Biology subjects

Fustier, M.-A.

Publications and source records attributed to Fustier, M.-A..

3 recordsLinked to original sources

bioRxiv2024

ZNF827 pleiotropic cardiovascular risk locus involves regulation by Nuclear factor-1

IntroductionSCAD (spontaneous coronary artery dissection) is a form of myocardial infarction that disproportionately affects young women. SCAD is caused by the formation of a hematoma within coronary artery wall, resulting in its blockage. Sixteen SCAD susceptibility loci are currently known, including ZNF827 gene locus on chromosome 4. Several common genetic variations within ZNF827 are also linked to coronary artery disease (CAD), systolic blood pressure (SBP), and ascending aortic diameter. The molecular processes driving these genetic connections, however, are unknown. MethodsWe performed fine-mapping and genetic colocalization analysis at ZNF827 locus on multiple GWAS signals and quantitative expression traits. We explored the regulatory function of sequences of interest using a luciferase reporter system in rat smooth muscle cells. We used siRNA to knockdown the expression of gene and assessed transcriptomic changes through bulk RNA-Seq. ResultsThe genetic association signals for SCAD, CAD, blood pressure, and aorta dimensions could all be explained by a single causal variant. We identified rs13128814 as the most likely causative variant. This variant overlaps epigenetic regulatory markers specifically active in vascular SMCs and fibroblasts. A 1kb region containing the SCAD-risk allele (A) of rs13128814 variant had a transcriptional activation impact, while the protective allele (G) had no effect. In silico predictions found nuclear factor 1 (NF1) transcription factors preferentially bind to the A allele of rs13128814. We found that overexpressing NFIA (Nuclear Factor 1 A-Type) activated transcription in this area. SCAD association and ZNF827 eQTL colocalization in various vascular tissues suggested the latter as a plausible target gene in this locus. Knockdown of ZNF827 in iPSC-derived SMCs and fibroblasts, followed by RNA-seq, identified a large number of dysregulated genes, including multiple genes involved in cardiovascular disease. ConclusionOur findings in ZNF827 locus support the hypothesis that the rs13128814 variant, which may affect the binding of NF1 family transcription factors and cause ZNF827 expression to be deregulated, is the molecular mechanism underpinning the relationship of the ZNF827 locus with numerous cardiovascular disorders. ZNF827 acts as a regulator of gene expression in vascular SMCs and fibroblasts. Further investigation of ZNF827 function in vascular tissue will be required to understand the implications of its dysregulation on cardiovascular physiopathology.

cell biology↗

bioRxiv2021

The haplotype-resolved chromosome pairs and transcriptome of a heterozygous diploid African cassava cultivar

BackgroundCassava (Manihot esculenta) is an important clonally propagated food crop in tropical and sub-tropical regions worldwide. Genetic gain by molecular breeding is limited because cassava has a highly heterozygous, repetitive and difficult to assemble genome. FindingsHere we demonstrate that Pacific Biosciences high-fidelity (HiFi) sequencing reads, in combination with the assembler hifiasm, produced genome assemblies at near complete haplotype resolution with higher continuity and accuracy compared to conventional long sequencing reads. We present two chromosome scale haploid genomes phased with Hi-C technology for the diploid African cassava variety TME204. Genome comparisons revealed extensive chromosome re-arrangements and abundant intra-genomic and inter-genomic divergent sequences despite high gene synteny, with most large structural variations being LTR-retrotransposon related. Allele-specific expression analysis of different tissues based on the haplotype-resolved transcriptome identified both stable and inconsistent alleles with imbalanced expression patterns, while most alleles expressed coordinately. Among tissue-specific differentially expressed transcripts, coordinately and biasedly regulated transcripts were functionally enriched for different biological processes. We use the reference-quality assemblies to build a cassava pan-genome and demonstrate its importance in representing the genetic diversity of cassava for downstream reference-guided omics analysis and breeding. ConclusionsThe haplotype-resolved genome allows the first systematic view of the heterozygous diploid genome organization in cassava. The completely phased and annotated chromosome pairs will be a valuable resource for cassava breeding and research. Our study may also provide insights into developing cost-effective and efficient strategies for resolving complex genomes with high resolution, accuracy and continuity.

genomics↗

bioRxiv2019

Genomic footprints of local adaptation along elevation gradients associate with present phenotypic variation in teosintes

Local adaptation across species range is widespread. Yet, much has to be discovered on its environmental drivers, the underlying functional traits and their molecular determinants. Because elevation gradients display continuous environmental changes at a short geographical scale, they provide an exceptional opportunity to investigate these questions. Here, we used two common gardens to phenotype 1664 plants from 11 populations of annual teosintes. These populations were sampled across two elevation gradients in Mexico. Our results point to a syndrome of adaptation to altitude with the production of offspring that flowered earlier, produced less tillers, and larger, longer and heavier grains with increasing elevation. We genotyped these plants for 178 outlier single nucleotide polymorphisms (SNPs), which had been chosen because they displayed excess of allele differentiation and/or correlation with environmental variables in six populations with contrasted altitudes. A high proportion of outlier SNPs associated with the phenotypic variation of at least one trait. We tested phenotypic pairwise correlations between traits, and found that the higher the correlation, the greater the number of common associated SNPs. In addition, allele frequencies at 87 of the outlier SNPs correlated with an environmental component best summarized by altitudinal variation on a broad sample of 28 populations. Chromosomal inversions were enriched for both phenotypically-associated and environmentally-correlated SNPs. Altogether, our results are consistent with the set-up of an altitudinal syndrome promoted by local adaptation of teosinte populations in the face of gene flow. We showed that pleiotropy is pervasive and potentially has constrained the evolution of traits. Finally, we recovered variants underlying phenotypic variation at adaptive traits. Because elevation mimics climate change through space, these variants may be relevant for future maize breeding. Author summaryAcross their native range, species encounter a diversity of habitats promoting local adaptation of geographically distributed populations. While local adaptation is widespread, much has yet to be discovered about the conditions of its emergence, the targeted traits, their molecular determinants and the underlying ecological drivers. Here we employed a reverse ecology approach, combining phenotypes and genotypes, to mine the determinants of local adaptation of teosinte populations distributed along two steep altitudinal gradients in Mexico. Evaluation of 11 populations in two common gardens located at mid-elevation pointed to the set-up of an altitudinal syndrome, in spite of gene flow. We scanned genomes to identify loci with allele frequencies shifts along elevation. Interestingly, variation at these loci was commonly associated to variation of phenotypes. Because elevation mimics climate change through space, these variants may be relevant for future maize breeding.

evolutionary biology↗