Biology subjects

Dereli, O.

Publications and source records attributed to Dereli, O..

3 recordsLinked to original sources

bioRxiv2024

PHACTboost: A Phylogeny-aware Boosting Algorithm to Compute the Pathogenicity of Missense Mutations

Most algorithms that are used to predict the effects of variants rely on evolutionary conservation. However, a majority of such techniques compute evolutionary conservation by solely using the alignment of multiple sequences while overlooking the evolutionary context of substitution events. We had introduced PHACT, a scoring-based pathogenicity predictor for missense mutations that can leverage phylogenetic trees, in our previous study. By building on this foundation, we now propose PHACTboost, a gradient boosting tree-based classifier that combines PHACT scores with information from multiple sequence alignments, phylogenetic trees, and ancestral reconstruction. The results of comprehensive experiments on carefully constructed sets of variants demonstrated that PHACTboost can outperform 40 prevalent pathogenicity predictors reported in the dbNSFP, including conventional tools, meta-predictors, and deep learning-based approaches as well as state-of-the-art tools, AlphaMissense, EVE, and CPT-1. The superiority of PHACTboost over these methods was particularly evident in case of hard variants for which different pathogenicity predictors offered conflicting results. We provide predictions of 219 million missense variants over 20,191 proteins. PHACTboost can improve our understanding of genetic diseases and facilitate more accurate diagnoses.

bioinformatics↗

bioRxiv2023

Evolutionary history of Calcium-sensing receptors sheds light into hyper/hypocalcemia-causing mutations

Calcium-sensing receptor evolution highlights hyper/hypocalcemia-causing mutations The Calcium Sensing Receptor (CaSR) is a key player in regulating calcium levels and has been linked to disorders like hypercalcemia and hypocalcemia. Despite advancements in understanding CaSRs structure and functions, there are still gaps in our understanding of its specific residues and their differences from receptors within the same class. In this study, we used phylogeny-based techniques to identify functionally equivalent orthologs of CaSR, predict residue significance, and compute specificity-determining position (SDP) scores to understand its evolutionary basis. The analysis revealed exceptional conservation of the CaSR subfamily, with high SDP scores being critical in receptor activation and pathogenicity. To further enhance the findings, gradient-boosting trees were applied to differentiate between gain- and loss-of-function mutations responsible for hypocalcemia and hypercalcemia. Lastly, we investigated the importance of these mutations in the context of receptor activation dynamics. In summary, through comprehensive exploration of the evolutionary history of the CaSR subfamily, coupled with innovative phylogenetic methodologies, we identified activating and inactivating residues, providing valuable insights into the regulation of calcium homeostasis and its connections to associated disorders.

evolutionary biology↗

bioRxiv2022

Downregulated NPAS4 in multiple brain regions is associated with Major Depressive Disorder

Major Depressive Disorder (MDD) is a commonly observed psychiatric disorder that affects more than 2% of the world population with a rising trend. However, disease-associated pathways and biomarkers are yet to be fully comprehended. In this study, we analyzed previously generated RNA-seq data across seven different brain regions from three distinct studies to identify differentially and co-expressed genes for patients with MDD. Differential gene expression (DGE) analysis revealed that NPAS4 is the only gene downregulated in three different brain regions. Furthermore, co-expressing gene modules responsible for glutamatergic signaling are negatively enriched in these regions. We used the results of both DGE and co-expression analyses to construct a novel MDD-associated pathway. In our model, we propose that disruption in glutamatergic signaling-related pathways might be associated with the downregulation of NPAS4 and many other immediate-early genes (IEGs) that control synaptic plasticity. In addition to DGE analysis, we identified the relative importance of KEGG pathways in discriminating MDD phenotype using a machine learning-based approach. We anticipate that our study will open doors to developing better therapeutic approaches targeting glutamatergic receptors in the treatment of MDD.

genetics↗