Gene Function Prediction in Five Model Eukaryotes Exclusively Based on Gene Relative Location Through Machine Learning

The function of most genes is unknown. The best results in automated function prediction are obtained with machine learning-based methods that combine multiple data sources, typically sequence derived features, protein structure and interaction data. Even though there is ample evidence showing that a gene’s function is not independent of its location, the few available examples of gene function prediction based on gene location rely on sequence identity between genes of different organisms and are thus subjected to the limitations of the relationship between sequence and function. Here we predict thousands of gene functions in five model eukaryotes (Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, Mus musculus and Homo sapiens) using machine learning models exclusively trained with features derived from the location of genes in the genomes to which they belong. Our aim was not to obtain the best performing method to automated function prediction but to explore the extent to which a gene's location can predict its function in eukaryotes. We found that our models outperform BLAST when predicting terms from Biological Process and Cellular Component Ontologies, showing that, at least in some cases, gene location alone can be more useful than sequence to infer gene function.

Time-Course of Changes in Photosynthesis and Secondary Metabolites in Canola (Brassica napus) Under Different UV-B Irradiation Levels in a Plant Factory With Artificial Light

This study aimed to evaluate short-duration (24 h) UV-B irradiation as a preharvest abiotic stressor in canola plants. Moreover, we quantified the expression levels of genes related to bioactive compounds synthesis in response to UV-B radiation. Canola seedlings were cultivated in a plant factory under artificial light (200 μmol m–2 s–1 photosynthetic photon flux density; white LED lamps; 16 h on/8 h off), 25°C/20°C daytime/nighttime air temperature, and 70% relative humidity. Eighteen days after sowing, the seedlings were subjected to supplemental UV-B treatment. The control plants received no UV-B irradiation. The plants were exposed to 3, 5, or 7 W m–2 UV-B irradiation. There were no significant differences in shoot fresh weight between the UV-B-irradiated and control plants. With increasing UV-B irradiation intensity and exposure time, the H2O2 content gradually increased, the expression levels of genes related to photosynthesis downregulated, and phenylpropanoid and flavonoid production, and also total phenolic, flavonoid, antioxidant, and anthocyanin concentrations were significantly enhanced. The genes related to secondary metabolite biosynthesis were immediately upregulated after UV-B irradiation. The relative gene expression patterns identified using qRT-PCR corroborated the variations in gene expression that were revealed using microarray analysis. The time point at which the genes were induced varied with the gene location along the biosynthetic pathway. To the best of our knowledge, this is the first study to demonstrate a temporal difference between the accumulation of antioxidants and the induction of genes related to the synthesis of this compound in UV-B-treated canola plants. Our results demonstrated that short-term UV-B irradiation could augment antioxidant biosynthesis in canola without sacrificing crop yield or quality.

Novel approaches in cancer treatment: preclinical and clinical development of small non-coding RNA therapeutics

Short or small interfering RNAs (siRNAs) and microRNA (miRNAs) are molecules similar in size and function able to inhibit gene expression based on their complementarity with mRNA sequences, inducing the degradation of the transcript or the inhibition of their translation.siRNAs bind specifically to a single gene location by sequence complementarity and regulate gene expression by specifically targeting transcription units via posttranscriptional gene silencing. miRNAs can regulate the expression of different gene targets through their imperfect base pairing.This process - known as RNA interference (RNAi) - modulates transcription in order to maintain a correct physiological environment, playing a role in almost the totality of the cellular pathways.siRNAs have been evolutionary evolved for the protection of genome integrity in response to exogenous and invasive nucleic acids such as transgenes or transposons. Artificial siRNAs are widely used in molecular biology for transient silencing of genes of interest. This strategy allows to inhibit the expression of any target protein of known sequence and is currently used for the treatment of different human diseases including cancer.Modifications and rearrangements in gene regions encoding for miRNAs have been found in cancer cells, and specific miRNA expression profiles characterize the developmental lineage and the differentiation state of the tumor. miRNAs with different expression patterns in tumors have been reported as oncogenes (oncomirs) or tumor-suppressors (anti-oncomirs). RNA modulation has become important in cancer research not only for development of early and easy diagnosis tools but also as a promising novel therapeutic approach.Despite the emerging discoveries supporting the role of miRNAs in carcinogenesis and their and siRNAs possible use in therapy, a series of concerns regarding their development, delivery and side effects have arisen.In this review we report the biology of miRNAs and siRNAs in relation to cancer summarizing the recent methods described to use them as novel therapeutic drugs and methods to specifically deliver them to cancer cells and overcome the limitations in the use of these molecules.

