Biology subjects

Laprise, C.

Publications and source records attributed to Laprise, C..

7 recordsLinked to original sources

bioRxiv2026

4,5-dihydroxyhexanoic acid is a robust circulating and urine marker of mitochondrial disease and its severity

Management of patients with mitochondrial respiratory chain diseases is challenging, in part because of our incomplete understanding of pathogenesis and a lack of biomarkers. Unknown metabolites account for >90% of detected features in modern metabolomics experiments and hold immense untapped promise for new basic and biomedical research. We recently used mass spectrometry-based metabolomics to identify and validate 19 circulating blood-based biomarkers for patients with the mitochondrial DNA (mtDNA) m.3243A>G pathogenic variant, which is the most frequent cause of the mitochondrial disorder MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). However, the most significantly changing biomarker corresponded to an "unknown" metabolite. Here, we combine cheminformatics with analytical chemistry and identify that feature as 4,5-dihydroxyhexanoic acid (4,5-DHHA), a metabolite previously associated with inherited defects of gamma-aminobutyric acid (GABA) catabolism, but with no prior links to mitochondrial respiratory chain disorders. We validate this finding in an independent MELAS cohort and further show that 4,5-DHHA levels correlate with disease severity and are elevated in patients with other forms of mitochondrial disease and sepsis. Furthermore, brain 4,5-DHHA levels were elevated in two genetic mouse models of mitochondrial disease. In vitro and tissue culture experiments indicate that 4,5-DHHA is generated when the GABA catabolite succinic semialdehyde reacts with an intermediate of the pyruvate dehydrogenase reaction and is sensitive to mitochondrial complex I function. Our work identifies 4,5-DHHA as a robust plasma and urine marker of mitochondrial dysfunction in humans and reveals new connections between the respiratory chain and GABA metabolism. Significance StatementInborn errors of the mitochondrial respiratory chain cause severe, progressive diseases, yet effective treatments and biomarkers remain limited. Modern metabolomics detects thousands of molecules in biofluids, but the vast majority are unidentified. In this study, we investigate the most significantly altered blood metabolite in patients with the most common mitochondrial disease - MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) - and identify it as an 4,5-dihydroxyhexanoic acid (4,5-DHHA). We show that 4,5-DHHA is reproducibly elevated and correlates with severity. Levels are increased across multiple mitochondrial disorders as well as in sepsis and rise when respiratory chain function is impaired. These findings establish 4,5-DHHA as a promising biomarker of mitochondrial dysfunction and reveal a link to dysregulated GABA metabolism.

biochemistry↗

bioRxiv2025

Season and city shape urban bioaerosol composition beyond vegetation and socioeconomic gradients

Urban vegetation varies with socio-economic gradients, as lower-income neighborhoods often host sparser and less diverse green spaces. This disparity may affect respiratory health by influencing exposure to bioaerosols. Understanding the characteristics of this aerobiome could help anticipate risks related to allergies and other respiratory conditions. Here, we hypothesized that urban vegetation cover and socio-economic status shape urban bioaerosols. We sampled bioaerosols at 65 sites across three Canadian cities of varying population size and density using an active air sampler over four months, and characterized their bacterial, fungal, and pollen composition using amplicon sequencing. Seasonal alpha diversity varied significantly for fungi and pollen. Based on beta diversity, sampling period alone explained up to 40% of pollen, 29% of fungal, and 11% of bacterial community composition variation. In contrast, vegetation cover explained only a minor portion of the variance in bioaerosol composition, and median household income, almost none. These findings provide a critical baseline for understanding the urban aerobiome and highlight the need to study how vegetation identity and diversity, rather than cover alone, may shape bioaerosol dynamics in cities. As cities grow and urban greening initiatives expand, demystifying the aerobiome dynamics becomes an urgent public health priority.

microbiology↗

bioRxiv2024

Fine-scale genetic structure and rare variant frequencies

In response to the current challenge in genetic studies to make new associations, we advocate for a shift toward leveraging population fine-scale structure. Our exploration brings to light distinct fine-structure within populations having undergone a founder effect, challenging the prior perception of homogeneity. This underscores that smaller, but well-defined cohorts, demonstrate an important increase in rare variant frequencies, offering a promising avenue for new genetic variants discovery.

genomics↗

bioRxiv2022

GENLIB: new function to simulate haplotype transmission in large complex genealogies

SummaryFounder populations with deep genealogical data are well suited for investigating genetic variants contributing to diseases. Here, we present a new function added to the genealogical analysis R package GENLIB, which can simulate the transmission of haplotypes from founders to probands along very large and complex user-specified genealogies. Availability and implementationThe new function is available in the latest version of the GENLIB package (v1.1.6), available on the CRAN repository and from https://github.com/R-GENLIB/GENLIB. Stand-alone scripts for analyzing the output of the function can be accessed at https://github.com/R-GENLIB/simuhaplo_scripts.

