References of "Georges, Michel"
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See detailDefining the genetic control of human blood plasma N-glycome using genome-wide association study.
Sharapov, Sodbo Zh; Tsepilov, Yakov A; Klaric, Lucija et al

in Human Molecular Genetics (2019), 28(12), 2062-2077

Glycosylation is a common post-translational modification of proteins. Glycosylation is associated with a number of human diseases. Defining genetic factors altering glycosylation may provide a basis for ... [more ▼]

Glycosylation is a common post-translational modification of proteins. Glycosylation is associated with a number of human diseases. Defining genetic factors altering glycosylation may provide a basis for novel approaches to diagnostic and pharmaceutical applications. Here we report a genome-wide association study of the human blood plasma N-glycome composition in up to 3811 people measured by Ultra Performance Liquid Chromatography (UPLC) technology. Starting with the 36 original traits measured by UPLC, we computed an additional 77 derived traits leading to a total of 113 glycan traits. We studied associations between these traits and genetic polymorphisms located on human autosomes. We discovered and replicated 12 loci. This allowed us to demonstrate an overlap in genetic control between total plasma protein and IgG glycosylation. The majority of revealed loci contained genes that encode enzymes directly involved in glycosylation (FUT3/FUT6, FUT8, B3GAT1, ST6GAL1, B4GALT1, ST3GAL4, MGAT3 and MGAT5) and a known regulator of plasma protein fucosylation (HNF1A). However, we also found loci that could possibly reflect other more complex aspects of glycosylation process. Functional genomic annotation suggested the role of several genes including DERL3, CHCHD10, TMEM121, IGH and IKZF1. The hypotheses we generated may serve as a starting point for further functional studies in this research area. [less ▲]

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See detailPresent and future impact of genomic information on Livestock production.
Georges, Michel ULiege; Charlier, Carole ULiege; Hayes, B.

in Nature Reviews. Genetics (2018)

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See detailMultiomics Analyses to Deliver the Most Effective Treatment to Every Patient With Inflammatory Bowel Disease.
Weersma, RK; Barrett, JC; Vermeire, S et al

in Gastroenterology. (2018), 155(5), 1-4

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See detailMONITORING METHOD FOR ADULT T-CELL LEUKEMIA/LYMPHOMA (ATL)
Georges, Michel ULiege; Van den Broeke, Anne; Durkin, Keith ULiege et al

Patent (2018)

The present invention refers to a method for preparing a linear PCR product from genomic DNA derived from cells of a host subject infected with an retrovirus or a subject suffering from a disease ... [more ▼]

The present invention refers to a method for preparing a linear PCR product from genomic DNA derived from cells of a host subject infected with an retrovirus or a subject suffering from a disease associated with said retrovirus, wherein the PCR product contains a target sequence comprising an integration site of the retrovirus in the host genomic DNA of the cells, said integration site comprising at least the terminal end of 3'-LTR or 5'-LTR sequence of the retrovirus and the adjacent host genomic DNA sequence, wherein the PCR product comprises a first terminus and a second terminus and sequences in the following order: sequences specific for the first terminus, a sequence comprising at least6 consecutive random nucleotides followed by a linker sequence, host genomic DNA sequence, at least the terminal endof 3'-LTR or 5' -LTR sequence of the retrovirus, sequences specific for the second terminus; wherein the PCR product is prepared by specific steps. The present invention also refers to a method for determining and longitudinally monitor the dominant leukemic T lymphocyte clone in subjects suffering from Adult T-cell leukemia/lymphoma (ATL), wherein a linear PCR product is prepared by the method according to the first aspect of the present invention, said PCR product is subjected to multiplex sequencing thereby determining all insertion sites and all shearing sites, the shearing sites are correlated to the respective insertion site, followed by counting the number of different shear sites for each insertion site representing a specific T lymphocyte clone, removing any PCR duplicate from consideration by eliminating reads that have the same insertion site and the same random tag, and determining the abundance of each specific T lymphocyte clone therefrom. [less ▲]

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See detailGenome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.
Waage, J.; Standl, M.; Curtin, J.A. et al

in Nature Genetics (2018), 50(8), 1072-1080

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See detailCodon-specific translation reprogramming promotes resistance to targeted therapy
Rapino, Francesca ULiege; Delaunay, Sylvain ULiege; Rambow, Florian et al

in Nature (2018), 558

Reprogramming of mRNA translation has a key role in cancer development and drug resistance. However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA ... [more ▼]

