References of "Georges, Michel"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailMapping the human genetic architecture of COVID-19 by worldwide meta-analysis
The COVID-19 Host Genetics Initiative; Rahmouni, Souad ULiege; Georges, Michel ULiege et al

in Nature (in press)

The genetic makeup of an individual contributes to susceptibility and response to viral infection. While environmental, clinical and social factors play a role in exposure to SARS-CoV-2 and COVID-19 ... [more ▼]

The genetic makeup of an individual contributes to susceptibility and response to viral infection. While environmental, clinical and social factors play a role in exposure to SARS-CoV-2 and COVID-19 disease severity, host genetics may also be important. Identifying host-specific genetic factors indicate biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-COV-2 infection and COVID-19 severity. We describe the results of three genome-wide association meta-analyses comprising up to 49,562 COVID-19 patients from 46 studies across 19 countries worldwide. We reported 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases. They also represent potentially actionable mechanisms in response to infection. We further identified smoking and body mass index as causal risk factors for severe COVID-19. The identification of novel host genetic factors associated with COVID-19, with unprecedented speed, was enabled by prioritization of shared resources and analytical frameworks. This working model of international collaboration provides a blue-print for future genetic discoveries in the event of pandemics or for any complex human disease. [less ▲]

Detailed reference viewed: 208 (20 ULiège)
See detailEvidence for inter-individual variation of ERV de novo transposition rate in the male cattle germline
Tang, Lijing ULiege; Harland, Chad; Durkin, Keith ULiege et al

Conference (2021, May 11)

Endogenous retrovirus (ERVs) is a component of mammalian genome, which records evolutionary fossils left over from ancient viral infections. Most ERVs have lost their mobilisation capacity due to ... [more ▼]

Endogenous retrovirus (ERVs) is a component of mammalian genome, which records evolutionary fossils left over from ancient viral infections. Most ERVs have lost their mobilisation capacity due to mutational accumulation and inter-LTR recombination, but some ERVs are still transpositionally active in germlines in some species. By mining a dataset of whole-genome sequences for 131 extended cattle pedigrees, we identified 5 de novo transpositions (dnT) from same ERV subfamily. Thus, the ERV dnT rate (dnTR) can be roughly estimated at 1 new insertion every ~50 gametes, yet with major differences between individuals (as 3 from the 5 detected events occurred in the same animal). To allow us to quantify the inter-individual variation in dnTR, we modified a method (Pooled CRISPR Inverse PCR sequencing: PCIP-seq) initially developed to detect somatic retroviral insertions (Artesi et al, 2021). The features of this method: I) CRISPR-based; II) UMI-like; III) natural replicates; IV) NGS-based; enable the measurements on individual dnRT reproducible and robust. By applying this approach to sperm samples from a cohort of sire with similar age, dnTR was quantified in the range from 0.23 to 2.07 with an average of 1.2 per 100 gametes, which keeps in line with the rate assessed in pedigrees. Moreover, we applied this method to sperm samples of 9 sires sampling at two ages cross about 10 years, no significant inflation of dnTR observed with age. However, a fraction of dnT were identified in two ages, which means sperms with recurrent insertions originated from clone of same spermatogonial stem cell (SSC), indicating those transposition events have been occurred before or during SSC establishment. Intriguingly, dnRT of mature testis is at least one to two magnitude higher than rate of sperm with same age, speculating a process involving harsh checkpoint to filter out sperms with too many dnT to guard integrity of genetic transmission. [less ▲]

Detailed reference viewed: 33 (8 ULiège)
See detailLIVE (EPI)GENOMIC BATTLE BETWEEN UNFIXED TRANSPOSABLE ELEMENTS AND THEIR COGNATE piRNA CLUSTERS IN CATTLE TESTES
Costa Monteiro Moreira, Gabriel ULiege; Tang, Lijing ULiege; Dupont, Sébastien ULiege et al

Conference (2021)

Transposable elements (TE) can affect genomic stability, gene function and trigger deleterious mutations. PIWI-interacting small RNAs (piRNAs) are known as important soldiers standing in the arms race ... [more ▼]

