Biology subjects

Dodge, S.

Publications and source records attributed to Dodge, S..

4 recordsLinked to original sources

bioRxiv2026

Sub-Chronic Chlorpyrifos Exposure Leads to Epigenetic and Sex-Specific Behavioral Changes in Adult Mice

Chlorpyrifos is a widely used organophosphate pesticide that exerts its primary toxic effect through inhibition of acetylcholinesterase (AChE). Although the acute neurotoxicity of chlorpyrifos is well characterized, the lasting biochemical, behavioral, and epigenetic consequences of sub-chronic exposure remain poorly understood, particularly when considering sex-specific differences. Therefore, we exposed male and female C57BL/6J mice to either peanut oil (n=19), low chlorpyrifos exposure (1 mg/kg/day; n=19), or high chlorpyrifos exposure (10 mg/kg/day n=10) repeatedly for 21 days via subcutaneous injection. Blood AChE activity, behavior, and hippocampal DNA methylation were measured across groups. During exposure, AChE activity decreased in both males and females but only returned to baseline after behavioral testing in females exposed to low chlorpyrifos levels. Behavioral tests also revealed a sex-specific phenotype, with females in the low exposure group exhibiting reduced forced swim test immobility and a significant time by exposure interaction in open field habituation. No significant behavioral effects were observed in males. Significant DNA methylation changes were observed at 3,538 CpG sites in male and female mice after high exposure. Sex-specific analyses revealed two female-specific differentially methylated CpGs after high exposure. Pathways enriched for differentially methylated genes included several related to synaptic remodeling, cholinergic synapse, and various endocrine systems. These findings demonstrate that repeated high chlorpyrifos exposure leads to persistent cholinergic disruption and DNA methylation changes. However, the female-specific behavioral changes seen are independent of AChE activity and widespread DNA methylation changes, suggesting additional mechanisms, present only in females, may underlie behavioral sensitivity to chlorpyrifos. New and NoteworthySub-chronic chlorpyrifos exposure in adult mice produced dose-dependent blood AChE suppression and widespread hippocampal DNA methylation changes in both sexes, with pathway enrichment including cholinergic synapse and endocrine systems. Behavioral effects were subtle, with females in the low exposure group showing reduced forced swim immobility and altered locomotor habituation. Notably, the female-specific behavioral changes seen are independent of AChE activity and DNA methylation changes, suggesting novel mechanisms may underlie female behavioral sensitivity to chlorpyrifos.

neuroscience↗

bioRxiv2022

Cost-efficient whole genome-sequencing using novel mostly natural sequencing-by-synthesis chemistry and open fluidics platform

We introduce a massively parallel novel sequencing platform that combines an open flow cell design on a circular wafer with a large surface area and mostly natural nucleotides that allow optical end-point detection without reversible terminators. This platform enables sequencing billions of reads with longer read length ([~]300bp) and fast runs times (<20hrs) with high base accuracy (Q30 > 85%), at a low cost of $1/Gb. We establish system performance by whole-genome sequencing of the Genome-In-A-Bottle reference samples HG001-7, demonstrating high accuracy for SNPs (99.6%) and Indels in homopolymers up to length 10 (96.4%) across the vast majority (>98%) of the defined high-confidence regions of these samples. We demonstrate scalability of the whole-genome sequencing workflow by sequencing an additional 224 selected samples from the 1000 Genomes project achieving high concordance with reference data.

genomics↗

bioRxiv2020

Low-coverage sequencing cost-effectively detects known and novel variation in underrepresented populations

BackgroundGenetic studies of biomedical phenotypes in underrepresented populations identify disproportionate numbers of novel associations. However, current genomics infrastructure--including most genotyping arrays and sequenced reference panels--best serves populations of European descent. A critical step for facilitating genetic studies in underrepresented populations is to ensure that genetic technologies accurately capture variation in all populations. Here, we quantify the accuracy of low-coverage sequencing in diverse African populations. ResultsWe sequenced the whole genomes of 91 individuals to high-coverage ([≥]20X) from the Neuropsychiatric Genetics of African Population-Psychosis (NeuroGAP-Psychosis) study, in which participants were recruited from Ethiopia, Kenya, South Africa, and Uganda. We empirically tested two data generation strategies, GWAS arrays versus low-coverage sequencing, by calculating the concordance of imputed variants from these technologies with those from deep whole genome sequencing data. We show that low-coverage sequencing at a depth of [≥]4X captures variants of all frequencies more accurately than all commonly used GWAS arrays investigated and at a comparable cost. Lower depths of sequencing (0.5-1X) performed comparable to commonly used low-density GWAS arrays. Low-coverage sequencing is also sensitive to novel variation, with 4X sequencing detecting 45% of singletons and 95% of common variants identified in high-coverage African whole genomes. ConclusionThese results indicate that low-coverage sequencing approaches surmount the problems induced by the ascertainment of common genotyping arrays, including those that capture variation most common in Europeans and Africans. Low-coverage sequencing effectively identifies novel variation (particularly in underrepresented populations), and presents opportunities to enhance variant discovery at a similar cost to traditional approaches.

genomics↗

bioRxiv2017

Characterization and remediation of sample index swaps by non-redundant dual indexing on massively parallel sequencing platforms

Here, we present an in-depth characterization of the index swapping mechanism on Illumina instruments that employ the ExAmp chemistry for cluster generation (HiSeqX, HiSeq4000, and NovaSeq). We discuss best practices for eliminating the effects of index swapping on data integrity by utilizing unique dual indexing for complete filtering of index swapped reads. We calculate mean swap rates across multiple sample preparation methods and sequencer models, demonstrating that different methods can have vastly different swap rates, and show that even non-ExAmp chemistry instruments display trace levels of index swapping. Finally, using computational methods we provide a greater insight into the mechanism of index swapping.

genomics↗