Biology subjects

Berube, P.

Publications and source records attributed to Berube, P..

9 recordsLinked to original sources

bioRxiv2026

Identifying molecular instructions to hard-wire a sensory neurons synaptic connectivity

The neural circuitry underlying innate behaviours must be pre-specified using precise molecular instructions. However, it is not clear what specific molecules are required to generate one neurons wiring pattern that make it distinct from a neighboring neurons wiring pattern. Here, we repeatedly sequenced three identified Drosophila sensory neurons that each have a unique and stereotyped hard-wired synaptic connectivity, to determine the cell surface molecules that distinguish their identities. Repeated sequencing of the same neuron between different animals revealed that the variability of transcription is < 1%. We find that less than 100 cell surface molecules can distinguish between a mechanosensory neuron from a chemosensory neuron. Functional characterization of the cell surface receptors verified their different roles in axonal and synaptic targeting. Finally, we expressed combinations of the different cell surface receptors to mis-wire the chemosensory neuron and increase its axonal branching.

neuroscience↗

bioRxiv2025

Brain Region-Specific Epigenomic Reorganization and Altered Cell States in Alzheimer's Disease

Alzheimers disease (AD) is the most common neurodegenerative disorder, yet the molecular mechanisms underlying its region- and cell-type-specific pathogenesis remain poorly defined. Here, we generated a large-scale, single-cell multi-omic atlas--integrating DNA methylation and 3D genome architecture--from postmortem brain tissue of matched AD patients and cognitively normal controls. Samples were collected from three brain regions with distinct vulnerability to AD pathology: the temporal cortex (TC), primary visual cortex (VC), and prefrontal cortex (PFC). Our dataset comprises over 230,000 individual cells, spanning major neuronal and glial populations, and provides a high-resolution view of multi-layer epigenomic regulation. We identified widespread AD-associated DNA methylation changes and marked reorganization of 3D genome structure, including alterations in A/B compartments, topologically associating domains (TADs), and chromatin loops. These changes are strongly region-specific: TC displays pronounced hypermethylation, transcriptional downregulation, and elevated boundary density, whereas VC shows opposing trends and PFC an intermediate profile. We further uncovered previously unrecognized AD-associated glial and neuronal states defined by coordinated epigenomic dysregulation and recurrent genomic deletions, particularly near telomeric regions. This region-resolved, single-cell multi-omic atlas reveals divergent epigenomic trajectories across brain regions and cell types in AD, offering new mechanistic insights and a framework for targeted therapeutic strategies.

genomics↗

bioRxiv2025

Genome assembly of five Tephritid species for the enhancement of the Sterile Insect Technique

Tephritidae insect pests account for extensive crop damage and yield losses globally. Modern, sustainable pest management approaches are species-specific and, therefore, high-quality genome assemblies are required for their application. Here, we present chromosome-level assemblies for five members of the Tephritidae family: Anastrepha fraterculus, Anastrepha ludens, Bactrocera dorsalis, Bactrocera zonata and Zeugodacus cucurbitae. The assemblies used long read sequencing polished with short read sequencing and scaffolded using Hi-C (chromatin conformation capture) sequencing. Prior to scaffolding the assembly deduplication was performed to separate a primary assembly and an alternate assembly, and each was then scaffolded independently. The scaffolded assemblies reached N50 length in the range of 60Mb to 120Mb. The scaffolded assemblies were verified with BUSCO and completeness was in the range 97% to 98.5% and had very low duplicated, fragmented and missing orthologs.

ecology↗

bioRxiv2024

Chromosome-level genome assembly of a doubled haploid brook trout (Salvelinus fontinalis)