Transposable elements (TE) can affect genomic stability, gene function and trigger deleterious mutations. PIWI-interacting small RNAs (piRNAs) are known as important soldiers standing in the arms race against TE mobilization in the germline. We previously demonstrated that several TE families are still active in present-day cattle breeds, including endogenous retroviruses (ERV), long and short interspersed repeats (LINE and SINE) and pseudogenes. We have collected testes samples from sexually immature (9 neonate; 100 juvenile = pre-pachytene stage) and mature (100 adult = pachytene stage) animals. piRNA and mRNA libraries were built for a subset of animals with different ages and reads were mapped to the ARS- UCD1.2 bovine reference. From the TE side, we established a catalogue of polymorphic (unfixed) ERV, LINE and processed pseudogenes in cattle, mining whole-genome sequencing data available from different breeds (n>1000). Intersecting piRNA data with our catalogue of TE insertions, we observed higher expression of piRNAs nearby ERVs, LINE and pseudogenes in pre-pachytene animals compared to pachytene animals. Combining TE insertion genotypes with the piRNA normalised counts, we detected polymorphic piRNA clusters directly driven by recent TE insertions. For all the three TE classes, manual inspection allowed us to indeed identify striking instances of births of new, allele-specific (cis), polymorphic piRNA clusters. Especially for pseudogenes, we identified polymorphic insertions driving piRNA clusters putatively affecting the corresponding parent gene expression in trans. We are performing an eQTL study based on TE genotypes and testis mRNA data to investigate the putative effect of polymorphic piRNA clusters on gene expression. Latest results will be presented. [less ▲]

Detailed reference viewed: 21 (3 ULiège)
See detailPedigree-based de novo rate estimation for structural variation in the cattle germline
Young-Lim, Lee; Costa Monteiro Moreira, Gabriel ULiege; Karim, Latifa ULiege et al

Poster (2021)

De novo mutations (dnm’s) are an important source of genetic diversity and hold paramount significance in understanding evolution and disease genetics. Although dnm’s are often assumed to arise from ... [more ▼]

De novo mutations (dnm’s) are an important source of genetic diversity and hold paramount significance in understanding evolution and disease genetics. Although dnm’s are often assumed to arise from parental germline, recent studies revealed that a significant proportion of the de novo single-nucleotide variants (dnSNVs) arose during early development, resulting in mosaicism. Structural variations, including deletions, duplications, and inversions, are expected to affect more base-pairs of the genomes than SNVs, due to their larger event size. Nevertheless, the rate of de novo structural variations (dnSVs), and the degree of post-zygotic dnSVs in cattle has not been investigated. Here, we exploited multi-generational pedigrees, where 131 deeply sequenced Dutch Holstein Friesian cattle trios are complemented with large half-sibs and grand-offspring data. Overall, we identified 21 dnSVs (16 deletions, 5 duplications, 1 inversion), in a size range of 56bp to 1.2Mb. Of these, 17 were late germline dnSVs, unravelling the germline dnSV rate of 0.13 dnSV per generation (95% CI 0.07-0.19; 1 dnSV per 7.7 births). Strikingly, 16 out of 17 of the germline dnSVs were of paternal origin, underlining male germlines as a main contributor for bovine dnSVs. Furthermore, we found 4 mosaic dnSVs, accounting for nearly ~20% of the total dnSVs, confirming previous report in bovine dnSNVs. Using the allelic imbalance in the offspring and imperfect linkage in the grand-offspring, we concluded that all mosaic dnSVs arouse in early cleavage cell divisions, before the primordial germ cell specification, hence affecting both germline and somatic tissues. Our study highlights the value of unique bovine pedigree structure for genetics studies. [less ▲]

Detailed reference viewed: 49 (2 ULiège)
Full Text
Peer Reviewed
See detailWobble tRNA modification and hydrophilic amino acid patterns dictate protein fate.
Rapino, Francesca ULiege; ZHOU, ZHAOLI; RONCERO SANCHEZ, Ana Maria et al

in Nature Communications (2021), 12(1), 2170

Regulation of mRNA translation elongation impacts nascent protein synthesis and integrity and plays a critical role in disease establishment. Here, we investigate features linking regulation of codon ... [more ▼]

Regulation of mRNA translation elongation impacts nascent protein synthesis and integrity and plays a critical role in disease establishment. Here, we investigate features linking regulation of codon-dependent translation elongation to protein expression and homeostasis. Using knockdown models of enzymes that catalyze the mcm(5)s(2) wobble uridine tRNA modification (U(34)-enzymes), we show that gene codon content is necessary but not sufficient to predict protein fate. While translation defects upon perturbation of U(34)-enzymes are strictly dependent on codon content, the consequences on protein output are determined by other features. Specific hydrophilic motifs cause protein aggregation and degradation upon codon-dependent translation elongation defects. Accordingly, the combination of codon content and the presence of hydrophilic motifs define the proteome whose maintenance relies on U(34)-tRNA modification. Together, these results uncover the mechanism linking wobble tRNA modification to mRNA translation and aggregation to maintain proteome homeostasis. [less ▲]

