Biology subjects

Lowry, E.

Publications and source records attributed to Lowry, E..

5 recordsLinked to original sources

bioRxiv2025

Epigenome-wide association study meta-analysis of wellbeing

Wellbeing is associated with both behavioral phenotypes as well as several key life outcomes, such as health, employment, and coping with stressful events. These phenotypes associated with wellbeing could be potential indicators of differential epigenetic patterns between individuals that differ in their levels of wellbeing. We performed the largest epigenome-wide (EWAS) meta-analysis of wellbeing to date by combining whole blood DNA methylation data (Illumina 450k array) from 13 cohorts from Europe, Australia, and the USA (N = 10,757 participants). After correcting for smoking and BMI, no epigenome-wide significant methylation sites were identified. We tested whether a weighted methylation score (MS) based on leave-one-cohort-out EWAS meta-analysis summary statistics predicted wellbeing in an independent cohort, and whether prediction was significant over and above the polygenic score (PGS) for wellbeing. The MS was associated with wellbeing (variance explained=0.22%, p=0.03) and was no longer significant after adding the polygenic score (PGS; variance explained=0.43%, p=0.0046, MS; variance explained=0.07%, p=0.2842). We further compared DNA methylation levels in 16 pairs of monozygotic twins discordant for wellbeing. These analyses revealed no significant within-pair DNA methylation differences at the top-sites from the meta-analysis or in MS. Our results suggest that larger EWAS meta-analyses with uniform phenotype assessment are required to identify methylation sites associated with wellbeing.

genomics↗

bioRxiv2025

Pathogenic BRCA1 DBD variants exhibit altered DNA binding affinities and susceptibility to menadione

Breast Cancer Susceptibility Gene 1 (BRCA1) codes for a DNA repair protein that facilitates the repair of double-stranded DNA breaks (DSBs) in human cells through the homologous recombination (HR) pathway. Mutations of BRCA1 are highly associated with breast cancer; however, many variants remain unclassified with unknown cellular phenotypes. The DNA binding activity of BRCA1 is localized primarily to its central region, which can be divided into two distinct domains: DNA Binding Domain 1 (DBD1; amino acids (aa) 330-554) and 2 (DBD2; aa 894-1057). We previously proposed a model in which DBD1 targets BRCA1 to DSBs for the promotion of DNA end resection, while DBD2 targets BRCA1 to telomeres to function in chromatin remodeling and telomere regulation. In this study, we hypothesized that unknown DBD variants (T374I, K408E, N417S, N909I, M1008I, and R1028H) with similar properties to known disease-causing variants (Q356H, F461L, R496H, D940Y, S1027N, and E1038G) would also be pathogenic. The affinities of each variant for single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), and a G-quadruplex (G4) sequence were measured via biolayer interferometry. The DNA repair phenotypes of each variant were analyzed by overexpression in HEK cells to determine correlation between binding activity and DNA damage response. Altogether, these results provide insight into how missense mutations affect the ability of BRCA1 DBDs to facilitate the DNA damage response.

biochemistry↗

bioRxiv2024

Colibactin-induced damage in bacteria is cell contact independent

The bacterial toxin colibactin, produced primarily by the B2 phylogroup of Escherichia coli, underlies some cases of colorectal cancers. Colibactin crosslinks DNA and induces genotoxic damage in both mammalian and bacterial cells. While the mechanisms facilitating colibactin delivery remain unclear, results from multiple studies supported a delivery model that necessitates cell-cell contact. We directly tested this requirement in bacterial cultures by monitoring the spatiotemporal dynamics of the DNA damage response using a fluorescent transcriptional reporter. We found that in mixed-cell populations, DNA damage saturated within twelve hours and was detectable even in reporter cells separated from colibactin producers by hundreds of microns. Experiments with distinctly separated producer and reporter colonies revealed that the intensity of DNA damage decays similarly with distance regardless of colony contact. Our work reveals that cell contact is inconsequential for colibactin delivery in bacteria and suggests that contact-dependence needs to be reexamined in mammalian cells as well. ImportanceColibactin is a bacteria-produced toxin that binds and damages DNA. It has been widely studied in mammalian cells due to its potential role in tumorigenesis. However, fundamental questions about its impact in bacteria remain underexplored. We used E. coli as a model system to study colibactin toxicity in neighboring bacteria and directly tested if cell-cell contact is required for toxicity, as has previously been proposed. We found that colibactin can induce DNA damage in bacteria hundreds of microns away and that the intensity of DNA damage presents similarly regardless of cell-cell contact. Our work further suggests that the requirement for cell-cell contact for colibactin-induced toxicity also needs to be reevaluated in mammalian cells.

microbiology↗

bioRxiv2020

DNA methylation signatures of aggression and closely related constructs: A meta-analysis of epigenome-wide studies across the lifespan

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N=15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha=1.2x10-7; Bonferroni correction). In cord blood samples of 2,425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r=0.74, p=0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripherl blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range=3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.

genetics↗

bioRxiv2020

Path integration changes as a cognitive marker for vascular cognitive impairment? - a pilot study

Path integration spatial navigation processes are emerging as promising cognitive markers for prodromal and clinical Alzheimers disease (AD). However, such path integration changes have been little explored in Vascular Cognitive Impairment (VCI), despite neurovascular change being a major contributing factor to dementia and potentially AD. In particular, the sensitivity and specificity of path integration impairments in VCI compared to AD is unclear. In the current pilot study, we explore path integration performance in AD and VCI patient groups and hypothesise that i) medial parietal mediated egocentric processes will be more affected in VCI and ii) medial temporal mediated allocentric processes will be more affected in AD. This retrospective cross-sectional study included early stage VCI patients (n=9), AD patients (n=10) and healthy age-matched controls (n=20). All participants underwent extensive neuropsychological testing, as well as spatial navigation testing. The spatial navigation tests included the virtual reality Supermarket task assessing egocentric (body-based) and allocentric (map-based) navigation as well as the Clock Orientation test assessing egocentric and path integration processes. Results showed that egocentric path integration processes are only impaired in VCI, potentially distinguishing it from AD. However, in contrast to our prediction, allocentric path integration was similarly impaired for VCI and AD. These preliminary findings suggest limited specificity of allocentric path integration deficits between VCI and AD. By contrast, egocentric path integration deficits emerge as more specific to VCI, potentially allowing for more specific diagnostic and treatment outcome measures for vascular impairment in dementia.

neuroscience↗