Impact Of Copy Number Variation Research Articles

Construction of an Immune-Related Prognostic Signature and lncRNA‒miRNA-mRNA ceRNA Network in Acute Myeloid Leukaemia.

The progression of acute myeloid leukaemia (AML) is influenced by the immune microenvironment in the bone marrow and dysregulated intracellular competing endogenous RNA (ceRNA) networks. Our study utilized data from UCSC Xena, Cancer Genome Atlas Program, Gene Expression Omnibus, Immunology Database and Analysis Portal. Using Cox regression analysis, we identified an immune-related prognostic signature. Genomic analysis of prognostic mRNA was conducted through Gene Set Cancer Analysis (GSCA), and a prognostic ceRNA network was constructed using the Encyclopedia of RNA Interactomes. Correlations between signature mRNAs and immune cell infiltration, checkpoints, and drug sensitivity were assessed using R software, GEPIA, and CellMiner, respectively. Adhering to the ceRNA hypothesis, we established a potential lncRNA/miRNA/mRNA regulatory axis. Our findings pinpointed nine immune-related prognostic mRNAs (KIR2DL1, CSRP1, APOBEC3G, CKLF, PLXNC1, PNOC, ANGPT1, IL1R2, and IL3RA). GSCA analysis revealed the impact of copy number variations and methylation on AML. The ceRNA network comprised 14 differentially expressed prognostic lncRNAs (DE-lncRNAs), six prognostic DE-miRNAs, and three prognostic immune-related IR-DEmRNAs. Correlation analyses linked these mRNA's expression to 22 immune cell types, six immune checkpoints, and potential sensitivity to 27 antitumor drugs. Finally, we identified a potential LINC00963/hsa-miR-431-5p/CSRP1 axis. This study offers innovative insights for AML diagnosis and treatment through a novel immune-related signature and ceRNA axis. Identified novel biomarkers, including two mRNAs (CKLF, PNOC), one miRNA (hsa-miR-323a-3p), and ten lncRNAs (SNHG25, LINC01857, AL390728.6, AC127024.5, Z83843.1, AP002884.1, AC007038.1, AC112512, AC020659.1, AC005921.3) present promising candidates as potential targets for precision medicine, contributing to the ongoing advancements in the field.

Impact of copy number variants in epilepsy plus neurodevelopment disorders

IntroductionEpilepsy, a neurological disorder characterized by recurring unprovoked seizures due to excessive neuronal excitability, is primarily attributed to genetic factors, accounting for an estimated 70 % of cases. Array-comparative genomic hybridization (aCGH) is a crucial genetic test for detecting copy number variants (CNVs) associated with epilepsy. This study aimed to analyze a cohort of epilepsy patients with CNVs detected through aCGH to enhance our understanding of the genetic underpinnings of epilepsy. MethodsA retrospective cross-sectional study was conducted using the aCGH database from the Genetics Department of the Faculty of Medicine of the University of Porto, encompassing 146 patients diagnosed with epilepsy, epileptic encephalopathy, or seizures. Clinical data were collected, and aCGH was performed following established guidelines. CNVs were classified based on ACMG standards, and patients were categorized into four groups according to their clinical phenotype. ResultsAmong the 146 included patients, 94 (64 %) had at least one CNV, with 22 (15.1 %) classified as pathogenic or likely pathogenic. Chromosomes 1, 2, 16, and X were frequently implicated, with Xp22.33 being the most reported region (8 CNVs). The phenotype "Epilepsy and global developmental delay/intellectual disability" showed the highest prevalence of clinically relevant CNVs. Various CNVs were identified across different groups, suggesting potential roles in epilepsy. ConclusionsThis study highlights the significance of aCGH in unraveling the genetic basis of epilepsy and tailoring treatment strategies. It contributes valuable insights to the expanding knowledge in the field, emphasizing the need for research to elucidate the diverse genetic causes of epilepsy.

Comprehensive Genome and Transcriptome Analysis Identifies SLCO3A1 Associated with Aggressive Behavior in Pigs.