Brook trout (Salvelinus fontinalis) is a socioeconomically important fish species for fisheries, aquaculture and aquatic conservation. We produced a 2.5 Gb reference assembly by combining Hi-C chromosome conformation capture with high-coverage short- and long-read sequencing of a fully homozygous mitotic gynogenic doubled haploid fish, which facilitates assembly of highly complex salmonid genomes. The assembly has a N50 of 50.98 Mb and 88.9% of the total assembled sequence length is anchored into 42 main chromosomes, of which 63.44% represents repeated contents, including 1,461,010 DNA transposons. 56,058 genes were found with the NCBI annotation pipeline, with 99% of the 3,640 expected conserved orthologs BUSCO genes (actinopterygii_odb10 lineage database). Additionally, we found significant homology within the 42 chromosomes, as expected for this pseudo-tetraploid species, as well as with the sister species lake trout (Salvelinus namaycush) and Atlantic salmon (Salmo salar). This assembly will serve as a reliable genomic resource for brook trout, thus enabling a wider range of reference-based applications to support ongoing research and management decision-making for the species.

genomics↗

bioRxiv2023

Epigenome erosion in Alzheimer's disease brain cells and induced neurons

Late-onset Alzheimers disease (LOAD) is typically sporadic, correlated only to advanced age, and has no clear genetic risk factors. The sporadic nature of LOAD presents a challenge to understanding its pathogenesis and mechanisms. Here, we comprehensively investigated the epigenome of LOAD primary entorhinal cortex brain tissues via single-cell multi-omics technologies, simultaneously capturing DNA methylation and 3D chromatin conformation. We identified AD-specific DNA methylation signatures and found they interact with bivalent promoters of AD differentially expressed genes. In addition, we discovered global chromosomal epigenome erosion of 3D genome structure within and across brain cell types. Furthermore, to evaluate whether these age- and disease-dependent molecular signatures could be detected in the in vitro cellular models, we derived induced neurons (iNs) converted directly from AD patients fibroblasts and found a set of conserved methylation signatures and shared molecular processes. We developed a machine-learning algorithm to identify robust and consistent methylation signatures of LOAD in vivo primary brain tissues and in vitro fibroblast-derived iNs. The results recapitulate the age- and disease-related epigenetic features in iNs and highlight the power of epigenome and chromatin conformation for identifying molecular mechanisms of neuronal aging and generating biomarkers for LOAD. HIGHLIGHTO_LIAD-specific DNA methylation signatures are identified in entorhinal cortex brain cell types C_LIO_LIThe AD differentially expressed genes linked with differentially methylated regions via loop interactions are enriched in a bivalent chromatin state C_LIO_LIChromosomal epigenome erosion of 3D genome structures occurs in LOAD brain cell types. C_LIO_LIShared and reliable methylation signatures are observed in both in vitro cellular iN models and primary brain tissues. C_LIO_LIMachine learning models identify robust and reliable methylation loci as AD biomarkers across cell types. C_LI

genomics↗

bioRxiv2023

Single-cell DNA Methylome and 3D Multi-omic Atlas of the Adult Mouse Brain

Cytosine DNA methylation is essential in brain development and has been implicated in various neurological disorders. A comprehensive understanding of DNA methylation diversity across the entire brain in the context of the brains 3D spatial organization is essential for building a complete molecular atlas of brain cell types and understanding their gene regulatory landscapes. To this end, we employed optimized single-nucleus methylome (snmC-seq3) and multi-omic (snm3C-seq1) sequencing technologies to generate 301,626 methylomes and 176,003 chromatin conformation/methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell type taxonomy that contains 4,673 cell groups and 261 cross-modality-annotated subclasses. We identified millions of differentially methylated regions (DMRs) across the genome, representing potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide multiplexed error-robust fluorescence in situ hybridization (MERFISH2) data validated the association of this spatial epigenetic diversity with transcription and allowed the mapping of the DNA methylation and topology information into anatomical structures more precisely than our dissections. Furthermore, multi-scale chromatin conformation diversities occur in important neuronal genes, highly associated with DNA methylation and transcription changes. Brain-wide cell type comparison allowed us to build a regulatory model for each gene, linking transcription factors, DMRs, chromatin contacts, and downstream genes to establish regulatory networks. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a companion whole-brain SMART-seq3 dataset. Our study establishes the first brain-wide, single-cell resolution DNA methylome and 3D multi-omic atlas, providing an unparalleled resource for comprehending the mouse brains cellular-spatial and regulatory genome diversity.