Reprogramming of mRNA translation has a key role in cancer development and drug resistance. However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA modifications are required for specific codon decoding during translation. Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U34) tRNA (U34 enzymes) are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAFV600E oncogene and by resistance to targeted therapy in melanoma. We show that BRAFV600E-expressing melanoma cells are dependent on U34 enzymes for survival, and that concurrent inhibition of MAPK signalling and ELP3 or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signalling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U34 enzymes. Mechanistically, U34 enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A mRNA and the maintenance of high levels of HIF1α protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U34 enzymes and HIF1α. Together, these results demonstrate that U34 enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation. [less ▲]

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See detailL'expérimentation animale ne se fait pas en dehors de tout contrôle (OPINION)
Muraille, Eric; de Kerchove d'Exaerde, Alban; Blanpain, Cedric et al

Article for general public (2018)

Proposer de réduire l'expérimentation animale pour raisons morales est louable. Mais ce choix de société ne doit pas être vendu au citoyen en lui laissant croire que la recherche conserverait la même ... [more ▼]

Proposer de réduire l'expérimentation animale pour raisons morales est louable. Mais ce choix de société ne doit pas être vendu au citoyen en lui laissant croire que la recherche conserverait la même qualité ou en serait améliorée. [less ▲]

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See detailHigh resolution mapping of cross-over events in cattle using NGS data
Kadri, Naveen Kumar ULiege; Harland, Chad; Charlier, Carole ULiege et al

in Proceedings of the World Congress on Genetics Applied to Livestock Production (2018, February 15)

High resolution mapping of cross-over events in cattle using NGS data Keywords: recombination, cattle, NGS Homologous recombination plays an important role in proper segregation of homologues in the first ... [more ▼]

High resolution mapping of cross-over events in cattle using NGS data Keywords: recombination, cattle, NGS Homologous recombination plays an important role in proper segregation of homologues in the first meiotic division. Failure in proper segregation results in aneuploidy, which is a leading cause for pregnancy loss in humans. Recently, global recombination rate has been studied in large cattle populations genotyped with SNP arrays ( 50K). However, the fine-scale resolution of these studies remained limited as a result of the relatively low marker density. Here we report high-resolution mapping of cross-over (CO) events in a cattle pedigree using whole genome sequence data. We carry out an extensive cleaning of our sequence data to remove errors (errors in the genome build, sequencing errors and presence of CNVs) that dramatically inflate CO counts. Using 5 million high quality sequence variants we identify 3,880 CO events in 155 male gametes and 3,088 CO events in 124 female gametes. The median resolution of the identified COs was 34 kb with about 70% of the events mapped to an interval less than 100 kb. The male and female map lengths were estimated at 27.5 M and 23.8 M respectively. Consistent with previous studies in cattle, we find higher recombination rate in males and higher frequency of COs at chromosome ends. Interestingly, compared to the map lengths estimated from SNP chip we find an increase of 3.7 and 2.7 M in male and female maps respectively. Despite the cleaning efforts, we cannot determine at this time whether the increased in map lengths correspond to CO missed with genotyping arrays, to spurious CO identified with NGS data (due to unidentified sources of errors) or both. [less ▲]

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See detailImproving the bioinformatics analysis of HTS clonality data in virus-induced leukemia
Hahaut, Vincent ULiege; Rosewick, Nicolas; Artesi, Maria ULiege et al

Poster (2018, February 02)

Proviral integration into the host genome is one of the main hallmarks of infection by oncogenic retroviruses. This event creates a life-long signature, each infected cell being characterized by a ... [more ▼]

Proviral integration into the host genome is one of the main hallmarks of infection by oncogenic retroviruses. This event creates a life-long signature, each infected cell being characterized by a specific integration site (IS). Monitoring of the clonal architecture over time (clone: population of cells sharing an identical IS) has significantly contributed to a better understanding of HIV persistence, gene therapy vector mediated treatment and deltaretrovirus-induced leukemia. Our lab recently developed an optimized high-throughput sequencing (HTS) based clonality method. It enables the identification of proviral integration sites genome-wide while simultaneously quantifying the abundance of the corresponding clones. The method is superior to any of the previously available protocols, mainly in terms of sensitivity, cost-effectiveness and hands-on time, making it suitable for routine clinical observation of infected individuals. Using this method, we recently showed that longitudinal monitoring of the dominant leukemic clone in patients infected by Human T-cell Leukemia Virus-1 (HTLV-1) better predicts therapeutic response (Artesi et al, Leukemia, 2017). We applied the method to biological samples isolated from HTLV-1 infected patients and Bovine Leukemia Virus (BLV) infected animals (bovine and sheep). This resulted in the generation of an unprecedented volume of raw sequence data. In this study we developed a novel clonality analysis pipeline that better exploits the potential of the method, improving previously published protocols. [less ▲]