Copy number variation (CNV) represents a significant reservoir of genetic diversity within the genome and exhibits a strong association with economically valuable traits in livestock. The manifestation of aggressive behavior in pigs has detrimental effects on production efficiency, immune competency, and meat quality. Nevertheless, the impact of CNV on the aggressive behavior of pigs remains elusive. In this investigation, we employed an integrated analysis of genome and transcriptome data to investigate the interplay between CNV, gene expression changes, and indicators of aggressive behavior in weaned pigs. Specifically, a subset of pigs comprising the most aggressive pigs (MAP, n = 12) and the least aggressive pigs (LAP, n = 11) was purposefully selected from a herd of 500 weaned pigs following a mixing procedure based on their composite aggressive score (CAS). Subsequently, we thoroughly analyzed copy number variation regions (CNVRs) across the entire genome using next-generation sequencing techniques, ultimately revealing the presence of 6869 CNVRs. Using genome-wide association study (GWAS) analysis and evaluating variance-stabilizing transformation (VST) values, we successfully identified distinct CNVRs that distinguished the MAP and LAP counterparts. Among the prioritized CNVRs, CNVR-4962 (designated as the top-ranked p-value and VST value, No. 1) was located within the Solute Carrier Organic Anion Transporter Family Member 3A1 (SLCO3A1) gene. The results of our analyses indicated a significantly higher (p < 0.05) copy number of SLCO3A1 in the MAP compared to the LAP. Furthermore, this increased copy number exhibited a positive correlation with the CAS of the pigs (p < 0.05). Furthermore, we integrated genomic data with transcriptomic data from the temporal lobe to facilitate the examination of expression quantitative trait loci (eQTL). Importantly, these observations were consistent with the mRNA expression pattern of SLCO3A1 in the temporal lobe of both MAP and LAP (p < 0.05). Consequently, our findings strongly suggest that CNVs affecting SLCO3A1 may influence gene expression through a dosage effect. These results highlight the potential of SLCO3A1 as a candidate gene associated with aggressive traits in pig breeding programs.

Impact of Copy Number Variants and Polygenic Risk Scores on Psychopathology in the UK Biobank

BackgroundOur understanding of the impact of copy number variants (CNVs) on psychopathology and their joint influence with polygenic risk scores (PRSs) remains limited. MethodsThe UK Biobank recruited 502,534 individuals ages 37 to 73 years living in the United Kingdom between 2006 and 2010. After quality control, genotype data from 459,855 individuals were available for CNV calling. A total of 61 commonly studied recurrent neuropsychiatric CNVs were selected for analyses and examined individually and in aggregate (any CNV, deletion, or duplication). CNV risk scores were used to quantify intolerance of CNVs to haploinsufficiency. Major depressive disorder and generalized anxiety disorder PRSs were generated for White British individuals (N = 408,870). Mood/anxiety factor scores were generated using item-level questionnaire data (N = 501,289). ResultsCNV carriers showed higher mood/anxiety scores than noncarriers, with the largest effects seen for intolerant deletions. A total of 11 individual deletions and 8 duplications were associated with higher mood/anxiety. Carriers of the 9p24.3 (DMRT1) duplication showed lower mood/anxiety. Associations remained significant for most CNVs when excluding individuals with psychiatric diagnoses. Nominally significant CNV × PRS interactions provided preliminary evidence that associations between select individual CNVs, but not CNVs in aggregate, and mood/anxiety may be modulated by PRSs. ConclusionsCNVs associated with risk for psychiatric disorders showed small to large effects on dimensional mood/anxiety scores in a general population cohort, even when excluding individuals with psychiatric diagnoses. CNV × PRS interactions showed that associations between select CNVs and mood/anxiety may be modulated by PRSs.

Impact of Copy Number Variants and Polygenic Risk Scores on Psychopathology in the UK Biobank

Impact of Copy Number Variants and Polygenic Risk Scores on Psychopathology in the UK Biobank

Clinical Impact of Copy Number Variation Revealed By Next Generation Sequencing in Acute Myeloid Leukemia

