Evidence After Imputation for a Role of MICA Variants in Nonprogression and Elite Control of HIV Type 1 Infection

Past genome-wide association studies (GWAS) involving individuals with AIDS have mainly identified associations in the HLA region. Using the latest software, we imputed 7 million single-nucleotide polymorphisms (SNPs)/indels of the 1000 Genomes Project from the GWAS-determined genotypes of individuals in the Genomics of Resistance to Immunodeficiency Virus AIDS nonprogression cohort and compared them with those of control cohorts. The strongest signals were in MICA, the gene encoding major histocompatibility class I polypeptide-related sequence A (P = 3.31 × 10−12), with a particular exonic deletion (P = 1.59 × 10−8) in full linkage disequilibrium with the reference HCP5 rs2395029 SNP. Haplotype analysis also revealed an additive effect between HLA-C, HLA-B, and MICA variants. These data suggest a role for MICA in progression and elite control of human immunodeficiency virus type 1 infectio

Maintenance of Miranda Localization in <i>Drosophila</i> Neuroblasts Involves Interaction with the Cognate mRNA

International audienc

Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders.

Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called episignatures ). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders

New Insights Into the Long Non-coding RNA SRA:Physiological Functions and Mechanisms of Action

Long non-coding RNAs (lncRNA) are emerging as new genetic/epigenetic regulators that can impact almost all physiological functions. Here, we focus on the long non-coding steroid receptor RNA activator (SRA), including new insights into its effects on gene expression, the cell cycle, and differentiation; how these relate to physiology and disease; and the mechanisms underlying these effects. We discuss how SRA acts as an RNA coactivator in nuclear receptor signaling; its effects on steroidogenesis, adipogenesis, and myocyte differentiation; the impact on breast and prostate cancer tumorigenesis; and, finally, its ability to modulate hepatic steatosis through several signaling pathways. Genome-wide analysis reveals that SRA regulates hundreds of target genes in adipocytes and breast cancer cells and binds to thousands of genomic sites in human pluripotent stem cells. Recent studies indicate that SRA acts as a molecular scaffold and forms networks with numerous coregulators and chromatin-modifying regulators in both activating and repressive complexes. We discuss how modifications to SRA's unique stem-loop secondary structure are important for SRA function, and highlight the various SRA isoforms and mutations that have clinical implications. Finally, we discuss the future directions for better understanding the molecular mechanisms of SRA action and how this might lead to new diagnostic and therapeutic approaches

Regulatory feedback from nascent RNA to chromatin and transcription

Transcription and chromatin function are regulated by proteins that bind to DNA, nucleosomes or RNA polymerase II, with specific non-coding RNAs (ncRNAs) functioning to modulate their recruitment or activity. Unlike ncRNAs, nascent pre-mRNA was considered to be primarily a passive player in these processes. In this Opinion article, we describe recently identified interactions between nascent pre-mRNAs and regulatory proteins, highlight commonalities between the functions of nascent pre-mRNA and nascent ncRNA, and propose that both types of RNA have an active role in transcription and chromatin regulation

Metropolitan Areas Growing and Under Stress: The Situation of the Detroit Public Library

published or submitted for publicatio

Analyse génomique de la coinfection par le virus VIH et VHC

Over 170 million people worldwide are infected by HCV and 37 million by HIV. Both viruses share the same modes of transmission, and HIV/HCV coinfection is common and represents a key element in the management of patients infected with HIV. Since the appearance of HAART, liver diseases have become the leading cause of death in HIV/HCV coinfected patients. The natural history and prognosis of hepatitis C are more severe in case of coinfection with HIV due to accelerated rate of fibrosis progression and rapid progression to cirrhosis and its complications. Factors accelerating liver fibrosis are known today such as the lack of recourse to anti-HCV treatment, active HCV replication and excessive alcohol consumption. There is increasing evidence that genetic variants contribute to liver fibrosis in HCV monoinfection, but this aspect has been little studied in HIV/HCV coinfection.I have exploited the genotype information from 494 coinfected patients from the cohort ANRS CO13 HEPAVIH. These patients are very-well documented regarding the history of their HIV/HCV infection and are very carefully followed-up, especially regarding the status of liver fibrosis. I have performed two genome-wide association studies to identify polymorphisms associated with the severity of fibrosis from complete data of 292 patients. The first study has dealt with the quantification of liver stiffness by Fibroscan® and an association with the 3p25 region has been identified, also replicated in monoinfection HCV. Two genes involved in cell signaling and structure of holding mechanisms (CAV3) but also in HCV replication (RAD18) appear as good candidates. The second study has unraveled two significant associations by comparing the METAVIR score group (F0F1F2 vs F3F4), especially in the CTNND2 gene implicated in a network of interactions with molecular mechanisms involved in liver diseases.These results are under publications in peer-review international scientific journals. These new insights into the molecular mechanisms of liver fibrosis in patients with HIV/HCV co- infection may help to define new targets for drug development or new diagnostic tests, to improve patient care.Plus de 170 millions d'individus sont infectés par le VHC dans le monde et 37 millions par le VIH. La coinfection VIH/VHC est fréquente et représente un élément clé de la prise en charge des patients infectés par le VIH. Depuis l'arrivée des HAART, les maladies du foie sont devenues la cause principale de mortalité chez les patients coinfectés VIH/VHC. L'évolution naturelle et le pronostic de l'hépatite C sont plus sévères en cas de coinfection par le VIH du fait d'une fibrose accélérée et d'une évolution rapide vers la cirrhose et ses complications. Certains facteurs accélérant la fibrose hépatique sont clairs aujourd'hui comme: l'absence de recours au traitement anti-VHC, la réplication active du VHC et la consommation excessive d'alcool. De plus, il existe de plus en plus de preuves que les variants génétiques contribuent à la fibrose hépatique chez les patients monoinfectés par le VHC, mais cet aspect a été peu étudié dans la coinfection VIH/VHC.Durant ma thèse, j'ai eu accès aux données d'un échantillon de 494 patients coinfectés génotypés issu de la cohorte ANRS CO13 HEPAVIH. L'histoire naturelle du VIH et du VHC y est renseignée de manière très détaillée et le suivi clinique des patients permet d'avoir des informations précises sur l'état de fibrose hépatique. J'ai pu alors réaliser deux études d'association « génome-entier » pour identifier des polymorphismes associés à la sévérité de la fibrose à l'aide de données complètes de 292 patients. La première étude a mis en évidence une association entre la quantification de l'élasticité hépatique par Fibroscan® et un locus, également répliqué dans la monoinfection par le VHC. Cette association a permis d'identifier deux gènes impliqués dans des mécanismes de maintien de structure et de signalisation cellulaire (CAV3) mais aussi dans la réplication du VHC (RAD18). La seconde étude a identifié deux associations significatives en comparant deux groupes de scores METAVIR (F0F1F2 vs F3F4), en particulier dans le gène CTNND2 qui est impliqué dans un réseau d'interaction associé à des mécanismes moléculaires lié à des maladies hépatiques.Ces deux études sont en cours de publication dans des revues scientifiques internationales à comité de lecture. Ces nouvelles perspectives dans la compréhension des mécanismes de fibrose dans le contexte de la coinfection VIH/VHC pourraient aider à l'identification de nouvelles cibles pour la création de médicaments ou de tests diagnostiques afin d'améliorer les soins des patients