An Ensemble Deep Learning based Predictor for Simultaneously Identifying Protein Ubiquitylation and SUMOylation Sites

Background Several computational tools for predicting protein Ubiquitylation and SUMOylation sites have been proposed to study their regulatory roles in gene location, gene expression, and genome replication. However, existing methods generally rely on feature engineering, and ignore the natural similarity between the two types of protein translational modification. This study is the first all-in-one deep network to predict protein Ubiquitylation and SUMOylation sites from protein sequences as well as their crosstalk sites simultaneously. Our deep learning architecture integrates several meta classifiers that apply deep neural networks to protein sequence information and physico-chemical properties, which were trained on multi-label classification mode for simultaneously identifying protein Ubiquitylation and SUMOylation as well as their crosstalk sites. Results The promising AUCs of our method on Ubiquitylation, SUMOylation and crosstalk sites achieved 0.838, 0.888, and 0.862 respectively on tenfold cross-validation. The corresponding APs reached 0.683, 0.804 and 0.552, which also validated our effectiveness. Conclusions The proposed architecture managed to classify ubiquitylated and SUMOylated lysine residues along with their crosstalk sites, and outperformed other well-known Ubiquitylation and SUMOylation site prediction tools.

Gene function prediction in five model eukaryotes based on gene relative location through machine learning

Motiviation: The function of most genes is unknown. The best results in gene function prediction are obtained with machine learning-based methods that combine multiple data sources, typically sequence derived features, protein structure and interaction data. Even though there is ample evidence showing that a gene's function is not independent of its location, the few available examples of gene function prediction based on gene location relay on sequence identity between genes of different organisms and are thus subjected to the limitations of the relationship between sequence and function. Results: Here we predict thousands of gene functions in five eukaryotes (Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, Mus musculus and Homo sapiens) using machine learning models trained with features derived from the location of genes in the genomes to which they belong. To the best of our knowledge this is the first work in which gene function prediction is successfully achieved in eukaryotic genomes using predictive features derived exclusively from the relative location of the genes. Contact: [email protected] Supplementary information: http://gfpml.bnd.edu.uy

Molecular cloning and characterization of common marmoset SULT1C subfamily members that catalyze the sulfation of thyroid hormones

Cytosolic sulfotransferase SULT1C subfamily is one of the most flexible gene subfamily during mammalian evolution. The physiological functions of SULT1C enzymes still remain to be fully understood. In this study, common marmoset (Callithrix jacchus), a promising primate animal model, was used to investigate the functional relevance of the SULT1C subfamily. Gene database search revealed three intact SULT1C genes and a pseudogene in its genome. These four genes were named SULT1C1, SULT1C2, SULT1C3P, and SULT1C5, according to the sequence homology and gene location. Since SULT1C5 is the orthologous gene for human SULT1C2P, we propose, here, to revisit the designation of human SULT1C2P to SULT1C5P. Purified recombinant SULT1C enzymes showed sulfating activities toward a variety of xenobiotic compounds and thyroid hormones. Kinetic analysis revealed high catalytic activities of SULT1C1 and SULT1C5 for 3,3’-T2. It appears therefore that SULT1C isoforms may play a role in the thyroid hormone metabolism in common marmoset.

Mutations in MED12 lead to mental retardation, including Opitz–Kaveggia syndrome, Ohdo syndrome, Lujan–Fryns syndrome, and psychosis. It's a target for gene therapy

Mutations in MED12 lead to mental retardation, including Opitz–Kaveggia syndrome, Ohdo syndrome, Lujan–Fryns syndrome, and psychosis. Malignant cell transformation was linked to a transcriptional machine failure and, as such, MED12 function dysregulation was engaged across many cancers. Its involvement in hormone-dependent cancers (uterine leiomyoma, breast fibroepithelial tumors, prostate cancer, and breast cancer) represents a unique target for such malignancies. Knowledge of downstream targets of MED12 alterations also includes specific targets that might be exploited in MED 12-mutated cancers. For example, MED 12 loss entails resistance to lung cancer tyrosine kinase inhibitors, pushing emphasis to alternative therapies. The entire genome sequencing area is growing quite rapidly, so we anticipate identifying MED12 mutations more regularly in people with intellectual disability. It is also worth noting that gene location on chromosome X mainly affects males, causing such gender bias illnesses. The study was published in the journal of Clinical and molecular Epidemiology, Biomarkers' Journal. The study concluded that MED12 is a crucial component of transcription regulatory machinery and any alterations in its structure or function are deleterious to cell growth, division, and differentiation processes. MED12 is, thus, a major transcription regulator affecting various behavioral disorders and malignancies. This research suffices to identify MED12 as a therapeutic target and biomarker for several diseases.