Introduction: Conventional karyotype analysis is one of the most important diagnostic tools to determine the prognosis of acute myeloid leukemia (AML), in which more than 50% of cases are affected. However, the low sensitivity of this technique hampers the detection of small genetic alterations like Copy Number Variation (CNV) that could affect the pathophysiology and prognosis of the disease. Current modern genomic technologies based on next generation sequencing (NGS) are capable to detect CNV at low frequencies.Objective: To analyse CNV of genes related to myeloid neoplasms profile in AML patients at diagnosis and evaluate their connection with the mutational profile, and its possible influence on the clinical-biological phenotype and prognosis of the disease.Materials and methods: The CNV and mutational profile were analysed in samples from 380 AML patients, from PLATAFO-LMA reference centres (IMIBIC, Córdoba and Dr Negrín Las Palmas de Gran Canaria) by NGS, applying a panel of 30 genes (154 regions) related to myeloid neoplasms (Sophia Myeloid Solution®) on Ilumina Myseq platform.Results: NGS detected CNV in at least one gene in 103 AML patients (27.1%). NGS detected 103 gains and 206 losses of genetic material. The median number of genes affected by CNV was 2 (range 1-12). When comparing with conventional karyotype information, CNV provided additional information in 51% of the cases.The chromosomes 7, 11 and 21 were most affected with CNV, occurring in 79 (76.7%), 40 (38.8%) and 36 (35%) patients, respectively. The gains of genetic material occurred more frequently on chromosome 21 in U2AF1 and RUNX1 genes, in 13 patients each. The loss of genetic material in EZH2 and BRAF genes occurred mutually. Interestingly, we observed the tendency that patients with CNV (loss) in NPM1 gene had shorter overall survival compared to cases with NPM1 mutated and without CNV in this gene (1 month vs. 13 months, p = 0.072) (Figure 1). Moreover CNV (loss) in TP53 gene was associated with mutations in this gene, other than deletions (p <0.05).In addition, NGS detected 390 mutations distributed in 29 genes in 103 AML with CNV. The median number of mutations was 3 (range 1-10) (Figure 2). Furthermore, only 2 patients did not have any mutation in genes analysed. The distribution and frequency of genes affected by CNV and by mutations was different (Figure 3).Conclusions: The CNV of genes related to myeloid neoplasms are frequent in AML patients (27.1%) and provides additional information to the conventional karyotype in half of the cases. The loss of NPM1 gene could affect survival of AML patients. The use of NGS with CNV analysis provides important information on copy number alterations that are not detected by the karyotype, which could significantly affect the pathophysiology of AML and with potential clinical impact, especially in patients with normal karyotype. [Display omitted] DisclosuresHernández Rivas: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees.

Diagnostic utility of next-generation sequencing-based panel testing in 543 patients with suspected skeletal dysplasia

BackgroundSkeletal dysplasia is typically diagnosed using a combination of radiographic imaging, clinical examinations, and molecular testing. Identifying a molecular diagnosis for an individual with a skeletal dysplasia can lead to improved clinical care, guide future medical management and treatment, and inform assessment of risk for familial recurrence. The molecular diagnostic utility of multi-gene panel testing using next-generation sequencing (NGS) has not yet been characterized for an unselected population of individuals with suspected skeletal dysplasia. In this study, we retrospectively reviewed patient reports to assess the diagnostic yield, reported variant characteristics, impact of copy number variation, and performance in prenatal diagnostics of panel tests for variants in genes associated with skeletal dysplasia and growth disorders.ResultsClinical reports of consecutive patients with a clinical indication of suspected skeletal dysplasia who underwent panel testing were examined. The 543 patients included in the study submitted samples for diagnostic genetic testing with an indication of suspected skeletal dysplasia or growth disorder and received one of three nested panel tests. A molecular diagnosis was established in 42.0% of patients (n = 228/543). Diagnostic variants were identified in 71 genes, nearly half of which (n = 35, 49.3%) contributed uniquely to a molecular diagnosis for a single patient in this cohort. Diagnostic yield was significantly higher among fetal samples (59.0%, n = 52/88) than postnatal samples (38.7%, n = 176/455; z = 3.55, p < 0.001). Diagnostic variants in fetal cases were identified across 18 genes. Thirteen diagnostic CNVs were reported, representing 5.7% of diagnostic findings and ranging in size from 241-bp to whole chromosome aneuploidy. Additionally, 11.4% (36/315) of non-diagnostic patient reports had suspicious variants of unknown significance (VUS), in which additional family studies that provide segregation data and/or functional characterization may result in reclassification to likely pathogenic.ConclusionsThese findings demonstrate the utility of panel testing for individuals with a suspected skeletal dysplasia or growth disorder, with a particularly high diagnostic yield seen in prenatal cases. Pursuing comprehensive panel testing with high-resolution CNV analysis can provide a diagnostic benefit, given the considerable phenotype overlap amongst skeletal dysplasia conditions.