bioinformatics↗

bioRxiv2022

Deciphering the genetic structure of the Quebec founder population using genealogies

Using genealogy to study the demographic history of a population makes it possible to overcome the models and assumptions often used in population genetics. The Quebec founder population is one of the few populations in the World having access to the complete genealogy of the last 400 years. The goal of this paper is to follow the evolution of the Quebec population structure generation per generation from the beginning of European colonization until the present day. To do so, we calculated the kinship coefficients of all ancestors pairs in the ascending genealogy of 665 individuals from eight regional and ethnocultural groups per 25-year period. We show that the Quebec population structure appeared in the St. Lawrence valley as early as 1750. At that time, the ancestors of two groups, the Sagueneans and the Acadians from the Gaspe Peninsula, experienced a marked increase in kinship and inbreeding levels which have shaped the contemporary population structure. Interestingly, this structure arose before the colonization of the Saguenay region and at the very beginning of the Gaspe Peninsula settlement. The resulting regional founder effects in these two groups, but also in the other regional groups, led to differences in the present-day identity-by-descent sharing and are directly linked to the number of most recent common ancestors and their genetic contribution to the studied subjects.

genetics↗

bioRxiv2019

GSDMA drives the most replicated association with asthma in naïve CD4+ T cells

BackgroundThe 17q12-21 locus is the most replicated association with asthma. However, no study had described the genetic mechanisms underlying this association considering all genes of the locus in immune cell samples isolated from asthmatic and non-asthmatic individuals.\n\nObjectiveThis study takes benefit of samples from naive CD4+ T cells and eosinophils isolated from the same 200 individuals to describe specific interactions between genetic variants, gene expression and DNA methylation levels for the 17q12-21 asthma locus.\n\nMethods and ResultsAfter isolation of naive CD4+ T cells and eosinophils from blood samples, next generation sequencing was used to measure DNA methylation levels and gene expression counts. Genetic interactions were then evaluated considering genetic variants from imputed genotype data. In naive CD4+ T cells but not eosinophils, 20 SNPs in the fourth and fifth haplotype blocks modulated both GSDMA expression and methylation levels, showing an opposite pattern of allele frequencies and expression counts in asthmatics compared to controls. Moreover, negative correlations have been measured between methylation levels of CpG sites located within the 1.5 kb region from the transcription start site of GSDMA and its expression counts.\n\nConclusionAvailability of sequencing data from two key cell types isolated from asthmatic and non-asthmatic individuals allowed identifying a new gene in naive CD4+ T cells that drives the association with the 17q12-21 locus, leading to a better understanding of the genetic mechanisms taking place in it.

genetics↗

bioRxiv2019

Polygenic risk scores of several subtypes of epilepsies in a founder population

ImportanceEpilepsy is defined as a group of neurological disorders characterized by epileptic seizures, brief episodes of symptoms that are caused by abnormal or excessive neuronal activity in the brain. Epilepsy affects around 3 percent of individuals. In the past 10 years, many groups have been working to better understand the complex genetic mechanisms underlying epilepsy. Together, they studied many different genetic mechanisms, but there is still a substantial missing heritability component in epilepsy genetics.\n\nObjectiveHere, we used polygenic risk scores (PRS) to quantify the cumulative effects of a number of variants, which may individually have a very small effect on susceptibility.\n\nDesignWe calculated PRS in 522 French-Canadian epilepsy patients divided into seven subtypes and French-Canadian controls.\n\nSettingAll study participants (cases and controls) were selected based on their French-Canadian ancestry.\n\nParticipantsThe epilepsy cohort was composed of families of at least three affected individuals with Idiopathic Generalized Epilepsy (IGE) or Non-acquired Focal Epilepsy (NAFE) previously collected and diagnosed by neurologists following the International League Against Epilepsy (ILAE) criteria.\n\nExposuresAll samples were processed on a common genotyping array.\n\nMain outcomes and ResultsWe show that the area under the curve (AUC) is almost always slightly greater than 0.5, especially in patients with IGE and subtypes. We also looked at the association of the PRS with the different phenotypes using a linear mixed effects model estimated by generalized estimating equation (GEE) with the pairwise identity-by-descent (IBD) matrix as a random effect. P-values of GEE were consistent with AUC calculations.\n\nConclusions and RelevanceGlobally, we support the notion that PRS and SNP-based heritability provide reliable measures to rightfully estimate the contribution of genetic factors to the pathophysiological mechanism of epilepsies, but further studies are needed on PRS before they can be used clinically.

genetics↗