Biology subjects

Morton, S.

Publications and source records attributed to Morton, S..

4 recordsLinked to original sources

bioRxiv2026

Structural variants in human congenital heart disease disrupt distal genomic regulatory contacts of developmental genes

Predicting the functional significance of structural variants (SVs) associated with genetic diseases remains challenging. To test the hypothesis that SVs from people with congenital heart disease (CHD) disrupt developmental chromatin interactions, we developed CardioAkita, a machine-learning model that predicts how variants alter 3D chromatin structure. Analyzing previously genotyped de novo SVs (dnSVs), we observed a positive association between CHD severity and CardioAkita scores across dozens of families. From whole-genome sequencing of three individuals with CHD we predicted disruptive dnSVs. Induced pluripotent stem cells engineered to harbor these variants confirmed CardioAkitas predictions of 3D chromatin changes, and further revealed aberrant expression of local genes including cardiac developmental genes, suggesting that chromatin reorganization plays a significant mechanistic role in the genetic etiology of CHD. Our findings highlight the potential for models of 3D chromatin organization to predict the pathogenicity and underlying mechanisms of SVs in human disease.

genomics↗

bioRxiv2025

Altered Protein Phosphorylation in a Novel Midbrain Organoid Model for Bipolar Disorder

Bipolar disorder (BD) is a severe psychiatric condition marked by episodes of mania and depression, with neurotransmitter imbalance in the midbrain believed to play a critical role in its pathophysiology. Despite this, there is currently no validated midbrain model for examining BD-associated molecular changes available. Leveraging recent advances in stem cell technology, we developed a midbrain organoid model using human induced pluripotent stem cells (hiPSCs) from BD patients and healthy controls (CTR). To address issues of variability and enhance the throughput in organoid production, we implemented liquid handling and high-content imaging techniques. Quality control metrics were established to identify organoids unsuitable for further study. Electrophysiological analysis via high-density microelectrode arrays (MEAs) revealed significantly elevated neuronal properties in individual BD organoids, including increased mean amplitude, conduction velocity, and extended axonal and dendritic growth. Transcriptome and proteome analyses indicated significant dysregulation of BD-relevant signaling pathways--such as those involving phosphatidylinositol, glycogen synthase kinase-3 beta, and AKT. Notably, we identified dysregulated casein kinase 2 (CSNK2A1) and calmodulin 3 (CALM3) in BD organoids, which were reversed by lithium treatment, highlighting potential novel targets for therapeutic intervention. This study validates the midbrain organoid model as a valuable tool for exploring the molecular underpinnings of BD and identifying new treatment avenues.

cell biology↗

bioRxiv2020

Whole Genome De Novo Variant Identification with FreeBayes and Neural Network Approaches

MotivationDe novo variant (DNV) calling typically relies on heuristic filters intrinsic to specific platforms and variant calling algorithms. FreeBayes and neural network approaches have overcome this limitation for variant calling, and we implemented a similar approach for DNV identification. ResultsWe developed a DNV calling framework that uses Genome Analysis Toolkit (GATK), FreeBayes and a neural network trained on Integrative Genomics Viewer pile-up plots (IGV-bot). We identified DNVs in 2,390 WGS trios and benchmarked results against heuristics based on GATK parameters. Results were validated in silico and with Sanger sequencing, with the latter showing true positive rates of 98.4% and 97.3% for SNVs and indels, respectively. Taken together we describe a scalable framework for DNV identification based on both FreeBayes and neural network methods. AvailabilitySource code and documentation are available at https://github.com/ShenLab/igv-classifier and https://github.com/frichter/dnv_pipeline under the MIT license. Contactys2411@cumc.columbia.edu

genomics↗

bioRxiv2019

A Short Bout of High-intensity Exercise Alters Ipsilesional Motor Cortical Excitability Post-stroke

BackgroundAcute exercise can increase motor cortical excitability and enhance motor learning in healthy individuals, an effect known as exercise priming. Whether it has the same effects in people with stroke is unclear. ObjectivesThe objective of this study was to investigate whether a short, clinically-feasible high-intensity exercise protocol can increase motor cortical excitability in non-exercised muscles of chronic stroke survivors. MethodsThirteen participants with chronic, unilateral stroke participated in two sessions, at least one week apart, in a crossover design. In each session, they underwent either high-intensity lower extremity exercise or quiet rest. Motor cortical excitability of the extensor carpi radialis muscles was measured bilaterally with transcranial magnetic stimulation before and immediately after either exercise or rest. Motor cortical excitability changes (post-exercise or rest measures normalized to pre-test measures) were compared between exercise vs. rest conditions. ResultsAll participants were able to reach the target high-intensity exercise level. Blood lactate levels increased significantly after exercise (p < 0.001, d = 2.85). Resting motor evoked potentials from the lesioned hemisphere increased after exercise compared to the rest condition (p = 0.046, d = 2.76), but this was not the case for the non-lesioned hemisphere (p = 0.406, d = 0.25). ConclusionsHigh-intensity exercise can increase lesioned hemisphere motor cortical excitability in a non-exercised muscle post-stroke. Our short and clinically-feasible exercise protocol shows promise as a potential priming method in stroke rehabilitation.

physiology↗