Biology subjects

Baril, C.

Publications and source records attributed to Baril, C..

5 recordsLinked to original sources

bioRxiv2026

Chromosomal mutational signatures of DNA damaging agents at single cell resolution

The chromosomal-scale mutational spectrum of small molecules that interact with DNA has been hard to study at scale, as mutational events are distributed in location and occur in parallel in different cells. Here, we present a framework that pairs phylogenetic ancestry reconstruction with mutational signature decomposition to characterise recent, cell-private copy number alteration (CNA) mutational patterns at single-cell resolution. We used this framework to characterise the cell-wise mutational spectrum of contemporaneous CNAs generated by double-strand-break-inducing chemotherapeutic drugs. We demonstrate that platinum salts, G-quadruplex stabilizers and topoisomerase II inhibitors, although mechanistically distinct, converge on a mutational signature dominated by telomere-bounded copy-number gains and losses. This signature is observed in different genetic backgrounds and in vivo in drug-treated patient-derived xenografts. We also observe a high rate of endogenous telomere-bounded mutational foreground in BRCA1 deficient cells. We show that the single cell genome derived signature exposures are drug dose-dependent, and use this to identify the decay of mutational load after drug withdrawal. We observe that both cisplatin and a G4 binder molecule (CX5461) exhibit foreground mutational signature persistence for at least 3 weeks after drug withdrawal, suggesting that residual effects of exposure may last longer than anticipated. Finally, extending the framework to serially drug-treated patient-derived xenograft (PDX) models, we show that telomere-bounded CNA signature exposure is associated with tumoural response to drug, consistent with loss of mutational activity on the genome after acquired resistance emerges. Together, our results show that our framework applied on scWGS identifies contemporaneous chromosomal mutation patterns induced by small molecules in human tissues.

cancer biology↗

bioRxiv2026

Minimally invasive monitoring of clonal evolution through integrated single cell and ctDNA analysis

Circulating cell-free DNA (cfDNA) offers a minimally invasive lens into tumor evolution. However, the accurate quantification of clonal composition from cfDNA remains challenging. Existing methods for clone tracking using liquid biopsies are constrained by issues such as their reliance on bulk tissue references, incomplete representations of clonal architecture or limited breadth of mutation panels. To address these limitations, we developed cfClone, a Bayesian framework that integrates single-cell whole-genome sequencing (scWGS) derived clonal structures with cfDNA whole-genome sequencing (cfDNA-WGS) data to enable high-resolution tissue-informed clonal tracking. By jointly modeling local copy-number alterations and haplotype-specific signals via Bayesian model selection and Markov chain Monte Carlo (MCMC) sampling, the algorithm yields uncertainty-aware estimates of clonal prevalence and tumour fraction (TF). Applied to longitudinal clinical cohorts, cfClone can be used to reconstruct evolutionary trajectories and uncovers clonal selection driving therapeutic resistance, including the de novo detection of emergent clonal populations. We demonstrate that cfClone achieves accurate TF estimates and circulating tumor DNA (ctDNA) detection in malignancies with varying degrees of copy-number variant (CNV) burden using semi-synthetic data. We then compare to the state of the art scWGS informed panel based approach, and demonstrate cfClone provides comparable accuracy while allowing for the tracking of more clones and detection of novel clones. Finally, we show how cfClone can be used to quantitatively track clonal dynamics in response to treatment in high grade serous ovarian cancer. Github link: https://github.com/Roth-Lab/cfclone

cancer biology↗

bioRxiv2024

Luminal breast epithelial cells from wildtype and BRCA mutation carriers harbor copy number alterations commonly associated with breast cancer

