A deep transcriptome meta-analysis reveals sex differences in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS), a chronic auto-immune, inflammatory, and degenerative disease of the central nervous system, affects both males and females; however, females suffer from a higher risk of developing MS (2-3:1 ratio relative to males). The precise sex-based factors influencing risk of MS are currently unknown. Here, we explore the role of sex in MS to identify molecular mechanisms underlying observed MS sex differences that may guide novel therapeutic approaches tailored for males or females. METHODS: We performed a rigorous and systematic review of genome-wide transcriptome studies of MS that included patient sex data in the Gene Expression Omnibus and ArrayExpress databases following PRISMA statement guidelines. For each selected study, we analyzed differential gene expression to explore the impact of the disease in females (IDF), in males (IDM) and our main goal: the sex differential impact of the disease (SDID). Then, for each scenario (IDF, IDM and SDID) we performed 2 meta-analyses in the main tissues involved in the disease (brain and blood). Finally, we performed a gene set analysis in brain tissue, in which a higher number of genes were dysregulated, to characterize sex differences in biological pathways. RESULTS: After screening 122 publications, the systematic review provided a selection of 9 studies (5 in blood and 4 in brain tissue) with a total of 474 samples (189 females with MS and 109 control females; 82 males with MS and 94 control males). Blood and brain tissue meta-analyses identified, respectively, 1 (KIR2DL3) and 13 (ARL17B, CECR7, CEP78, IFFO2, LOC401127, NUDT18, RNF10, SLC17A5, STMP1, TRAF3IP2-AS1, UBXN2B, ZNF117, ZNF488) MS-associated genes that differed between males and females (SDID comparison). Functional analyses in the brain revealed different altered immune patterns in females and males (IDF and IDM comparisons). The pro-inflammatory environment and innate immune responses related to myeloid lineage appear to be more affected in females, while adaptive responses associated with the lymphocyte lineage in males. Additionally, females with MS displayed alterations in mitochondrial respiratory chain complexes, purine, and glutamate metabolism, while MS males displayed alterations in stress response to metal ion, amine, and amino acid transport. CONCLUSION: We found transcriptomic and functional differences between MS males and MS females (especially in the immune system), which may support the development of new sex-based research of this disease. Our study highlights the importance of understanding the role of biological sex in MS to guide a more personalized medicine.

Client Applications and Server-Side Docker for Management of RNASeq and/or VariantSeq Workflows and Pipelines of the GPRO Suite.

The GPRO suite is an in-progress bioinformatic project for -omics data analysis. As part of the continued growth of this project, we introduce a client- and server-side solution for comparative transcriptomics and analysis of variants. The client-side consists of two Java applications called "RNASeq" and "VariantSeq" to manage pipelines and workflows based on the most common command line interface tools for RNA-seq and Variant-seq analysis, respectively. As such, "RNASeq" and "VariantSeq" are coupled with a Linux server infrastructure (named GPRO Server-Side) that hosts all dependencies of each application (scripts, databases, and command line interface software). Implementation of the Server-Side requires a Linux operating system, PHP, SQL, Python, bash scripting, and third-party software. The GPRO Server-Side can be installed, via a Docker container, in the user's PC under any operating system or on remote servers, as a cloud solution. "RNASeq" and "VariantSeq" are both available as desktop (RCP compilation) and web (RAP compilation) applications. Each application has two execution modes: a step-by-step mode enables each step of the workflow to be executed independently, and a pipeline mode allows all steps to be run sequentially. "RNASeq" and "VariantSeq" also feature an experimental, online support system called GENIE that consists of a virtual (chatbot) assistant and a pipeline jobs panel coupled with an expert system. The chatbot can troubleshoot issues with the usage of each tool, the pipeline jobs panel provides information about the status of each computational job executed in the GPRO Server-Side, while the expert system provides the user with a potential recommendation to identify or fix failed analyses. Our solution is a ready-to-use topic specific platform that combines the user-friendliness, robustness, and security of desktop software, with the efficiency of cloud/web applications to manage pipelines and workflows based on command line interface software.