Biology subjects

Marsh, J.

Publications and source records attributed to Marsh, J..

6 recordsLinked to original sources

bioRxiv2026

The NORAD-pumilio regulatory axis links lncRNA dysregulation to tau propagation-associated phenotypes

Long non-coding RNAs (lncRNAs) are increasingly implicated in neurodegenerative disease, yet their roles in tauopathy remain poorly understood. Here, we defined the lncRNA landscape across iPSC-derived neurons, astrocytes, and microglia harboring the frontotemporal dementia-associated MAPT IVS10+16 mutation and investigated how lncRNA dysregulation interfaces with tau pathology. Transcriptomic analyses revealed extensive cell-type specific lncRNA expression changes, with neurons exhibiting the greatest degree of mutation-associated remodeling. Comparative analyses with MAPT IVS10+16 patient brain tissue identified NORAD and MIR22HG as lncRNAs significantly dysregulated across all three cell types and human brains. NORAD was also altered in Alzheimers disease and Parkinsons disease brains, suggesting a broader role in neurodegenerative disease. Mechanistically, NORAD-associated protein networks converged on pathways related to RNA regulation, cytoskeletal organization, proteostasis, and tau interaction networks. Given the established role of NORAD in regulating PUM1 and PUM2 RNA-binding (pumilio) proteins, we examined the NORAD-pumilio axis and identified enrichment of pumilio-associated pathways linked to autophagy, endocytosis, proteostasis, and cytoskeletal regulation. NORAD depletion reduced tau seeding and uptake, whereas functional depletion of PUM1 or PUM2 increased both processes, supporting an antagonistic relationship between NORAD and pumilio signaling in modulation of tau aggregation. Together, these findings identify widespread lncRNA dysregulation across neural cell types in the setting of a MAPT mutation and nominate the NORAD-pumilio axis as a regulatory pathway linking RNA homeostasis and tau propagation biology.

neuroscience↗

bioRxiv2026

The distribution of fitness effects of new mutations in regulatory regions of the D. melanogaster genome

Although non-coding regions play important roles in gene regulation and contribute to individual fitness, the precise distribution of fitness effects (DFE) of new mutations in these regions remains poorly understood. Here, we carefully compile experimentally validated regulatory regions in non-coding regions in the Drosophila melanogaster genome and identify putatively neutral sites near them. Incorporating a realistic genomic architecture that mimics the placement of the regulatory and coding regions, as well as a realistic heterogeneity in recombination and mutation rates across the genome, we use forward-in-time simulations to assess the power and accuracy of population genetics approaches that infer the DFE of new mutations in these regions. While the parameters of DFEs primarily comprising moderately and strongly deleterious mutations are estimated accurately, those of a DFE comprising mostly mildly deleterious mutations are misinferred. Applying these insights to three African D. melanogaster populations, we find that a large fraction of new mutations in functionally important non-coding regions are moderately deleterious, as opposed to strongly deleterious in coding regions. While the fraction of beneficial substitutions in regulatory regions (0.25-0.45) was also lower in coding regions ([~]0.5), our results suggest that non-coding regions contribute a majority of new deleterious mutations and beneficial substitutions in D. melanogaster populations. By incorporating both the genomic distribution and the inferred DFE of non-coding regions, we demonstrate that the effects of background selection across the genome are more accurately captured than with coding regions alone, highlighting the importance of considering selection on non-coding regions when interpreting patterns of genomic variation.

