Genomic copy-number variants drive apoptotic resistance and relapses on immune checkpoint inhibitors
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PROVIDER: PRJNA1276619 | ENA |
REPOSITORIES: ENA
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Project description:Genomic copy-number variants drive apoptotic resistance and relapses on immune checkpoint inhibitors
| PRJNA1276620 | ENA
Project description:Ebstein anomaly (EA) is a rare congenital defect characterized by apical displacement of the septal tricuspid leaflets and atrialization of the right ventricle. The etiology of EA is unclear; however, recurrence in families and the association of EA with genetic syndromes and copy number variants (CNVs) suggest a genetic component.We performed a population-based study to search for recurrent and novel CNVs in a previously unreported set of EA cases.We genotyped 60 EA cases identified from all live births (2,891,076) from selected California counties (1991-2010) using the Illumina HumanOmni2.5-8 array. We identified 38 candidate CNVs in 28 (46%) cases and prioritized and validated 11 CNVs based on the genes included.Five CNVs (41%) overlapped or were close to genes involved in early myocardial development, including NODAL, PDLIM5, SIX1, ASF1A and FGF12. We also replicated a previous association of EA with CNVs at 1p34.1 and AKAP12. Finally, we identified four CNVs overlapping or in close proximity to the transcription factors HES3, TRIM71, CUX1 and EIF4EBP2.This study supports the relationship of genetic factors to EA and demonstrates that defects in cardiomyocytes and myocardium differentiation may play a role. Abnormal differentiation of cardiomyocytes and how genetic factors contribute should be examined for their association with EA.
| S-EPMC5720705 | biostudies-other
Project description:MotivationEstimating the frequency distribution of copy number variants (CNVs) is an important aspect of the effort to characterize this new type of genetic variation. Currently, most studies report a strong skew toward low-frequency CNVs. In this article, our goal is to investigate the frequencies of CNVs. We employ a two-step procedure for the CNV frequency estimation process. We use family information a posteriori to select only the most reliable CNV regions, i.e. those showing high rates of Mendelian transmission.ResultsOur results suggest that the current skew toward low-frequency CNVs may not be representative of the true frequency distribution, but may be due, among other reasons, to the non-negligible false negative rates that characterize CNV detection methods. Moreover, false positives are also likely, as low-frequency CNVs are hard to detect with small sample sizes and technologies that are not ideally suited for their detection. Without appropriate validation methods, such as incorporation of biologically relevant information (for example, in our case, the transmission of heritable CNVs from parents to offspring), it is difficult to assess the validity of specific CNVs, and even harder to obtain reliable frequency estimates.
| S-EPMC2562008 | biostudies-literature
Project description:Studies of copy number variants (CNVs) in miscarriages are rare in comparison to post-natal cases with developmental abnormalities. The overall characteristics of miscarriage CNVs (size, gene content and function) are therefore largely unexplored. Our goal was to assess and compare the characteristics of CNVs identified in 101 euploid miscarriages from four high-resolution array studies that documented both common miscarriage CNVs (i.e. CNVs found in controls from the Database of Genomic Variants, DGV) and rare miscarriage CNVs (not reported in DGV). Our miscarriage analysis included 24 rare CNVs with 93 genes, and 372 common CNVs (merged into 119 common CNV regions; CNVRs) with 354 genes. The rare and common CNVs were comparable in size (median size of ∼ 0.16 and 0.14 Mb, respectively); however, rare CNVs showed a significantly higher gene density, with 56 genes/Mb in rare and 24 genes/Mb in common CNVs (P = 0.03). Rare CNVs also had two times more genes with mouse knock-out models which were reported for 42% of rare and 19% of common CNV genes. No specific pathway enrichment was noted for 24 rare CNV genes, but common CNV genes showed significant enrichment in genes from immune-response related pathways and pregnancy/reproduction-related biological processes. Our analysis of CNVs from euploid miscarriages suggests that both rare and common CNVs could have a role in miscarriage by impacting pregnancy-related genes or pathways. Cataloguing of all CNVs and detailed description of their characteristics (e.g. gene content, genomic breakpoints) is desirable in the future for better understanding of their relevance to pregnancy loss.
| S-EPMC4518138 | biostudies-literature
Project description:Large-scale genomic studies have made major progress in identifying genetic risk variants for schizophrenia. A key finding from these studies is that there is an increased burden of genomic copy number variants (CNVs) in schizophrenia cases compared with controls. The mechanism through which these CNVs confer risk for the symptoms of schizophrenia, however, remains unclear. One possibility is that schizophrenia risk CNVs impact basic associative learning processes, abnormalities of which have long been associated with the disorder. To investigate whether genes in schizophrenia CNVs impact on specific phases of associative learning we combined human genetics with experimental gene expression studies in animals. In a sample of 11 917 schizophrenia cases and 16 416 controls, we investigated whether CNVs from patients with schizophrenia are enriched for genes expressed during the consolidation, retrieval or extinction of associative memories. We show that CNVs from cases are enriched for genes expressed during fear extinction in the hippocampus, but not genes expressed following consolidation or retrieval. These results suggest that CNVs act to impair inhibitory learning in schizophrenia, potentially contributing to the development of core symptoms of the disorder.
