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Searched keyword : Variant analysis

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viral evolution around Ebola Treatment Centre in Macenta and according to disease outcomes

The 2013-2015 Ebola virus disease epidemic is the largest outbreak so far described with 27 305 cases and 11 169 deaths. The virus spread by human to human contact throughout Western Africa and never before has a variant been transmitted for such a sustained period of time. Ebola virus are RNA virus so as other RNA viruses they could accumulate mutations during evolution. Therefore it is an emergency to monitor viral changes and adaptation within and between individuals in order to help researchers to better understand susceptibility to Ebola infections, to guide research on therapeutic targets and to ensure accurate diagnosis. New technologies can provide information about pathogen’s evolution and in our lab we have access to an Ion PGMTM sequencer. Thanks to the national reference center for viral hemorrhagic fever (VHF) we have at our disposal a large number of samples collected from Ebola infected patients especially from Guinea. We have developed an Amplicon approach using sixteen couples of specific primers for Ebola viruses and a RNA sequencing method based on randomly primed cDNA synthesis to product our libraries. Ion PGMTM Hi-Q sequencing kit will be used to sequence up to 400 bp inserts loaded onto 316v2TM or 318v2TM chip. Through high depth sequencing we would like to follow up the profiling of intra and inter host viral quasispecies at different time of the epidemic in the geographic area of the Ebola Treatment Centre in Macenta. Thanks to the activities of national reference center for VHF and the Biomics Pole one aim of the project is also to occasionally compare viral quasispecies and consensus sequences between patients who get uncommon symptoms from those who get classical illness and to study intra host quasispecies in different biological fluids (cerebrospinal fluid, sperm, urine) to see if there are differences between persistent species and viral quasispecies found during symptomatic step.

Project status : Closed

Influence of chromatin dynamics on genomic stability during replication

Genomic DNA is hierarchically packed within the living cells and genome duplication requires the concerted effort of many thousands of individual replication units. As such, to ensure the integrity of transmission of the genetic information, both eukaryotes and prokaryotes have evolved sophisticated mechanisms to monitor DNA replication. Some of these mechanisms aim to maintain both a temporal and a spatial organization of the replication program, leading to multiple replication time regions and the compartmentalization into replication foci, subnuclear sites which accumulate numerous DNA replication factors. It should be noted that Saccharomyces cerevisiae represents an exception to the standard eukaryotic strategy for genome duplication. Similar to bacteria, S. cerevisiae possess well-defined replication origin sequences that can fire at a very efficient rate during S phase, leading to a very homogenous pattern of DNA replication. A common mo del suggests that, once replication starts dynamic events take place since co-regulated replication forks, having similar replication timing, cluster within a discrete number of foci that show distinct patterns of nuclear localization over the S-phase. Once initiated, the DNA synthesis might be compromised if the replication fork encounters an RFB (Replication Fork Barrier) such as DNA lesions, tightly bound protein-DNA complexes etc. The RFBs are considered a potential source of genetic instability and may lead to many chromosomal rearrangements. As a consequence, eukaryotes employ a complex DNA damage response against RFBs, which aims to maintain the stability of the stalled forks and provides the time required to repair and resume replication. Recent observations suggest that the non-random organization of the nucleus affects where repair occurs. The aim of this project is to reach a better understanding of the influence of the nuclear spatial architecture and organization at replication fork blocks.

Project status : Closed

How ribosomal protein gene position impacts in the genome evolution during a long term evolution experiment.

Increasing evidence indicates that nucleoid spatiotemporal organization is crucial for bacterial physiology since these microorganism lack a compartmentalized nucleus. However, it is still unclear how gene order within the chromosome can influence cell physiology. In silico approaches have shown that genes involved in transcription and translation processes, in particular ribosomal protein (RP) genes, tend to be located near the replication origin (oriC) in fast-growing bacteria suggesting that such a positional bias might be an evolutionarily conserved growth-optimization strategy. Recently we systematically relocated a locus containing half of ribosomal protein genes (S10) to different genomic positions in Vibrio cholerae. These experiments revealed drastic differences in growth rate and infectivity within this isogenic strain set. We showed that genomic positioning of ribosomal protein genes is crucial for physiology by providing replication-dependent higher dosage in fast growing conditions. Therefore it might play a key role in genome evolution of bacterial species. We aim at observing how the genomic positioning of these genes would influence the evolution of Vibrio cholerae. To gain insight into the evolutionary consequences of relocating RP genes, we let evolve either the wild type or the most affected strains for 1000 generations in fast-growing conditions. NGS will be performed and analyzedon the evolved populations to understand the genetic changes responsible of the observed phenotypic changes.