Detailed reference viewed: 39 (15 ULiège)
Full Text
Peer Reviewed
See detailPCIP-seq: simultaneous sequencing of integrated viral genomes and their integration sites with long reads
Artesi, Maria ULiege; Hahaut, Vincent ULiege; Cole, Basiel et al

in Genome Biology (2021), 22

Detailed reference viewed: 27 (12 ULiège)
Full Text
Peer Reviewed
See detailNew approach to determine the healthy immune variations by combining clustering methods
Lieferinckx, Claire; De Grève, Zacharie; Toubeau, Jean‑François et al

in Scientific Reports (2021), 11

Immune-mediated infammatory diseases are characterized by variability in disease presentation and severity but studying it is a challenging task. Defning the limits of a healthy immune system is therefore ... [more ▼]

Immune-mediated infammatory diseases are characterized by variability in disease presentation and severity but studying it is a challenging task. Defning the limits of a healthy immune system is therefore a prior step to capture variability in disease conditions. The goal of this study is to characterize the global immune cell composition along with their infuencing factors. Blood samples were collected from 2 independent cohorts of respectively 389 (exploratory) and 208 (replication) healthy subjects. Twelve immune cells were measured in blood together with biological parameters. Three complementary clustering approaches were used to evaluate if variability related to the immune cells could be characterized as clusters or as a continuum. Large coefcients of variation confrmed the inter-individual variability of immune cells. Considering all subset variations in an overall analysis, it appeared that the immune makeup was organized as a continuum through the two cohorts. Some intrinsic and environmental factors afected the inter-individual variability of cells but without unveiling separable groups with similar features. This study provides a framework based on complementary clustering approach for analyzing inter-individual variability of immune cells. Our analyses support the absence of clusters in our two healthy cohorts. Also, our study reports some infuence of age, gender, BMI, cortisol, season and CMV infection on immune variability [less ▲]

Detailed reference viewed: 27 (6 ULiège)
Full Text
Peer Reviewed
See detailCRELD1 modulates homeostasis of the immune system in mice and humans
Bonaguro, Lorenzo; Köhne, Maren; Schmidleithner, Jonas et al

in Nature Immunology (2020), 12

CRELD1 is a pivotal factor for heart development, the function of which is unknown in adult life. We here provide evidence that CRELD1 is an important gatekeeper of immune system homeostasis. Exploiting ... [more ▼]

CRELD1 is a pivotal factor for heart development, the function of which is unknown in adult life. We here provide evidence that CRELD1 is an important gatekeeper of immune system homeostasis. Exploiting expression variance in large human cohorts contrasting individuals with the lowest and highest CRELD1 expression levels revealed strong phenotypic, functional and transcriptional differences, including reduced CD4+ T cell numbers. These findings were validated in T cell-specific Creld1-deficient mice. Loss of Creld1 was associated with simultaneous overactivation and increased apoptosis, resulting in a net loss of T cells with age. Creld1 was transcriptionally and functionally linked to Wnt signaling. Collectively, gene expression variance in large human cohorts combined with murine genetic models, transcriptomics and functional testing defines CRELD1 as an important modulator of immune homeostasis. [less ▲]

Detailed reference viewed: 29 (1 ULiège)
See detailFine resolution CNV catalogue from deeply sequenced cattle genomes
Lee, Young-Lim; Takeda, Haruko ULiege; Costa Monteiro Moreira, Gabriel ULiege et al

Conference (2020, December 02)

Detailed reference viewed: 51 (18 ULiège)
See detailINTER-INDIVIDUAL VARIATION OF DE NOVO ERV TRANSPOSITION RATE IN THE CATTLE GERMLINE
Tang, Lijing ULiege; Harland, Chad; Durkin, Keith ULiege et al

Poster (2020, October 06)

By studying a lethal recessive disease (cholesterol deficiency in Holstein-Friesian cattle breed), we recently discovered a family of endogenous retroviruses (ERV) still active in present-day cattle ... [more ▼]

