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White, L. K.

Publications and source records attributed to White, L. K..

10 recordsLinked to original sources
bioRxiv2026

Olfactory Deficits and Structural Anomalies of the Peripheral Olfactory System in 22q11.2 Deletion Syndrome

Background: Approximately 25% of individuals with 22q11.2 deletion syndrome (22q11DS) develop a psychotic disorder, and the syndrome shares key neurodevelopmental features with psychosis in the general population. The olfactory system develops early in utero, providing a window into gestational disruptions relevant to psychosis risk. We hypothesized that 22q11DS would show impairments in olfactory function and structural anomalies of the olfactory system relative to psychosis spectrum (PS) youth without a known genetic syndrome and typically developing controls (TD). Methods: Participants included individuals with 22q11DS (n=101), PS (n=56), and TD (n=52). Sinonasal symptoms, odor identification, and discrimination (Sniffin' Sticks) behaviorally. Structural 3T MRI measured olfactory bulb volume, sulcus depth, and sulcus length. Sample sizes vary per analysis. Results: Relative to TD, 22q11DS showed elevated sinonasal burden (p<.001), lower odor identification (p<.001), and lower odor discrimination (p<.001). PS showed elevated sinonasal burden (p<.001) and marginally lower odor identification (p=.06), but no discrimination deficit. Olfactory bulb volume was significantly smaller in 22q11DS versus TD (p=.007, r=.39); PS showed a non-significant trend (p=.07). Olfactory sulcus depth (p=.52) and length (p=.82) did not differ across groups. Conclusions: 22q11DS is associated with elevated sinonasal burden, robust olfactory identification and discrimination deficits exceeding those of PS and reduced olfactory bulb volume. The co-occurrence of functional deficits and reduced bulb volume without sulcal anomalies may distinguish the 22q11DS olfactory phenotype from that of PS. These hypothesis-generating findings are consistent with partially dissociable neurodevelopmental mechanisms and support the utility of 22q11DS as a genetic model for psychosis risk.

neuroscience↗
bioRxiv2026

Loss of polr1c disrupts myelination in a zebrafish model of POLR1C-associated disease

Pathogenic variants in POLR1C, which encodes a shared subunit of RNA Polymerases (Pols) I and III, cause Treacher Collins syndrome (TCS) and POLR3-related leukodystrophy. While Pol I and Tp53-dependent mechanisms have been implicated in the pathogenesis of TCS, the basis of hypomyelination in POLR1C-associated POLR3-related leukodystrophy remains incompletely understood. Here, we show that polr1c mutant zebrafish exhibit reduced myelination in addition to previously described craniofacial anomalies. Oligodendrocyte precursor cells exhibit increased activation of the Tp53 pathway; however, these cells do not undergo apoptosis. Consistent with this finding, tp53 inhibition reduces cell death in polr1c mutants but fails to restore myelination, indicating that myelination deficits are not driven by Tp53-dependent progenitor loss in this model. polr1c mutants also exhibit reduced rRNA transcription by Pol I and reduced expression of some Pol III-transcribed tRNAs. Altogether, these data indicate distinct tissue-specific responses to polr1c deficiency and suggest persistent impairment of rRNA transcription contributes to deficient myelin development. These findings expand the developmental consequences of polr1c loss and advance our understanding of the molecular basis of POLR1C-associated diseases.

developmental biology↗
bioRxiv2026

Fragmentation Patterns of Human Telomeric Chromatin in Plasma cfDNA

The unique chromatin structure at telomeres protects the linear ends of chromosomes from DNA surveillance machineries. Here, we demonstrate that circulating cell-free DNA (cfDNA) from plasma can map chromatin structure at telomeres. We find that the telomeric 6-mer repeats (TTAGGG/CCCTAA) are the most abundant circulating 6-mers in cfDNA. Telomeric sequences in cfDNA contain subnucleosomal footprints distinct from the rest of the genome, arising from specific cleavages in the C-rich strand, and a nucleosome repeat length of 145 bp, markedly shorter than the [~]170 bp observed genome-wide. The abundance of cfDNA telomeric footprints decreases with age, and this decline is exacerbated by Dyskeratosis Congenita (DC), a telomere biology disorder. Promoter subnucleosome enrichment from cfDNA identifies DC-specific gene signatures that reflect disease states and show enrichment towards chromosome ends. In this work, we demonstrate that cfDNA captures telomere chromatin structure and its genome-wide impact non-invasively, including disease-specific signatures in DC.