| S-EPMC5285462 | biostudies-literature
Project description:Copy number variants (CNVs) represent a substantial source of genetic variation in mammals. However, the occurrence of CNVs in horses and their subsequent impact on phenotypic variation is unknown. We performed a study to identify CNVs in 16 horses representing 15 distinct breeds (Equus caballus) and an individual gray donkey (Equus asinus) using a whole-exome tiling array and the array comparative genomic hybridization methodology. We identified 2368 CNVs ranging in size from 197 bp to 3.5 Mb. Merging identical CNVs from each animal yielded 775 CNV regions (CNVRs), involving 1707 protein- and RNA-coding genes. The number of CNVs per animal ranged from 55 to 347, with median and mean sizes of CNVs of 5.3 kb and 99.4 kb, respectively. Approximately 6% of the genes investigated were affected by a CNV. Biological process enrichment analysis indicated CNVs primarily affected genes involved in sensory perception, signal transduction, and metabolism. CNVs also were identified in genes regulating blood group antigens, coat color, fecundity, lactation, keratin formation, neuronal homeostasis, and height in other species. Collectively, these data are the first report of copy number variation in horses and suggest that CNVs are common in the horse genome and may modulate biological processes underlying different traits observed among horses and horse breeds.
| S-EPMC3337435 | biostudies-literature
Project description:BackgroundCopy number variants (CNVs) have been associated with the risk of schizophrenia, autism and intellectual disability. However, little is known about their spectrum of psychopathology in adulthood.MethodsWe investigated the psychiatric phenotypes of adult CNV carriers and compared probands, who were ascertained through clinical genetics services, with carriers who were not. One hundred twenty-four adult participants (age 18-76), each bearing one of 15 rare CNVs, were recruited through a variety of sources including clinical genetics services, charities for carriers of genetic variants, and online advertising. A battery of psychiatric assessments was used to determine psychopathology.ResultsThe frequencies of psychopathology were consistently higher for the CNV group compared to general population rates. We found particularly high rates of neurodevelopmental disorders (NDDs) (48%), mood disorders (42%), anxiety disorders (47%) and personality disorders (73%) as well as high rates of psychiatric multimorbidity (median number of diagnoses: 2 in non-probands, 3 in probands). NDDs [odds ratio (OR) = 4.67, 95% confidence interval (CI) 1.32-16.51; p = 0.017) and psychotic disorders (OR = 6.8, 95% CI 1.3-36.3; p = 0.025) occurred significantly more frequently in probands (N = 45; NDD: 39[87%]; psychosis: 8[18%]) than non-probands (N = 79; NDD: 20 [25%]; psychosis: 3[4%]). Participants also had somatic diagnoses pertaining to all organ systems, particularly conotruncal cardiac malformations (in individuals with 22q11.2 deletion syndrome specifically), musculoskeletal, immunological, and endocrine diseases.ConclusionsAdult CNV carriers had a markedly increased rate of anxiety and personality disorders not previously reported and high rates of psychiatric multimorbidity. Our findings support in-depth psychiatric and medical assessments of carriers of CNVs and the establishment of multidisciplinary clinical services.
| S-EPMC10244007 | biostudies-literature
Project description:Colitis associated with immune checkpoint inhibitors
| PRJNA849977 | ENA
Project description:Height is a highly heritable and classic polygenic trait. Recent genome-wide association studies (GWAS) have revealed that at least 180 genetic variants influence adult height. However, these variants explain only about 10% of the phenotypic variation in height. Genetic analysis of short individuals can lead to the discovery of novel rare gene defects with a large effect on growth. In an effort to identify novel genes associated with short stature, genome-wide analysis for copy number variants (CNVs), using single-nucleotide polymorphism arrays, in 162 patients (149 families) with short stature was performed. Segregation analysis was performed if possible, and genes in CNVs were compared with information from GWAS, gene expression in rodents' growth plates and published information. CNVs were detected in 40 families. In six families, a known cause of short stature was found (SHOX deletion or duplication, IGF1R deletion), in two combined with a de novo potentially pathogenic CNV. Thirty-three families had one or more potentially pathogenic CNVs (n=40). In 24 of these families, segregation analysis could be performed, identifying three de novo CNVs and nine CNVs segregating with short stature. Four were located near loci associated with height in GWAS (ADAMTS17, TULP4, PRKG2/BMP3 and PAPPA). Besides six CNVs known to be causative for short stature, 40 CNVs with possible pathogenicity were identified. Segregation studies and bioinformatics analysis suggested various potential candidate genes.
| S-EPMC3992565 | biostudies-literature
Project description:Heritage breeds can be considered a genetic reservoir of genetic variability to be conserved and valorized considering their historical, cultural, and adaptive characteristics and possibly for their high potential in commercial hybrid genetic improvement by gene introgression. The aim of the present research is to investigate via Copy Number Variant (CNVs) the genomic makeup of 4 Italian autochthonous turkey breeds (Bronzato Comune-BrCI, 24; Ermellinato di Rovigo-ErRo, 24; Parma e Piacenza-PrPc, 25; Romagnolo-RoMa, 29). CNVs detection was performed using two different software and an interbreed CNVs comparison was carried out. A total of 1077 CNVs were identified in 102 turkeys, summarized into 519 CNV regions (CNVRs), which resulted after merging in 101 and 18 breed and shared regions. Biodiversity was analyzed using the effective information supplied by CNVs analysis, and BrCI and ErRo were characterized by a low mapped CNV number. Differences were described at a genomic level related to physiological, reproductive, and behavioral traits. The comparison with other three Italian turkey breeds (Brianzolo, Colle Euganei, and Nero Italiano) using a CNV data set available in the literature showed high clustering properties at the genomic level, and their relationships are strictly linked to the geographical origin and to the history of the rural structure of their native regions.
| S-EPMC7913726 | biostudies-literature