Contribution of Different Mechanisms to Ciprofloxacin Resistance in Salmonella spp.

Development of fluoroquinolone resistance can involve several mechanisms that include chromosomal mutations in genes (gyrAB and parCE) encoding the target bacterial topoisomerase enzymes, increased expression of the AcrAB-TolC efflux system, and acquisition of transmissible quinolone-resistance genes. In this study, 176 Salmonella isolates from animals with a broad range of ciprofloxacin MICs were collected to analyze the contribution of these different mechanisms to different phenotypes. All isolates were classified according to their ciprofloxacin susceptibility pattern into five groups as follows: highly resistant (HR), resistant (R), intermediate (I), reduced susceptibility (RS), and susceptible (S). We found that the ParC T57S substitution was common in strains exhibiting lowest MICs of ciprofloxacin while increased MICs depended on the type of GyrA mutation. The ParC T57S substitution appeared to incur little cost to bacterial fitness on its own. The presence of PMQR genes represented an route for resistance development in the absence of target-site mutations. Switching of the plasmid-mediated quinolone resistance (PMQR) gene location from a plasmid to the chromosome was observed and resulted in decreased ciprofloxacin susceptibility; this also correlated with increased fitness and a stable resistance phenotype. The overexpression of AcrAB-TolC played an important role in isolates with small decreases in susceptibility and expression was upregulated by MarA more often than by RamA. This study increases our understanding of the relative importance of several resistance mechanisms in the development of fluoroquinolone resistance in Salmonella from the food chain.

Identifying the Lipidomic Effects of a Rare Loss-of-Function Deletion in ANGPTL3

Background - The identification and understanding of therapeutic targets for atherosclerotic cardiovascular disease (ASCVD) is of fundamental importance given its global health and economic burden. Inhibition of angiopoietin-like 3 (ANGPTL3) has demonstrated a cardioprotective effect, showing promise for ASCVD treatment, and is currently the focus of ongoing clinical trials. Here we assessed the genetic basis of variation in ANGPTL3 levels in the San Antonio Family Heart Study. Methods - We assayed ANGPTL3 protein levels in ~1,000 Mexican Americans from extended pedigrees. By drawing upon existing plasma lipidome profiles and genomic data we conducted analyses to understand the genetic basis to variation in ANGPTL3 protein levels, and accordingly the correlation with the plasma lipidome. Results - In a variance components framework we identified that variation in ANGPTL3 was significantly heritable (h 2 =0.33, P=1.31×10 -16 ). To explore the genetic basis of this heritability, we conducted a genome-wide linkage scan and identified significant linkage (LOD = 6.18) to a locus on chromosome 1 at 90 cM, corresponding to the ANGPTL3 gene location. In the genomes of 23 individuals from a single pedigree, we identified a loss of function (LoF) variant, rs398122988 (N121Kfs*2), in ANGPTL3 , that was significantly associated with lower ANGPTL3 levels (β=−1.69 SDU, P=3.367×10 -13 ), and accounted for the linkage signal at this locus. Given the known role of ANGPTL3 as an inhibitor of endothelial and lipoprotein lipase we explored the association of ANGPTL3 protein levels and rs398122988 with the plasma lipidome and related phenotypes, identifying novel associations with phosphatidylinositols. Conclusions - Variation in ANGPTL3 protein levels is heritable and under significant genetic control. Both ANGPTL3 levels and LoF variants in ANGPTL3 have significant associations with the plasma lipidome. These findings further our understanding of ANGPTL3 as a therapeutic target for ASCVD.

Plasmids facilitate pathogenicity, not cooperation, in bacteria

Horizontal gene transfer via plasmids could favour cooperation in bacteria, because transfer of a cooperative gene turns non-cooperative cheats into cooperators. This hypothesis has received support from both theoretical and genomic analyses. In contrast, with a comparative analysis across 51 diverse species, we found that genes for extracellular proteins, which are likely to act as cooperative ‘public goods’, were not more likely to be carried on either: (i) plasmids compared to chromosomes; or (ii) plasmids that transfer at higher rates. Our results were supported by theoretical modelling which showed that while horizontal gene transfer can help cooperative genes initially invade a population, it does not favour the longer-term maintenance of cooperation. Instead, we found that genes for extracellular proteins were more likely to be on plasmids when they coded for pathogenic virulence traits, in pathogenic bacteria with a broad host-range. Taken together, these results support an alternate hypothesis, that plasmid gene location confers benefits other than horizontal gene transfer.