By studying a lethal recessive disease (cholesterol deficiency in Holstein-Friesian cattle breed), we recently discovered a family of endogenous retroviruses (ERV) still active in present-day cattle populations. To study the inter-individual variation of ERV de novo transposition rate (dnTR), we first used a pedigree-based method. As part of a larger project aimed at studying germline de novo mutation rate (Damona project), we generated a dataset of whole-genome sequences for 131 extended trios ((grand-) parents, proband and at least 5 grand-offspring). Here we mined them specifically for germline de novo ERV insertions - defined as insertions (i) detected in the proband, (ii) absent from its parents and (iii) transmitted to the next generation. Five de novo insertions were identified: 1 of maternal origin, 4 paternal, including 3 from the same sire and 2 within the same sperm cell. Thus, the ERV dnTR can be roughly estimated at 1 new insertion every ~50 gametes, yet with major differences between individuals (as 3 from the 5 detected events occurred in the same animal). To allow us to increase the number of studied gametes, we modified a method (Pooled CRISPR Inverse PCR sequencing: PCIP-seq) initially developed to detect somatic retroviral insertions (Artesi et al, 2020). We optimized it to directly locate and quantify de novo ERV insertional events in the male germline (sperm DNA). We are currently applying it to a large cohort of sires (n > 200). The resulting normalized sire-specific dnTR will be treated as a quantitative molecular phenotype to perform a genome-wide association study in order to pinpoint genomic loci influencing ERV dnTR in the cattle germline. This new quantitative method can easily be adapted to other families of active transposable elements in livestock. [less ▲]

Detailed reference viewed: 23 (3 ULiège)
Full Text
Peer Reviewed
See detailAlzheimer’s disease genetic risk and sleep phenotypes: association with more slow-waves and daytime sleepiness
Muto, Vincenzo ULiege; Koshmanova, Ekaterina ULiege; Ghaemmaghami Tabrizi, Pouya ULiege et al

in Sleep (2020)

Study objectives: Sleep disturbances and genetic variants have been identified as risk factors for Alzheimer's disease. Our goal was to assess whether genome-wide polygenic risk scores (PRS) for AD ... [more ▼]

Study objectives: Sleep disturbances and genetic variants have been identified as risk factors for Alzheimer's disease. Our goal was to assess whether genome-wide polygenic risk scores (PRS) for AD associate with sleep phenotypes in young adults, decades before typical AD symptom onset. Methods: We computed whole-genome Polygenic Risk Scores (PRS) for AD and extensively phenotyped sleep under different sleep conditions, including baseline sleep, recovery sleep following sleep deprivation and extended sleep opportunity, in a carefully selected homogenous sample of healthy 363 young men (22.1 y ± 2.7) devoid of sleep and cognitive disorders. Results: AD PRS was associated with more slow wave energy, i.e. the cumulated power in the 0.5-4 Hz EEG band, a marker of sleep need, during habitual sleep and following sleep loss, and potentially with large slow wave sleep rebound following sleep deprivation. Furthermore, higher AD PRS was correlated with higher habitual daytime sleepiness. Conclusions: These results imply that sleep features may be associated with AD liability in young adults, when current AD biomarkers are typically negative, and the notion that quantifying sleep alterations may be useful in assessing the risk for developing AD. [less ▲]

Detailed reference viewed: 96 (23 ULiège)
See detailBIRTH OF POLYMORPHIC PIRNA CLUSTERS DRIVEN BY TRANSPOSABLE ELEMENT INSERTIONS IN THE MALE CATTLE GERMLINE
Costa Monteiro Moreira, Gabriel ULiege; Tang, Lijing ULiege; Dupont, Sébastien ULiege et al

Poster (2020)

We aim at studying the two sides of the same coin: (i) one major line of host defense against the mobilization of transposable elements (TE): the PIWI-interacting RNA (piRNA) pathway and (ii) the activity ... [more ▼]

We aim at studying the two sides of the same coin: (i) one major line of host defense against the mobilization of transposable elements (TE): the PIWI-interacting RNA (piRNA) pathway and (ii) the activity of TE in the bovine germline. We previously demonstrated that several TE families are still active in present-day cattle breeds. These include endogenous retroviruses (ERV), long and short interspersed repeats (LINE and SINE) and processed pseudogenes. We have collected testes samples from sexually immature (pre-pachytene stage; n=100) and mature (pachytene stage; n=100) animals. From the host defense side, we are sequencing oxidized piRNA libraries, reads are mapped to the ARS-UCD1.2 bovine reference sequence and piRNA clusters are annotated using proTRAC (Rosenkranz & Zischler, 2012). From the TE side, we developed a bioinformatics tool to mine available whole genome sequences (WGS; n>1000) of the corresponding breeds to establish a catalog of polymorphic (unfixed) TE segregating in these breeds. Custom, array-based, genotyping assays, targeting insertion sites, are developed to directly genotype our testes collection. We will integrate piRNA and TE genotyping data to establish the degree of interplay between host defense and young TE to answer the following question: are unfixed piRNA clusters directly driven by recent TE insertions? Preliminary data on pre-pachytene testes with matched WGS, piRNA and mRNA sequences allowed us to indeed identify striking instances of births of new, allele-specific, polymorphic piRNA clusters derived from unfixed (i) ERVK, (ii) LINE1 and (iii) processed pseudogene intronic insertions. Latest results will be presented. [less ▲]