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See detailHarnessing genomic information for livestock improvement.
Georges, Michel ULiege; Charlier, Carole ULiege; Hayes, Ben

in Nature Reviews. Genetics (2018)

The world demand for animal-based food products is anticipated to increase by 70% by 2050. Meeting this demand in a way that has a minimal impact on the environment will require the implementation of ... [more ▼]

The world demand for animal-based food products is anticipated to increase by 70% by 2050. Meeting this demand in a way that has a minimal impact on the environment will require the implementation of advanced technologies, and methods to improve the genetic quality of livestock are expected to play a large part. Over the past 10 years, genomic selection has been introduced in several major livestock species and has more than doubled genetic progress in some. However, additional improvements are required. Genomic information of increasing complexity (including genomic, epigenomic, transcriptomic and microbiome data), combined with technological advances for its cost-effective collection and use, will make a major contribution. [less ▲]

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See detailIBD risk loci are enriched in multigenic regulatory modules encompassing causative genes
Yukihide, Momozawa; Dmitrieva, Joelia Borisovna ULiege; Theatre, Emilie ULiege et al

in Nature Communications (2018)

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that ... [more ▼]

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome dataset (9 disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9,720 regulatory modules, of which ∼3,000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that are driveing the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. We resequence 45 of the corresponding 100 candidate genes in 6,600 Crohn disease (CD) cases and 5,500 controls and show that they are significantly enriched in causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using standard burden tests. [less ▲]

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See detailAnalysis of Genes Associated With Monogenic Primary Immunodeficiency Identifies Rare Variants in XIAP in Patients With Crohn's Disease.
Amininejad, Leila; Charloteaux, Benoît ULiege; Theatre, Emilie ULiege et al

in Gastroenterology (2018), 154(8), 2165-2177

BACKGROUND & AIMS: A few rare monogenic primary immunodeficiencies (PIDs) are characterized by chronic intestinal inflammation that resembles Crohn's disease (CD). We investigated whether 23 genes ... [more ▼]

BACKGROUND & AIMS: A few rare monogenic primary immunodeficiencies (PIDs) are characterized by chronic intestinal inflammation that resembles Crohn's disease (CD). We investigated whether 23 genes associated with 10 of these monogenic disorders contain common, low-frequency, or rare variants that increase risk for CD. METHODS: Common and low frequency variants in 1 Mb loci centered on the candidate genes were analyzed using meta-data corresponding to genotypes of approximately 17,000 patients with CD or without CD (controls) in Europe. The contribution of rare variants was assessed by high-throughput sequencing of 4750 individuals, including 660 early-onset and/or familial cases among the 2390 patients with CD. Variants were expressed from vectors in SW480 or HeLa cells and functions of their products were analyzed in immunofluorescence, luciferase, immunoprecipitation, and immunoblot assays. RESULTS: We reproduced the association of the interleukin 10 locus with CD (P = .007), although none of the significantly associated variants modified the coding sequence of interleukin 10. We found XIAP to be significantly enriched for rare coding mutations in patients with CD vs controls (P = .02). We identified 4 previously unreported missense variants associated with CD. Variants in XIAP cause the PID X-linked lymphoproliferative disease type 2, yet none of the carriers of these variants had all the clinical features of X-linked lymphoproliferative disease type 2. Identified XIAP variants S123N, R233Q, and P257A were associated with an impaired activation of NOD2 signaling after muramyl dipeptide stimulation. CONCLUSIONS: In a systematic analysis of variants in 23 PID-associated genes, we confirmed the association of variants in XIAP with CD. Further screenings for CD-associated variants and analyses of their functions could increase our understanding of the relationship between PID-associated genes and CD pathogenesis. [less ▲]

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See detailCCDC88B is required for pathogeneisis of inflammatory bowel disease.
Fodil, N.; Moradin, N.; Yeretssian, G. et al

in Nature Communications (2017), 8(1), 932

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See detailThe Landscape And Evolution Of Somatic Mutations In Bovine Leukemia Virus Induced Tumors
Durkin, Keith ULiege; Artesi, Maria ULiege; Hahaut, Vincent ULiege et al

Conference (2017, September 21)

Bovine Leukemia Virus (BLV) is a deltaretrovirus that integrates into B-cells producing a lifelong infection in cattle. Like its close relative Human T-cell leukemia virus-1 (HTLV-1), BLV induces an ... [more ▼]