Project status : Pending

SNP based analysis of French Bordetella pertussis isolates: comparison of isolates producing all the vaccine antigens to isolates producing only some of them.

Whooping cough is a vaccine-preventable disease due to Bordetella pertussis. Even if vaccination has allowed the control of the disease, isolates are still circulating and cyclic increases of incidence are observed every 3 to 5 years even in vaccinated countries. Most developed countries now use acellular vaccines containing 3 to 5 vaccine antigens (pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (PRN) fimbrial proteins (FIM2/FIM3)) that have replaced whole cell vaccines. In regions vaccinating with acellular vaccines with a high coverage, isolates no more producing some vaccine antigens (mainly PRN) have been reported in the last years.   Bordetella pertussis reference genome has been fully annotated in 2003 by the Sanger Institute. Analysis and comparison of different B.pertussis genomic sequences showed that circulating B.pertussis isolates differ from vaccine and reference strains. Genome evolution is characterized by gene deletions, antigenic divergences, SNP accumulations…Recent genomic analysis gathering isolates from different countries showed that the worldwide B. pertussis population has evolved in the last 60 years,. Gene categories under selection were identified underlying that Bvg-activated genes and genes coding for surface-exposed proteins were important for adaptation. However these analyses concerned only overall vaccine antigen producing isolates.   The PTMMH Unit includes the National Center of reference for Bordetellosis. In the last years some particular B.pertussis French isolates no more producing PRN but also FHA or PT have been collected, analyzed and sequenced. We would like to further analyze these genomic data with a focus on the vaccine antigen deficient isolates through a SNP-based comparison of these isolates vs co-circulating isolates producing all vaccine antigens and vs a reference strain.

Project status : Closed

Massive amplification at an unselected locus accompanies complex chromosomal rearrangements in yeast

Project status : Closed

Comparative analysis of the virulence plasmids of Shigella Spp. and entero-invasive Escherichia coli

Context. Bacteria of the genus Shigella and strains of entero-invasive Escherichia coli (EIEC) are responsible of bacillary dysentery (shigellosis) in humans. Although (very) closely related to E. coli, the genus Shigella is divided in four "species": S. boydii, S. dysenteriae, S. flexneri and S. sonnei. Most virulence determinants enabling these bacteria to enter into and disseminate within epithelial cells are encoded by a 200-kb virulence plasmid (VP). The first complete sequence of a VP (pWR100 from a S. flexneri strain of serotype 5a) was determined by our laboratory in 2000. The VP contains genes of different origins, as attested by their G+C content ranging from 30 to 60%, traces of four plasmids and a large numbers of various insertions sequences (IS) representing 30-40% of the total sequence (Buchrieser et al., 2000). In addition to IS sequences, the VP carries members of several multigene families (exhibiting over 90% identity). Such repeated sequences are potentially prone to recombination (allelic exchange, gene conversion) and deletion. Based on the analysis of three genes carried by the VP, it has been proposed that, depending of the species / phylogenetic group, there are two forms of the VP (pInvA & pInvB) that were acquired independently in different original E. coli strains. General questions. What are the architectures of the VP from different phylogenetic groups and how different are pInvA and pInvB ? Which genes are conserved in all VP and which genes are unique to some VP ? Did recombinations occur and, if so, where and when ? To answer these questions, a comparative analysis of the genetic organization and gene conservation among the VP from different phylogenetic groups of Shigella/EIEC has been undertaken using the available complete (or presented as such) sequences of 15 VP, including three members for each of five phylogenetic groups (S. boydii, S. dysenteriae 1, S. flexneri, S. sonnei and EIEC).

Project status : Closed

Identification of genes involved in the attenuation of virulence of rough M. abscessus Tn5 mutants in zebrafish

Mycobacterium abscessus is the fast growing mycobacterial species the most frequently associated with lung infection, characterized by severe and very inflammatory cases, after a slow and chronic infectious process. The Cystic Fibrosis patients are particularly susceptible to this bacteria. M. abscessus can exist in a smooth (S) or rough (R) shape depending respectively on the presence or absence of glycopeptidolipids (GPL) associated with the wall of the bacillus. These GPL are involved in motility and biofilm formation, two important features of bacterial colonization. A correlation between the morphotype R, capable of producing morphological structures called "cording" visible in microscopy, and virulence was established. Natural switching from a phenotype S to R allow the transition from a colonizing status to an invasive and pathogenic form. Our project is focusing on deciphering specific mechanisms and analysis of benefits from this transition S/R in vivo. On the basis of transcriptomic data and RNA-Seq previously obtained and/or by screening a transpositional library of colonies deficient in the cording formation, several genes were selected and their corresponding mutants were generated. Since are analyzed : i) the (glyco)lipid composition of their wall; ii) their respective virulence in zebrafish and mouse models and iii) the involvement/recruitment of macrophages and neutrophils and their role in inflammation in response to infection. Our aims are to identify and describe new virulence determinants specific to the establishment of chronic stages of M. abscessus and identification of molecular locks of the S/R switch to understand how an environmental mycobacterium evolves into a pathogen in the host.