Cancer-associated mutations have been documented in normal tissues, but the prevalence and nature of somatic copy number alterations and their role in tumor initiation and evolution is not well understood. Here, using single cell DNA sequencing, we describe the landscape of CNAs in >42,000 breast epithelial cells from women with normal or high risk of developing breast cancer. Accumulation of individual cells with one or two of a specific subset of CNAs (e.g. 1q gain and 16q, 22q, 7q, and 10q loss) is detectable in almost all breast tissues and, in those from BRCA1 or BRCA2 mutations carriers, occurs prior to loss of heterozygosity (LOH) of the wildtype alleles. These CNAs, which are among the most common associated with ductal carcinoma in situ (DCIS) and malignant breast tumors, are enriched almost exclusively in luminal cells not basal myoepithelial cells. Allele-specific analysis of the enriched CNAs reveals that each allele was independently altered, demonstrating convergent evolution of these CNAs in an individual breast. Tissues from BRCA1 or BRCA2 mutation carriers contain a small percentage of cells with extreme aneuploidy, featuring loss of TP53, LOH of BRCA1 or BRCA2, and multiple breast cancer-associated CNAs in addition to one or more of the common CNAs in 1q, 10q or 16q. Notably, cells with intermediate levels of CNAs are not detected, arguing against a stepwise gradual accumulation of CNAs. Overall, our findings demonstrate that chromosomal alterations in normal breast epithelium partially mirror those of established cancer genomes and are chromosome- and cell lineage-specific.

cancer biology↗

bioRxiv2023

Metatranscriptomic analysis of common mosquito vector species in the Canadian Prairies

The microbiome plays vital roles in the life history of mosquitoes, including their development, immunity, longevity, and vector competence. Recent advances in sequencing technologies have allowed for detailed exploration into the diverse microorganisms harboured by these medically important insects. Although these meta-studies have catalogued the microbiomes of mosquitoes on several continents, much of the information currently available for North America is limited to the state of California. In this study, we collected >35,000 mosquitoes throughout Manitoba, Canada over a two-year period, and then harnessed RNA sequencing and targeted RT-PCR to characterize the microbiomes of the eight most pervasive and important vector and pest species. The consensus microbiome of each species was overwhelmingly composed of viruses, but also included fungi, bacteria, protozoa, and parasitic invertebrates. The microbial assemblages were heterogeneous between species, even within the same genus. We detected notable pathogens, including the causal agents of Cache Valley Fever, avian malaria, and canine heartworm. The remaining microbiome consisted largely of putatively insect-specific viruses that are not well characterized, including 17 newly discovered viruses from 10 different families. Future research should focus on evaluating the potential application of these viruses in biocontrol, as biomarkers, and/or in disrupting mosquito vectorial capacity. Interestingly, we also detected viruses that naturally infect honeybees and thrips, which were presumably acquired indirectly through nectar foraging behaviours. Overall, we provide the first comprehensive catalogue of the microorganisms harboured by the most common and important mosquito vectors and pests in the Canadian Prairies.

microbiology↗

bioRxiv2020

Rala and the exocyst control Pvr trafficking and signaling to ensure lymph gland homeostasis in Drosophila melanogaster

The balance between hematopoietic progenitors and differentiated hemocytes is finely tuned during development. In the larval hematopoietic organ of Drosophila, called the lymph gland, the receptor tyrosine kinase Pvr signals from differentiated cells to maintain a pool of undifferentiated progenitors. However, little is known about the processes that support Pvr function. The small GTPase Ral is involved in the regulation of several membrane trafficking events. Drosophila has a single Ral protein, Rala, which has been implicated in the development of various tissues. Here, we investigated the involvement of Rala in the larval fly hematopoietic system. We discovered that the loss of Rala activity phenocopies Pvr loss of function by promoting hemocyte progenitor differentiation. Moreover, using epistasis analysis, we found that the guanine exchange factor RalGPS lies upstream of Rala in this event, whereas the exocyst and Rab11 are acting downstream. Strikingly, the loss of Rala activity leads to a considerable accumulation of Pvr at the plasma membrane, hence suggesting a trafficking defect and reduced Pvr function. Consistent with this hypothesis, Rala loss of function phenotype in the lymph gland is fully suppressed by constitutive STAT activity, which normally mediates Pvr function in the lymph gland. Together, our findings unravel a novel RalGPS-Rala-exocyst-Rab11 axis for the maintenance of lymph gland homeostasis through Pvr.

developmental biology↗