ECOLE: Learning to call copy number variants on whole exome sequencing data.

Copy number variants (CNV) are shown to contribute to the etiology of several genetic disorders. Accurate detection of CNVs on whole exome sequencing (WES) data has been a long sought-after goal for use in clinics. This was not possible despite recent improvements in performance because algorithms mostly suffer from low precision and even lower recall on expert-curated gold standard call sets. Here, we present a deep learning-based somatic and germline CNV caller for WES data, named ECOLE. Based on a variant of the transformer architecture, the model learns to call CNVs per exon, using high-confidence calls made on matched WGS samples. We further train and fine-tune the model with a small set of expert calls via transfer learning. We show that ECOLE achieves high performance on human expert labelled data for the first time with 68.7% precision and 49.6% recall. This corresponds to precision and recall improvements of 18.7% and 30.8% over the next best-performing methods, respectively. We also show that the same fine-tuning strategy using tumor samples enables ECOLE to detect RT-qPCR-validated variations in bladder cancer samples without the need for a control sample. ECOLE is available at https://github.com/ciceklab/ECOLE .

Polishing copy number variant calls on exome sequencing data via deep learning.

Accurate and efficient detection of copy number variants (CNVs) is of critical importance owing to their significant association with complex genetic diseases. Although algorithms that use whole-genome sequencing (WGS) data provide stable results with mostly valid statistical assumptions, copy number detection on whole-exome sequencing (WES) data shows comparatively lower accuracy. This is unfortunate as WES data are cost-efficient, compact, and relatively ubiquitous. The bottleneck is primarily due to the noncontiguous nature of the targeted capture: biases in targeted genomic hybridization, GC content, targeting probes, and sample batching during sequencing. Here, we present a novel deep learning model, DECoNT, which uses the matched WES and WGS data, and learns to correct the copy number variations reported by any off-the-shelf WES-based germline CNV caller. We train DECoNT on the 1000 Genomes Project data, and we show that we can efficiently triple the duplication call precision and double the deletion call precision of the state-of-the-art algorithms. We also show that our model consistently improves the performance independent of (1) sequencing technology, (2) exome capture kit, and (3) CNV caller. Using DECoNT as a universal exome CNV call polisher has the potential to improve the reliability of germline CNV detection on WES data sets.

DORMAN: Database of Reconstructed MetAbolic Networks.

Genome-scale reconstructed metabolic networks have provided an organism specific understanding of cellular processes and their relations to phenotype. As they are deemed essential to study metabolism, the number of organisms with reconstructed metabolic networks continues to increase. This everlasting research interest lead to the development of online systems/repositories that store existing reconstructions and enable new model generation, integration, and constraint-based analyses. While features that support model reconstruction are widely available, current systems lack the means to help users who are interested in analyzing the topology of the reconstructed networks. Here, we present the Database of Reconstructed Metabolic Networks - DORMAN. DORMAN is a centralized online database that stores SBML-based reconstructed metabolic networks published in the literature, and provides web-based computational tools for visualizing and analyzing the model topology. Novel features of DORMAN are (i) interactive visualization interface that allows rendering of the complete network as well as editing and exporting the model, (ii) hierarchical navigation that provides efficient access to connected entities in the model, (iii) built-in query interface that allow posing topological queries, and finally, and (iv) model comparison tool that enables comparing models with different nomenclatures, using approximate string matching. DORMAN is online and freely accessible at http://ciceklab.cs.bilkent.edu.tr/dorman.