Project status : Closed

Mapping the genomic architecture of human neuroanatomical diversity

Our recent analyses suggest that the genetic determinants of human neuroanatomical diversity are massively polygenic. Like other quantitative traits such as height – but also IQ or ASD risk – neuroanatomical diversity seems to result from the aggregated effect of thousands of frequent variants, each of small effect. GWAS should then require populations of hundreds of thousands of individuals to start to detect the individual variants. GCTA (genomic complex trait analysis) offers an alternative approach to obtain valuable neurogenetic information despite the current impossibility to detect enough individual variants to explaining any substantial part of the variability. We are currently pooling together neuroimaging genomics data from multiple international projects (in particular, IMAGEN, ENIGMA, UK Biobank) to replicate and extend our earlier analyses. We aim to: (1) Compute the amount of variance captured by genome-wide SNPs (SNP-heritability) for the several brain regions: ICV, BV, Hip, Th, Ca, Pa, Pu, Amy and Acc, (2) Compute the matrix of SNP-based genetic correlation among structures, (3) Partition the variance captured by SNPs among structural and functional sets: per chromosome, genic vs non-genic, low/medium/high minor-allele frequency, positive/negative selection, involved or not in neurodevelopment, etc. (4) Compare our results with those obtained using GWAS-based estimations (for example, those used in ENIGMA2). GCTA requires the computation of matrices of genetic relationship among all individuals, and thus, direct access to the genotyping data. Once the matrices are computed, the genotyping data is no longer required, and it is not possible to reconstruct an individual's genome from the matrices. Our analysis of the IMAGEN cohort was based on 1,765 Individuals, which gave us sufficient statistical power (80%) to detect only strong heritabilities (h2~45%), and the estimations had very large standard errors (~20%). A cohort of 4,000 subjects should allow us to decrease the standard error to ~8% (80% power to detect h2=22%), and a cohort of 8,000 subjects should decrease it to ~4% (80% power to detect h2=11%). In this way, we could obtain more accurate estimates, but also detect eventually more subtle effects related to functional genomic partitions.   References Yang et al (2010) Common SNPs explain a large proportion of heritability for human height. Nature Genetics, doi: 10.1038/ng.608 Davies et al (2011) Genome-wide association studies establish that human intelligence is highly heritable and polygenic. Molecular Psychiatry, doi: 10.1038/mp.2011.85 Gaugler et al (2014) Most genetic risk for autism resides with common variation. Nature Genetics, doi: 10.1038/ng.3039 Wood et al (2014) Defining the role of common variation in the genomic and biological architecture of adult human height, doi: 10.1038/ng.3097

Project status : In Progress

The resurgence of a neglected disease, Yellow fever: from jungle to urban environments

Yellow fever virus (YFV), a Flavivirus transmitted by mosquitoes causes a severe hemorrhagic fever in humans. Despite the availability of a safe and effective vaccine (17D), YFV is still a public health problem in tropical Africa and South America. In the Americas, the massive campaign of mosquito control during the first half of the 20th century led to the eradication of Aedes aegypti from most American countries, and as a consequence, urban outbreaks of YF were no longer observed. However, the relaxation of vector control led to the reinfestation of urban areas by Ae. aegypti and the subsequent establishment of the Asian tiger mosquito Aedes albopictus. In Brazil, while human cases are sporadically detected in the Amazonian basin where sylvatic YFV strains circulate between non-human primates and arboreal canopy-dwelling mosquitoes (Haemagogus sp.), they are increasingly reported outside the jungle moving towards the Atlantic coast, the most populated area. In the absence of routine immunization programs, YF may come back in the American towns as it was in the past. The causes leading to the current YF resurgence are multifactorial. From a mosquito vector viewpoint, changes in vector densities, distribution, vector competence or vector as a site of selection for epidemic YFV strains, can be regarded as critical factors. Our project aims to address the contribution of the invasive mosquito Ae. albopictus as a missing link to allow a selvatic YF strain (1D) to become adapted for a transmission in urban areas by the human-biting mosquito, Ae. aegypti. It will be done through three specific objectives: (i) identify Ae. albopictus-adaptive mutations after serial cycling of the selvatic YFV-1D on Brazilian Ae. albopictus mosquitoes, (ii) evaluate their potential to be transmitted to a vertebrate host, and (iii) deepen the transmission of the experimentally selected viruses by field-collected mosquito populations.

Project status : Closed