Bovine Leukemia Virus (BLV) is a deltaretrovirus that integrates into B-cells producing a lifelong infection in cattle. Like its close relative Human T-cell leukemia virus-1 (HTLV-1), BLV induces an aggressive leukemia/lymphoma in about ~5% of infected individuals. While not a natural host it is possible to infect sheep with BLV and in contrast to cattle, all infected sheep develop tumors at an accelerated rate (~18 months). Historically research into both viruses has primarily focused on their transcripts/proteins. However secondary somatic events are likely to be important as only a subset of infected individuals, following many decades of infection, develop a tumor. At the current time little is known about the landscape of somatic changes in BLV induced tumors and the timing of their occurrence. To address this we have carried out whole genome sequencing of BLV induced tumors from two cattle, and from five sheep with matched normal tissue. This revealed frequent aneuploidy, with orthologous regions of the genome involved in both species and elevated mitochondria DNA copy numbers in tumors. Recurrent structural variants (SVs) were seen affecting the tumor suppressors CDKN2A and ARID1A, both on OAR2. On average ~1400 somatic SNVs were observed in each ovine tumor, with high/moderate impact variants in known cancer drivers genes such as KMT2A, ATRX, RPL22 and KRAS. The five sheep were also sampled at regular time points, prior to leukemia onset, allowing us to examine tumor clone evolution. High throughput sequencing of proviral integration sites showed that the tumor clone represents only a small fraction of the infected cells for the majority of the disease, only expanding rapidly in the terminal stages. Low coverage sequencing of samples prior to tumor development indicates that aneuploidy of OAR9 is a feature of the majority of BLV infected clones. Preliminary nested PCR also showed that many SVs were present prior to tumor development. High throughput approaches are being developed to track both SVs and SNV in the preleukemic stages of the disease. [less ▲]

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See detailIdentification and management of recessive genetic defects in Belgian Blue beef cattle
Druet, Tom ULiege; Sartelet, Arnaud ULiege; Hubin, Xavier et al

Conference (2017, August)

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See detailSomatic Structural And Numerical Aberrations In Bovine Leukemia Virus Induced Tumors
Durkin, Keith ULiege; Artesi, Maria ULiege; Hahaut, Vincent ULiege et al

Poster (2017, July)

Bovine Leukemia Virus (BLV) is a deltaretrovirus that integrates into B-cells producing a lifelong infection in cattle. Like its close relative Human T-cell leukemia virus-1 (HTLV-1), BLV induces an ... [more ▼]

Bovine Leukemia Virus (BLV) is a deltaretrovirus that integrates into B-cells producing a lifelong infection in cattle. Like its close relative Human T-cell leukemia virus-1 (HTLV-1), BLV induces an aggressive leukemia/lymphoma in about ~5% of infected individuals. While not a natural host it is possible to infect sheep with BLV and in contrast to cattle, all infected sheep develop tumors at an accelerated rate (~18 months). Historically research into both viruses has primarily focused on their transcripts/proteins. However secondary events are likely to be important as only a subset of infected individuals, following many decades of infection, develop a tumor. At the current time little is known about the landscape of somatic changes in BLV induced tumors. To examine gross numerical and structural variants (SVs) we assayed 12 bovine tumors on the BovineSNP50 Illumina BeadChip as well as 22 ovine tumors on the OvineSNP50 Illumina BeadChip. We also carried out whole genome sequencing (~30X) on 4 ovine tumors with matched normal tissue. Initial examination of the tumors revealed frequent aneuploidy, with orthologous regions of the genome involved in both species. Focal SVs identified included an amplification (>4 copies) of the terminus of BTA16 in three tumors (contains PTPRC & miR-181), while the tumor suppressor CDKN2A on OAR2 was deleted in multiple ovine tumors. For the 4 sequenced tumors multiple time points over the course of infection were available allowing us to determine when these SVs arose via nested PCR. Interestingly we observed that the SVs involving well know cancer driver genes generally appear many months prior to tumor development. These preliminary results indicate that tumors induced by HTLV-1 and BLV display somatic structural changes that impinge on overlapping sets of genes and point to the emergence of SVs affecting cancer driver genes in the preleukemic clone, well before the clone undergoes rapid expansion. [less ▲]

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See detailCis-perturbation of cancer drivers by the HTLV-1/BLV proviruses is an early determinant of leukemogenesis
Rosewick, Nicolas; Durkin, Keith ULiege; Artesi, Maria ULiege et al

in Nature Communications (2017), 8

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