Detailed reference viewed: 28 (7 ULiège)
Full Text
Peer Reviewed
See detailAn Improved Sequencing-Based Bioinformatics Pipeline to Track the Distribution and Clonal Architecture of Proviral Integration Sites
Rosewick, Nicolas; Hahaut, Vincent ULiege; Durkin, Keith ULiege et al

in Frontiers in Microbiology (2020), 11

Detailed reference viewed: 30 (6 ULiège)
Full Text
Peer Reviewed
See detailGlycosylation of immunoglobulin G is regulated by a large network of genes pleiotropic with inflammatory diseases.
Klarić, Lucija; Tsepilov, Yakov A.; Stanton, Chloe M. et al

in Science Advances (2020), 6(8), 0301

Effector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in many ... [more ▼]

Effector functions of immunoglobulin G (IgG) are regulated by the composition of a glycan moiety, thus affecting activity of the immune system. Aberrant glycosylation of IgG has been observed in many diseases, but little is understood about the underlying mechanisms. We performed a genome-wide association study of IgG N-glycosylation (N = 8090) and, using a data-driven network approach, suggested how associated loci form a functional network. We confirmed in vitro that knockdown of IKZF1 decreases the expression of fucosyltransferase FUT8, resulting in increased levels of fucosylated glycans, and suggest that RUNX1 and RUNX3, together with SMARCB1, regulate expression of glycosyltransferase MGAT3. We also show that variants affecting the expression of genes involved in the regulation of glycoenzymes colocalize with variants affecting risk for inflammatory diseases. This study provides new evidence that variation in key transcription factors coupled with regulatory variation in glycogenes modifies IgG glycosylation and has influence on inflammatory diseases. [less ▲]

Detailed reference viewed: 28 (1 ULiège)
Full Text
Peer Reviewed
See detailGenetic architecture of individual variation in recombination rate on the X chromosome in cattle.
Zhang, Junjie; Kadri, Naveen Kumar ULiege; Mullaart, Erik et al

in Heredity (2020), 125(5), 304-316

Meiotic recombination is an essential biological process that ensures proper chromosome segregation and creates genetic diversity. Individual variation in global recombination rates has been shown to be ... [more ▼]

Meiotic recombination is an essential biological process that ensures proper chromosome segregation and creates genetic diversity. Individual variation in global recombination rates has been shown to be heritable in several species, and variants significantly associated with this trait have been identified. Recombination on the sex chromosome has often been ignored in these studies although this trait may be particularly interesting as it may correspond to a biological process distinct from that on autosomes. For instance, recombination in males is restricted to the pseudo-autosomal region (PAR). We herein used a large cattle pedigree with more than 100,000 genotyped animals to improve the genetic map of the X chromosome and to study the genetic architecture of individual variation in recombination rate on the sex chromosome (XRR). The length of the genetic map was 46.4 and 121.2 cM in males and females, respectively, but the recombination rate in the PAR was six times higher in males. The heritability of CO counts on the X chromosome was comparable to that of autosomes in males (0.011) but larger than that of autosomes in females (0.024). XRR was highly correlated (0.76) with global recombination rate (GRR) in females, suggesting that both traits might be governed by shared variants. In agreement, a set of eleven previously identified variants associated with GRR had correlated effects on female XRR (0.86). In males, XRR and GRR appeared to be distinct traits, although more accurate CO counts on the PAR would be valuable to confirm these results. [less ▲]

Detailed reference viewed: 34 (2 ULiège)
See detailAlzheimer s disease genetic risk and sleep phenotypes: association with more slow-waves and daytime sleepiness
Muto, Vincenzo ULiege; Koshmanova, Ekaterina ULiege; Ghaemmaghami, Pouya  et al

E-print/Working paper (2020)

Detailed reference viewed: 73 (18 ULiège)