Utku Norman1, A Ercument Cicek1,2. 1. Computer Engineering Department, Bilkent University, Ankara, Turkey. 2. Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, PA, USA.
Abstract
MOTIVATION: Whole exome sequencing (WES) studies for autism spectrum disorder (ASD) could identify only around six dozen risk genes to date because the genetic architecture of the disorder is highly complex. To speed the gene discovery process up, a few network-based ASD gene discovery algorithms were proposed. Although these methods use static gene interaction networks, functional clustering of genes is bound to evolve during neurodevelopment and disruptions are likely to have a cascading effect on the future associations. Thus, approaches that disregard the dynamic nature of neurodevelopment are limited. RESULTS: Here, we present a spatio-temporal gene discovery algorithm, which leverages information from evolving gene co-expression networks of neurodevelopment. The algorithm solves a prize-collecting Steiner forest-based problem on co-expression networks, adapted to model neurodevelopment and transfer information from precursor neurodevelopmental windows. The decisions made by the algorithm can be traced back, adding interpretability to the results. We apply the algorithm on ASD WES data of 3871 samples and identify risk clusters using BrainSpan co-expression networks of early- and mid-fetal periods. On an independent dataset, we show that incorporation of the temporal dimension increases the predictive power: predicted clusters are hit more and show higher enrichment in ASD-related functions compared with the state-of-the-art. AVAILABILITY AND IMPLEMENTATION: The code is available at http://ciceklab.cs.bilkent.edu.tr/st-steiner. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
MOTIVATION: Whole exome sequencing (WES) studies for autism spectrum disorder (ASD) could identify only around six dozen risk genes to date because the genetic architecture of the disorder is highly complex. To speed the gene discovery process up, a few network-based ASD gene discovery algorithms were proposed. Although these methods use static gene interaction networks, functional clustering of genes is bound to evolve during neurodevelopment and disruptions are likely to have a cascading effect on the future associations. Thus, approaches that disregard the dynamic nature of neurodevelopment are limited. RESULTS: Here, we present a spatio-temporal gene discovery algorithm, which leverages information from evolving gene co-expression networks of neurodevelopment. The algorithm solves a prize-collecting Steiner forest-based problem on co-expression networks, adapted to model neurodevelopment and transfer information from precursor neurodevelopmental windows. The decisions made by the algorithm can be traced back, adding interpretability to the results. We apply the algorithm on ASD WES data of 3871 samples and identify risk clusters using BrainSpan co-expression networks of early- and mid-fetal periods. On an independent dataset, we show that incorporation of the temporal dimension increases the predictive power: predicted clusters are hit more and show higher enrichment in ASD-related functions compared with the state-of-the-art. AVAILABILITY AND IMPLEMENTATION: The code is available at http://ciceklab.cs.bilkent.edu.tr/st-steiner. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.