Biology subjects

Plassais, J.

Publications and source records attributed to Plassais, J..

5 recordsLinked to original sources

bioRxiv2021

Multi-omics approach identifies germline regulatory variants associated with hematopoietic malignancies in retriever dog breeds

Histiocytic sarcoma is an aggressive hematopoietic malignancy of mature tissue histiocytes with a poorly understood etiology in humans. A histologically and clinically similar counterpart affects flat-coated retrievers (FCRs) at unusually high frequency, with 20% developing the lethal disease. The similar clinical presentation combined with the closed population structure of dogs, leading to high genetic homogeneity, makes dogs an excellent model for genetic studies of cancer susceptibility. To determine the genetic risk factors underlying histiocytic sarcoma in FCRs, we conducted multiple genome-wide association studies (GWASs), identifying two loci that confer significant risk on canine chromosomes (CFA) 5 (Pwald=4.83x10-9) and 19 (Pwald=2.25x10-7). We subsequently undertook a multi-omics approach that has been largely unexplored in the canine model to interrogate these regions, generating whole genome, transcriptome, and chromatin immunoprecipitation sequencing. These data highlight the PI3K pathway gene PIK3R6 on CFA5, and proximal candidate regulatory variants that are strongly associated with histiocytic sarcoma and predicted to impact transcription factor binding. The CFA5 association colocalizes with susceptibility loci for two hematopoietic malignancies, hemangiosarcoma and B-cell lymphoma, in the closely related golden retriever breed, revealing the risk contribution this single locus makes to multiple hematological cancers. By comparison, the CFA19 locus is unique to the FCR and harbors risk alleles associated with upregulation of TNFAIP6, which itself affects cell migration and metastasis. Together, these loci explain ~35% of disease risk, an exceptionally high value that demonstrates the advantages of domestic dogs for complex trait mapping and genetic studies of cancer susceptibility.

genetics↗

bioRxiv2021

Epigenetic clock and methylation studies in dogs

DNA methylation profiles have been used to develop biomarkers of aging known as epigenetic clocks, which predict chronological age with remarkable accuracy and show promise for inferring health status as an indicator of biological age. Epigenetic clocks were first built to monitor human aging but the principles underpinning them appear to be evolutionarily conserved, as they have now been successfully developed for over 120 mammalian species. Here we describe reliable and highly accurate epigenetic clocks shown to apply to 51 domestic dog breeds. The methylation profiles were generated using a custom array with DNA sequences that are conserved across all mammalian species (HorvathMammalMethylChip40). Canine epigenetic clocks were constructed to estimate age and also predict mortality risk by estimating average time-to-death. We also present two highly accurate human-dog dual species epigenetic clocks (R=0.97), which may facilitate the ready translation from canine to human use (or vice versa) of anti-aging treatments being developed for longevity and preventive medicine. Finally, epigenome-wide association studies herein reveal individual methylation sites that may underlie the inverse relationship between breed weight and lifespan. Overall, we describe robust biomarkers to measure aging and potentially health status in canines.

developmental biology↗

bioRxiv2021

DNA Methylation Networks Underlying Mammalian Traits

Epigenetics has hitherto been studied and understood largely at the level of individual organisms. Here, we report a multi-faceted investigation of DNA methylation across 11,117 samples from 176 different species. We performed an unbiased clustering of individual cytosines into 55 modules and identified 31 modules related to primary traits including age, species lifespan, sex, adult species weight, tissue type and phylogenetic order. Analysis of the correlation between DNA methylation and species allowed us to construct phyloepigenetic trees for different tissues that parallel the phylogenetic tree. In addition, while some stable cytosines reflect phylogenetic signatures, others relate to age and lifespan, and in many cases responding to anti-aging interventions in mice such as caloric restriction and ablation of growth hormone receptors. Insights uncovered by this investigation have important implications for our understanding of the role of epigenetics in mammalian evolution, aging and lifespan.

evolutionary biology↗

bioRxiv2020

Incorporating phylogenetic information in microbiome abundance studies has no effect on detection power and FDR control

