Dhindsa, R. | bioRxiv Science

bioRxiv2020

Ancestry adjustment improves genome-wide estimates of regional intolerance

Genomic regions subject to purifying selection are more likely to carry disease causing mutations. Cross species conservation is often used to identify such regions but has limited resolution to detect selection on short evolutionary timescales such as that occurring in only one species. In contrast, intolerance looks for depletion of variation relative to expectation within a species, allowing species specific features to be identified. When estimating the intolerance of noncoding sequence methods strongly leverage variant frequency distributions. As the expected distributions depend on demography, if not properly controlled for, ancestral population source may obfuscate signals of selection. We demonstrate that properly incorporating demography in intolerance estimation greatly improved variant classification (13% increase in AUC relative to comparison constraint test, CDTS; and 9% relative to conservation). We provide a genome-wide intolerance map that is conditional on demographic history that is likely to be particularly valuable for variant prioritization.

genetics↗

bioRxiv2018

meaRtools: an R package for the Comprehensive Analysis of Neuronal Networks Recorded on Multi-Electrode Arrays

Here we present an open-source R package meaRtools that provides a platform for analyzing neuronal networks recorded on Microelectrode Arrays (MEAs). Cultured neuronal networks monitored with MEAs are now being widely used to characterize in vitro models of neurological disorders and to evaluate pharmaceutical compounds. meaRtools provides core algorithms for MEA spike train analysis, feature extraction, statistical analysis and plotting of multiple MEA recordings with multiple genotypes and treatments. meaRtools functionality covers novel solutions for spike train analysis, including algorithms to assess electrode cross-correlation using the spike train tiling coefficient (STTC), mutual information, synchronized bursts and entropy within cultured wells. Also integrated is a solution to account for bursts variability originating from mixed-cell neuronal cultures. The package provides a statistical platform built specifically for MEA data that can combine multiple MEA recordings and compare extracted features between different genetic models or treatments. We demonstrate the utilization of meaRtools to successfully identify epilepsy-like phenotypes in neuronal networks from Celf4 knockout mice. The package is freely available under the GPL license (GPL>=3) and is updated frequently on the CRAN web-server repository. The package, along with full documentation can be downloaded from: https://cran.r-project.org/web/packages/meaRtools/.\n\nAuthor summaryCultured neuronal networks are widely used to study and characterize neuronal network activity. Among the many uses of neuronal cultures are the capabilities to evaluate neurotoxicity and the effects of pharmacological compounds on cellular physiology. Multi-well microelectrode arrays (MEAs) can collect high-throughput data from multiple neuronal cultures simultaneously, and thereby make possible hypotheses-driven inquiries into neurobiology and neuropharmacology. The analysis of MEA-derived information presents many computational challenges. High frequency data recorded simultaneously from hundreds of electrodes can be difficult to handle. The need to compare network activity across various drug treatments or genotypes recorded on the same plate from experiments lasting several weeks presents another challenge. These challenges inspired us to develop meaRtools; an MEA data analysis package that contains new methods to characterize network activity patterns, which are illustrated here using examples from a genetic mouse model of epilepsy. Among the highlights of meaRtools are novel algorithms designed to characterize neuronal activity dynamics and network properties such as bursting and synchronization, options to combine multiple recordings and use a robust statistical framework to draw appropriate statistical inferences, and finally data visualizations and plots. In summary, meaRtools provides a platform for the analyses of singular and longitudinal MEA experiments.

neuroscience↗