genomics↗
bioRxiv2026

The PMADS Project: A Longitudinal Multimodal Cohort Study to Understand Risk for Perinatal Mood and Anxiety Disorders

BackgroundPerinatal mood and anxiety disorders (PMADs) are among the most common and consequential complications of pregnancy. The perinatal period is also characterized by profound hormonal fluctuations and large-scale brain plasticity. However, the mechanisms linking these neurobiological changes to psychiatric risk are poorly understood. Prospective, clinically informed studies are needed to identify quantitative biomarkers and clarify pathways linking perinatal neurobiology to PMADs risk. MethodsThis report describes the design of a prospective, longitudinal cohort study integrating multimodal neuroimaging, biofluid sampling, and deep clinical phenotyping to enable precision characterization of neurobiological trajectories of PMADs risk. Twenty-five individuals at elevated risk for PMADs will be recruited prior to conception and followed across six in-person timepoints spanning the menstrual cycle, pregnancy, and early postpartum, with additional remote follow-ups through the first postpartum year. Data collection includes high-resolution structural MRI, functional brain mapping using multi-echo resting-state fMRI, diffusion MRI, arterial spin labeling, ultra-high field MR-based techniques for measuring glutamate (GluCEST and 1HMRS), biofluid sampling, and comprehensive clinical, behavioral, and cognitive assessments. Structured clinical interviews assess categorical diagnoses while dimensional symptom measures capture heterogeneity and transdiagnostic features of perinatal psychopathology. Longitudinal analyses will model nonlinear trajectories of brain and symptom change across the perinatal period as well as evaluate whether preconception network features and menstrual cycle-related brain changes are associated with subsequent perinatal symptom emergence. DiscussionThis cohort study establishes a longitudinal, multimodal framework for investigating neurobiological changes across the transition to pregnancy in individuals at elevated risk for PMADs. By anchoring pregnancy-related brain changes to preconception and menstrual cycle-related variability within the same individuals, this study is designed to evaluate associations between preconception hormone sensitivity, pregnancy-induced neuroplasticity, and PMADs risk. The resulting dataset will provide a deeply phenotyped longitudinal resource for investigating brain-behavior relationships across the perinatal period. Findings are expected to inform future larger-scale studies aimed at advancing mechanistic understanding of PMADs, improving individualized risk stratification, and supporting development of personalized preventive and neuromodulatory interventions.

neuroscience↗
bioRxiv2025

An open, fully-processed data resource for studying mood and sleep variability in the developing brain

Brain development during adolescence and early adulthood coincides with shifts in emotion regulation and sleep. Despite this, few existing datasets simultaneously characterize affective dynamics, sleep variation, and multimodal measures of brain development. Here, we describe the study protocol and initial release (n = 10) of an open data resource of neuroimaging paired with densely sampled behavioral measures in adolescents and young adults. All participants complete multi-echo functional MRI, compressed-sensing diffusion MRI, and advanced arterial spin-labeled MRI. Behavioral measures include ecological momentary assessment, actigraphy, extensive cognitive assessments, and detailed clinical phenotyping focused on emotion regulation. Raw and processed data are openly available without a data use agreement and will be regularly updated as accrual continues. Together, this resource will accelerate research on the links between mood, sleep, and brain development.

neuroscience↗
bioRxiv2024

Nanopore sequencing of intact aminoacylated tRNAs

Transfer RNAs (tRNA) are decorated during biogenesis with a variety of modifications that modulate their stability, aminoacylation, and decoding potential during translation. The complex landscape of tRNA modification presents significant analysis challenges and to date no single approach enables the simultaneous measurement of important but disparate chemical properties of individual, mature tRNA molecules. We developed a new, integrated approach to analyze the sequence, modification, and aminoacylation state of tRNA molecules in a high throughput nanopore sequencing experiment, leveraging a chemical ligation that embeds the charged amino acid in an adapted tRNA molecule. During nanopore sequencing, the embedded amino acid generates unique distortions in ionic current and translocation speed, enabling application of machine learning approaches to classify charging status and amino acid identity. Specific applications of the method indicate it will be broadly useful for examining relationships and dependencies between tRNA sequence, modification, and aminoacylation.