We consider the problem of incorporating evolutionary information (e.g. taxonomic or phylogenic trees) in the context of metagenomics differential analysis. Recent results published in the literature propose different ways to leverage the tree structure to increase the detection rate of differentially abundant taxa. Here, we propose instead to use a different hierachical structure, in the form of a correlation-based tree, as it may capture the structure of the data better than the phylogeny. We first show that the correlation tree and the phylogeny are significantly different before turning to the impact of tree choice on detection rates. Using synthetic data, we show that the tree does have an impact: smoothing p-values according to the phylogeny leads to equal or inferior rates as smoothing according to the correlation tree. However, both trees are outperformed by the classical, non hierachical, Benjamini-Hochberg (BH) procedure in terms of detection rates. Other procedures may use the hierachical structure with profit but do not control the False Discovery Rate (FDR) a priori and remain inferior to a classical Benjamini-Hochberg procedure with the same nominal FDR. On real datasets, no hierarchical procedure had significantly higher detection rate that BH. Although intuition advocates the use of a hierachical structure, be it the phylogeny or the correlation tree, to increase the detection rate in microbiome studies, current hierachical procedures are still inferior to non hierachical ones and effective procedures remain to be invented.

microbiology↗

bioRxiv2018

Laparoscopic Roux-en-Y gastric bypass profoundly changes gut microbiota compared to laparoscopic sleeve gastrectomy: a metagenomic comparative analysis

BackgroundBariatric surgery is an effective therapeutic procedure for morbidly obese patients as it induces sustained weight loss. The two most common interventions are Laparoscopic Sleeve Gastrectomy (LSG) and Laparoscopic Roux-en-Y Gastric Bypass (LRYGB).\n\nObjectiveCharacterizing the gut microbiota changes induced by LSG and LRYGB.\n\nDesign89 and 108 patients who underwent LSG and LRYGB respectively, were recruited from three countries: USA, France and Switzerland. Stools were collected before and 6 months after surgery. Microbial DNA was analysed with shotgun metagenomic sequencing (SOLiD 5500xl Wildfire). MSPminer, a novel innovative tool to characterize new in silico biological entities, was used to identify 715 Metagenomic Species Pan-genome (MSPs). 148 functional modules were analysed using GOmixer and KEGG database.\n\nResultsBoth interventions resulted in a similar increase of Shannons diversity index and gene richness of gut microbiota, in parallel with weight loss, but the changes of microbial composition were different. LRYGB led to higher relative abundance of aero-tolerant bacteria, such as Escherichia coli and buccal species, such as Streptococcus and Veillonella spp. In contrast, anaerobes such as Clostridium were more abundant after LSG, suggesting better conservation of anaerobic conditions in the gut. Function-level changes included higher potential for bacterial use of supplements such as vitamin B12, B1 and iron upon LRYGB. Moreover, after LRYGB, potential for nitrate and Trimethylamine oxidized (TMAO) respiration was detected.\n\nConclusionMicrobiota changes after bariatric surgery depend on the nature of the intervention. LRYGB induces greater taxonomic and functional changes in gut microbiota than LSG and may lead to a more dysbiotic microbiome. Possible long-term health consequences of these alterations remain to be established.\n\nSignificance of this studyO_ST_ABSWhat is already known on this subject?C_ST_ABSPrevious studies have reported changes of microbial composition after bariatric surgery with shotgun metagenomics, but lacked statistical power to document the changes. Important shifts in gut microbiome have been observed after LRYGB and LSG with an increase of aerotolerants from buccal microbiota. However, it is not clear how different the changes are between LRYGB and LSG although both procedures induce quite similar results with respect to weight loss, comorbidities remission and global glycaemic improvement outcomes.\n\nWhat are the new findings?LSG and LRYGB have specific but different impacts on gut microbial composition 6 months after bariatric surgery. The changes could be related to specific physiological effects. LRYGB promotes an important invasion of oral colonizers with Veillonella and Streptococcus genera. In contrast, these changes were less important after LSG. Moreover, microbial transportation potential of iron and vitamin B12 were also higher after LRYGB than LSG. We concluded that the type of surgery leads to different gut microbiome and functional profiles.\n\nHow might it impact on clinical practice in the foreseeable future?Microbiome composition and functional profiles are not altered to the same extent by LRYGB and LSG 6 months after surgery. This difference should be considered when advising the patient on the type of bariatric surgery or post op diet.

microbiology↗