autophagosome induction using a bioinformatic approach.

Autophagy is crucial for maintaining physiological homeostasis, but its role in infectious diseases is not yet adequately understood. The binding of Anaplasma translocated substrate-1 (ATS1) to the human Beclin1 (BECN1) protein is responsible for the modulation of autophagy pathway. ATS1-BECN1 is a novel type of interaction that facilitates Anaplasma phagocytophilum proliferation, leading to intracellular infection via autophagosome induction and segregation from the lysosome. Currently, there is no report of post translational modifications (PTMs) of BECN1 or cross-talk required for ATS-BECN1 complex formation. Prediction/modeling of the cross-talk between phosphorylation and other PTMs (O-ß-glycosylation, sumoylation, methylation and palmitoylation) has been attempted in this study, which might be responsible for regulating function after the interaction of ATS1 with BECN1. PTMs were predicted computationally and mapped onto the interface of the docked ATS1-BECN1 complex. Results show that BECN1 phosphorylation at five residues (Thr91, Ser93, Ser96, Thr141 and Ser234), the interplay with O-ß-glycosylation at three sites (Thr91, Ser93 and Ser96) with ATS1 may be crucial for attachment and, hence, infection. No other PTM site at the BECN1 interface was predicted to associate with ATS1. These findings may have significant clinical implications for understanding the etiology of Anaplasma infection and for therapeutic studies.