Biology subjects

Gamache, I.

Publications and source records attributed to Gamache, I..

6 recordsLinked to original sources

bioRxiv2026

CETP alternative splicing variation impacts human traits

The cholesteryl ester transfer protein (CETP) is an important protein in reverse cholesterol transport and has been identified as a significant factor associated with cardiovascular disease (CVD), making it a widely studied pharmaceutical target. Three protein-coding isoforms of CETP exist, distinguished by the alternative splicing of one exon each. The isoform primarily responsible for cholesterol-related functions in the plasma is well studied, but specific functions of each isoform remain poorly understood. In this study, we demonstrate the significance of considering CETPs isoforms in analyses of human traits. Using bulk RNA-seq data from multiple tissues, we characterized the expression patterns and genetic regulation determinants of CETP transcripts. Leveraging publicly available GWAS summary statistics, we conducted multivariable Mendelian Randomisation (MVMR) to estimate the impact of variation in isoform proportions on phenotypes, highlighting the importance of CETPs isoforms in pituitary and thyroid glands. Furthermore, we uncovered tissue-specific associations between CETPs isoforms and CVD-associated phenotypes. Additionally, we observed that the epistatic interaction previously reported between CETP and ADCY9, a gene implicated in modulating a CETP modulators response, may be mediated through the regulation of alternative splicing of exon 9. Our results underscore the importance of a comprehensive understanding of CETPs isoforms, which can significantly impact both fundamental and clinical research efforts.

genetics↗

bioRxiv2026

Viral inhibition of the anaphase promoting complex enhances replication by elevating nucleotide pools

The anaphase promoting complex/cyclosome (APC/C) is a large, ubiquitin ligase and a central regulator of cell cycle progression. By targeting key substrates for degradation during mitosis and G1 phase, the APC/C coordinates metabolic fluctuations that occur during the cell cycle. A diverse range of viruses have convergently evolved mechanisms to bind and inhibit the APC/C; however, a molecular understanding for these interactions has never been demonstrated. Here, we use chicken anemia virus (CAV), a small single-stranded DNA virus encoding only three proteins, to demonstrate the importance of viral APC/C inhibition during replication. We show that the Vp3 protein of CAV inhibits the APC/C, causing a dramatic mitotic arrest during infection. Mutant virus lacking Vp3 are defective for replication and can be rescued by APC/C inhibition. Metabolomic profiling during CAV infection revealed that Vp3 expression mediates a broad increase in nucleotide pools. Moreover, viral inhibition of the APC/C resulted in stabilization of enzymes required for nucleotide biosynthesis. These findings suggest that the APC/C is a general target of many viruses to elevate nucleotide levels and facilitate viral genome replication. Author SummaryViruses dramatically reshape the cells they infect in order to replicate. To do this efficiently, many viruses disrupt the hosts normal control systems, particularly those that regulate cell growth and division. One such system is the anaphase promoting complex/cyclosome (APC/C), a key cellular machine that controls when specific proteins are broken down during the cell cycle. Surprisingly, a wide range of viruses--including adenovirus, HIV, human papillomavirus, herpesvirus, and others--have been shown to interfere with the APC/C. Until now, however, it was unclear why so many unrelated viruses target this same pathway. In our study, we used chicken anemia virus (CAV), one of the smallest known animal viruses, as a simple model to uncover the underlying mechanism. CAV produces just three proteins, one of which--called VP3--strongly inhibits the APC/C. We found that this inhibition increases the availability of nucleotides, the basic building blocks needed to copy viral DNA. By disrupting normal cell cycle control, the virus effectively redirects cellular resources toward its own replication. These findings reveal APC/C inhibition as a common and powerful strategy used by diverse viruses, offering new insight into how viruses exploit host cells and highlighting potential targets for future antiviral therapies.

microbiology↗

bioRxiv2023

Signatures of co-evolution and co-regulation in the CYP3A and CYP4F genes in humans