genomics↗

bioRxiv2021

A compendium of novel genomics technologies provides a chromosome-scale assembly and insights into the sex determining system of the Greenland Halibut

Despite the commercial importance of Greenland Halibut (Reinhardtius hippoglossoides), important gaps still persist in our knowledge of this species, including its reproductive biology and sex determination mechanism. In this study, we combined single molecule sequencing of long reads (Pacific Sciences) with Chromatin Conformation Capture sequencing (Hi-C) data to provide the first chromosome-level genome reference for this species. The high-quality assembly encompassed more than 598 Megabases (Mb) assigned to 1 594 scaffolds (scaffold N50 = 25 Mb) with 96 % of its total length distributed among 24 chromosomes. The investigation of its syntenic relationships with other economically important flatfish species revealed a high conservation of synteny blocks among members of this phylogenetic clade. Sex determination analysis revealed that flatfishes do not escape the rule applied to other teleost fish and exhibit a high level of plasticity and turnover in sex-determination mechanisms. A whole-genome sequence analysis of 198 individuals allowed us to draw a full picture of the molecular sex determination (SD) system for Greenland Halibut, revealing that this species possesses a very nascent male heterogametic XY system, with a putative major effect of the sox2 gene, also described as the main SD driver in two other flatfishes. Interestingly, our study also suggested for the first time in flatfishes that a putative Y-autosomal fusion could be associated with a reduction of recombination typical of early steps of sex chromosome evolution.

genomics↗

bioRxiv2020

Novel integrative elements and genomic plasticity in ocean ecosystems

Horizontal gene transfer accelerates microbial evolution, promoting diversification and adaptation. The globally abundant marine cyanobacterium Prochlorococcus has a highly streamlined genome with frequent gene exchange reflected in its extensive pangenome. The source of its genomic variability, however, remains elusive since most cells lack the common mechanisms that enable horizontal gene transfer, including conjugation, transformation, plasmids and prophages. Examining 623 genomes, we reveal a diverse system of mobile genetic elements - cargo-carrying transposons we named tycheposons - that shape Prochlorococcus genomic plasticity. The excision and integration of tycheposons at seven tRNA genes drive the remodeling of larger genomic islands containing most of Prochlorococcus flexible genes. Most tycheposons carry genes important for niche differentiation through nutrient acquisition; others appear similar to phage parasites. Tycheposons are highly enriched in extracellular vesicles and phage particles in ocean samples, suggesting efficient routes for their dispersal, transmission and propagation. Supported by evidence for similar elements in other marine microbes, our work underpins the role of vesicle- and virus-mediated transfer of mobile genetic elements in the diversification and adaptation of microbes in dilute aquatic environments - adding a significant piece to the puzzle of what governs microbial evolution in the planets largest habitat.

microbiology↗

bioRxiv2017

Reconstruction of developmental landscapes by optimal-transport analysis of single-cell gene expression sheds light on cellular reprogramming.

Understanding the molecular programs that guide cellular differentiation during development is a major goal of modern biology. Here, we introduce an approach, WADDINGTON-OT, based on the mathematics of optimal transport, for inferring developmental landscapes, probabilistic cellular fates and dynamic trajectories from large-scale single-cell RNA-seq (scRNA-seq) data collected along a time course. We demonstrate the power of WADDINGTON-OT by applying the approach to study 65,781 scRNA-seq profiles collected at 10 time points over 16 days during reprogramming of fibroblasts to iPSCs. We construct a high-resolution map of reprogramming that rediscovers known features; uncovers new alternative cell fates including neuraland placental-like cells; predicts the origin and fate of any cell class; highlights senescent-like cells that may support reprogramming through paracrine signaling; and implicates regulatory models in particular trajectories. Of these findings, we highlight Obox6, which we experimentally show enhances reprogramming efficiency. Our approach provides a general framework for investigating cellular differentiation.

bioinformatics↗