evolutionary biology↗

bioRxiv2025

Effects of rescaling forward-in-time population genetic simulations

Forward-in-time population genetic simulations enable modelling of a wide array of complex evolutionary scenarios. Simulating small genomic regions, and rescaling by reducing population size by a scaling factor while maintaining population-scaled parameters, are common approaches for improving computational tractability. However, simulating whole chromosomes in large populations remains computationally prohibitive and its unclear what scaling factors produce consistent evolutionary dynamics between rescaled and unscaled populations. Here, we thoroughly test the effects of rescaling in populations experiencing direct and linked effects of selection for various scaling factors and genomic lengths in D. melanogaster-like populations by comparing them with theoretical expectations. We find that while rescaling has minimal effects with most length and scaling factor combinations, simulating long regions with large scaling factors can introduce biases in summary statistics including neutral diversity, allele frequencies, linkage disequilibrium, and non-neutral divergence. These deviations occur particularly when the crossover rate exceeds 0.44 per individual/generation because substantial multiple-crossover events are likely to occur within individuals, reducing the effective rate of genetic recombination. In addition, when the genome-wide deleterious mutation rate is high (U >> 1) in highly rescaled long regions, we observe increased Hill-Robertson interference effects and progeny skew, the extent of which was strongly dependent on the fitness effects of selected mutations. We find that hitchhiking effects near functional regions are relatively unaffected by rescaling the population, even with large scaling factors. Our findings expose potential pitfalls when simulating long regions with rescaling and highlight parameter spaces within which expected evolutionary dynamics are conserved.

genetics↗

bioRxiv2024

Autophagic enhancer rescues Tau accumulation in a stem cell model of frontotemporal dementia

Tau degradation is disrupted in neurodegenerative tauopathies, such as frontotemporal dementia (FTD), which may contribute to Tau aggregation. The prevailing hypothesis has been that Tau degradation is stymied due to an imbalance in proteostasis that occurs with age. Here, we used Airyscan super resolution imaging to illustrate that a pathogenic FTD mutation in the MAPT gene, which encodes Tau, is sufficient to alter multiple steps of the autophagy lysosomal pathway and impair Tau degradation. We discovered lysosomes clogged with both Tau and phosphorylated Tau, stalled lysosome motility, disrupted molecular motors, enhanced autophagic flux, and slowed cargo degradation in mutant Tau neurons. Treatment of mutant Tau neurons with a small molecule autophagy enhancer drug increases autophagic flux and cargo degradation, reduces phospho-Tau levels, and reduces Tau accumulation in lysosomes without restoring defects in lysosomal motility. This study reveals novel effects of mutant Tau and provides a window through which therapeutic treatments targeting autophagy may promote Tau homeostasis.

neuroscience↗

bioRxiv2019

An EEG study of detection without localisation in change blindness

Previous studies of change blindness have suggested a distinction between detection and localisation of changes in a visual scene. Using a simple paradigm with an array of coloured squares, the present study aimed to further investigate differences in event-related potentials (ERPs) between trials in which participants could detect the presence of a colour change but not identify the location of the change (sense trials), versus those where participants could both detect and localise the change (localise trials). Individual differences in performance were controlled for by adjusting the difficulty of the task in real time. Behaviourally, reaction times for sense, blind, and false alarm trials were distinguishable when comparing across levels of participant certainty. In the EEG data, we found no significant differences in the visual awareness negativity ERP, contrary to previous findings. In the N2pc range, both awareness conditions (localise and sense) were significantly different to trials with no change detection (blind trials), suggesting that this ERP is not dependent on explicit awareness. Within the late parietal positivity range, all conditions were significantly different. These results suggest that changes can be sensed without knowledge of the location of the changing object, and that participant certainty scores can provide valuable information about the perception of changes in change blindness.

neuroscience↗

bioRxiv2017

Maternal and fetal genetic contribution to gestational weight gain

BackgroundClinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG.\n\nParticipants and MethodsA genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10,543 mothers and up to 16,317 offspring of European origin, with replication in 10,660 mothers and 7,561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (e.g. maternal BMI and glucose, birthweight).\n\nResultsWe found that approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and that the fetal genome made a surprisingly minor contribution to explaining variation in GWG. We were unable to identify any genetic variants that reached genome-wide levels of significance (P<5x10-8) and replicated. Some established maternal variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birthweight variants were largely unrelated to GWG.\n\nConclusionWe found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.

genetics↗