1Cytochromes P450 (CYP450) are hemoproteins generally involved in the detoxification of the body of xenobiotic molecules. They participate in the metabolism of many drugs and genetic polymorphisms in humans have been found to impact drugs responses and metabolic functions. In this study, we investigate the genetic diversity for CYP450 genes. We found that two clusters, CYP3A and CYP4F, are notably differentiated across human populations with evidence for selective pressures acting on both clusters: we found signals of recent positive selection in CYP3A and CYP4F genes and signals of balancing selection in CYP4F genes. Furthermore, unusual linkage disequilibrium pattern is detected in both clusters, suggesting co-evolution of genes within clusters. Several of these selective signals co-localize with expression quantitative trait loci, which suggest co-regulation and epistasis within these highly important gene families. We also found that SNPs under selection in Africans within the CYP3A cluster are associated to CYP3A5 expression levels which are causally associated with reticulocytes count, as established by mendelian randomization. Furthermore, as the CYP3A and CYP4F subfamilies are involved in the metabolism of nutrients and drugs, our findings linking natural selection and gene expression in these gene clusters are of importance in understanding population differences in human health.

genetics↗

bioRxiv2021

Data-driven approaches for genetic characterization of SARS-CoV-2 lineages

The genome of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the pathogen that causes coronavirus disease 2019 (COVID-19), has been sequenced at an unprecedented scale, leading to a tremendous amount of viral genome sequencing data. To understand the evolution of this virus in humans, and to assist in tracing infection pathways and designing preventive strategies, we present a set of computational tools that span phylogenomics, population genetics and machine learning approaches. To illustrate the utility of this toolbox, we detail an in depth analysis of the genetic diversity of SARS-CoV-2 in first year of the COVID-19 pandemic, using 329,854 high-quality consensus sequences published in the GISAID database during the pre-vaccination phase. We demonstrate that, compared to standard phylogenetic approaches, haplotype networks can be computed efficiently on much larger datasets, enabling real-time analyses. Furthermore, time series change of Tajimas D provides a powerful metric of population expansion. Unsupervised learning techniques further highlight key steps in variant detection and facilitate the study of the role of this genomic variation in the context of SARS-CoV-2 infection, with Multiscale PHATE methodology identifying fine-scale structure in the SARS-CoV-2 genetic data that underlies the emergence of key lineages. The computational framework presented here is useful for real-time genomic surveillance of SARS-CoV-2 and could be applied to any pathogen that threatens the health of worldwide populations of humans and other organisms.

bioinformatics↗

bioRxiv2021

Germline Missense Variants in CDC20 Result in Aberrant Mitotic Progression and Familial Cancer

CDC20 is a co-activator of the anaphase promoting complex/cyclosome (APC/C) and is essential for mitotic progression. APC/CCDC20 is inhibited by the spindle assembly checkpoint (SAC), which prevents premature separation of sister chromatids and aneuploidy in daughter cells. Although overexpression of CDC20 is common in many cancers, oncogenic mutations have never been identified in humans. Using whole exome sequencing, we identified heterozygous missense CDC20 variants (L151R and N331K) that segregate with cancer in two families. Characterization of these mutants showed they retain APC/C activation activity but show reduced binding to BUBR1, a component of the SAC. Expression of L151R and N331K promoted mitotic slippage in HeLa cells and primary skin fibroblasts derived from carriers. CRISPR/Cas9 was used to generate mice carrying N331K. Homozygous mice carrying N331K were non-viable, however, heterozygotes displayed accelerated oncogenicity in Myc-driven cancers. These findings highlight an unappreciated role for CDC20 variants as tumor promoting genes in humans.

cancer biology↗

bioRxiv2021

A sex-specific evolutionary interaction between ADCY9 and CETP

Pharmacogenomic studies have revealed associations between rs1967309 in the adenylyl cyclase type 9 (ADCY9) gene and clinical responses to the cholesteryl ester transfer protein (CETP) modulator dalcetrapib, however, the mechanism behind this interaction is still unknown. Here, we characterized selective signals at the locus associated with the pharmacogenomic response in human populations and we show that rs1967309 region exhibits signatures of positive selection in several human populations. Furthermore, we identified a variant in CETP, rs158477, which is in long-range linkage disequilibrium with rs1967309 in the Peruvian population. The signal is mainly seen in males, a sex-specific result that is replicated in the LIMAA cohort of over 3,400 Peruvians. Analyses of RNA-seq data further suggest an epistatic interaction on CETP expression levels between the two SNPs in multiple tissues, which also differs between males and females. We also detected interaction effects of the two SNPs with sex on cardiovascular phenotypes in the UK Biobank, in line with the sex-specific genotype associations found in Peruvians at these loci. We propose that ADCY9 and CETP coevolved during recent human evolution due to sex-specific selection, which points towards a biological link between dalcetrapibs pharmacogene ADCY9 and its therapeutic target CETP.

genetics↗