molecular biology↗
bioRxiv2024

Quantification of subcellular RNA localization through direct detection of RNA oxidation

Across cell types and organisms, thousands of RNAs display asymmetric subcellular distributions. The study of this process often requires quantifying abundances of specific RNAs at precise subcellular locations. To analyze subcellular transcriptomes, multiple proximity-based techniques have been developed in which RNAs near a localized bait protein are specifically labeled, facilitating their biotinylation and purification. However, these complex methods are often laborious and require expensive enrichment reagents. To streamline the analysis of localized RNA populations, we developed Oxidation-Induced Nucleotide Conversion sequencing (OINC-seq). In OINC-seq, RNAs near a genetically encoded, localized bait protein are specifically oxidized in a photo-controllable manner. These oxidation events are then directly detected and quantified using high-throughput sequencing and our software package, PIGPEN, without the need for biotin-mediated enrichment. We demonstrate that OINC-seq can induce and quantify RNA oxidation with high specificity in a dose- and light-dependent manner. We further show the spatial specificity of OINC-seq by using it to quantify subcellular transcriptomes associated with the cytoplasm, ER, nucleus, and the inner and outer membranes of mitochondria. Finally, using transgenic zebrafish, we demonstrate that OINC-seq allows proximity-mediated RNA labeling in live animals. In sum, OINC-seq together with PIGPEN provide an accessible workflow for the analysis of localized RNAs across different biological systems.

molecular biology↗
bioRxiv2024

Comparative analysis of 43 distinct RNA modifications by nanopore tRNA sequencing

Transfer RNAs are the fundamental adapter molecules of protein synthesis and the most abundant and heterogeneous class of noncoding RNA molecules in cells. The study of tRNA repertoires remains challenging, complicated by the presence of dozens of post transcriptional modifications. Nanopore sequencing is an emerging technology with promise for both tRNA sequencing and the detection of RNA modifications; however, such studies have been limited by the throughput and accuracy of direct RNA sequencing methods. Moreover, detection of the complete set of tRNA modifications by nanopore sequencing remains challenging. Here we show that recent updates to nanopore direct RNA sequencing chemistry (RNA004) combined with our own optimizations to tRNA sequencing protocols and analysis workflows enable high throughput coverage of tRNA molecules and characterization of nanopore signals produced by 43 distinct RNA modifications. We share best practices and protocols for nanopore sequencing of tRNA and further report successful detection of low abundance mitochondrial and viral tRNAs, providing proof of concept for use of nanopore sequencing to study tRNA populations in the context of infection and organelle biology. This work provides a roadmap to guide future efforts towards de novo detection of RNA modifications across multiple organisms using nanopore sequencing.

molecular biology↗
bioRxiv2022

Direct detection of RNA repair by nanopore sequencing

Ligation by plant and fungal RNA ligases yields an internal 2'-phosphate group on each RNA ligation product. In budding yeast, this covalent mark occurs at the splice junction of two targets of ligation: intron-containing tRNAs and the messenger RNA HAC1. The repertoire of RNA molecules repaired by RNA ligation has not been explored due to a lack of unbiased approaches for identifying RNA ligation products. Here, we define several unique signals produced by 2'-phosphorylated RNAs during nanopore sequencing. A 2'-phosphate at the splice junction of HAC1 mRNA inhibits 5'[->]3' degradation, enabling detection of decay intermediates in yeast RNA repair mutants by nanopore sequencing. During direct RNA sequencing, intact 2'-phosphorylated RNAs produce diagnostic changes in nanopore current properties and base calling features, including stalls produced as the modified RNA translocates through the nanopore motor protein. These approaches enable directed studies to identify novel RNA repair events from multiple species.

molecular biology↗