Convergent evolution of a genomic rearrangement may explain cancer resistance in hystrico- and sciuromorpha rodents

The rodents of hystricomorpha and sciuromorpha suborders exhibit remarkably lower incidence of cancer. The underlying genetic basis remains obscure. We report a convergent evolutionary split of human 3p21.31, a locus hosting a large number of tumour-suppressor genes (TSGs) and frequently deleted in several tumour types, in hystrico- and sciuromorphs. Analysis of 34 vertebrate genomes revealed that the synteny of 3p21.31 cluster is functionally and evolutionarily constrained in most placental mammals, but exhibit large genomic interruptions independently in hystricomorphs and sciuromorphs, owing to relaxation of underlying constraints. Hystrico- and sciuromorphs, therefore, escape from pro-tumorigenic co-deletion of several TSGs in cis. The split 3p21.31 sub-clusters gained proximity to proto-oncogene clusters from elsewhere, which might further nullify pro-tumorigenic impact of copy number variations due to co-deletion or co-amplification of genes with opposing effects. The split of 3p21.31 locus coincided with the accelerated rate of its gene expression and the body mass evolution of ancestral hystrico- and sciuromorphs. The genes near breakpoints were associated with the traits specific to hystrico- and sciuromorphs, implying adaptive significance. We conclude that the convergently evolved chromosomal interruptions of evolutionarily constrained 3p21.31 cluster might have impacted evolution of cancer resistance, body mass variation and ecological adaptations in hystrico- and sciuromorphs.

Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome

Copy Number Variation (CNV) at the 1q21.1 locus is associated with a range of neurodevelopmental and psychiatric disorders in humans, including abnormalities in head size and motor deficits. Yet, the functional consequences of these CNVs (both deletion and duplication) on neuronal development remain unknown. To determine the impact of CNV at the 1q21.1 locus on neuronal development, we generated induced pluripotent stem cells from individuals harbouring 1q21.1 deletion or duplication and differentiated them into functional cortical neurons. We show that neurons with 1q21.1 deletion or duplication display reciprocal phenotype with respect to proliferation, differentiation potential, neuronal maturation, synaptic density and functional activity. Deletion of the 1q21.1 locus was also associated with an increased expression of lower cortical layer markers. This difference was conserved in the mouse model of 1q21.1 deletion, which displayed altered corticogenesis. Importantly, we show that neurons with 1q21.1 deletion and duplication are associated with differential expression of calcium channels and demonstrate that physiological deficits in neurons with 1q21.1 deletion or duplication can be pharmacologically modulated by targeting Ca2+ channel activity. These findings provide biological insight into the neuropathological mechanism underlying 1q21.1 associated brain disorder and indicate a potential target for therapeutic interventions.

Omnigenic Impact of Copy Number Variants on Cognition and Psychopathology in the Philadelphia Neurodevelopmental Cohort

Omnigenic Impact of Copy Number Variants on Cognition and Psychopathology in the Philadelphia Neurodevelopmental Cohort

Impact of copy number variant and single nucleotide polymorphism of the programmed death-ligand 1 gene, programmed death-ligand 1 protein expression and therapy regimens on overall survival in a large group of Caucasian patients with non-small cell lung carcinoma.

Anti-programmed death-1 or anti-programmed death-ligand 1 (PD-L1) blockade may be ineffective in some patients with non-small cell lung cancer (NSCLC) with high percentage of tumor cells with PD-L1 expression. In addition, immunotherapy may provide great benefits in patients without PD-L1 expression. The present study assessed PD-L1 protein expression by immunohistochemistry, copy number variation (CNV) of PD-L1 and two single nucleotide polymorphisms (SNPs), rs822335 and rs822336, in the promoter of PD-L1 by quantitative PCR in 673 patients with NSCLC. Overall survival time of patients with NSCLC depending on the assessed predictive factors (PD-L1 CNV or SNP) and the treatment methods (immunotherapy in first/second line of treatment or chemotherapy) was analyzed. The present study revealed significantly higher PD-L1 copies number in patients with ≥10% and ≥50% of tumor cells with PD-L1 expression compared to patients with lower percentage of PD-L1-positive tumor cells (P=0.02 and P=0.0002, respectively). There was a significant positive correlation (R=0.2; P=0.01) between number of PD-L1 copies and percentage of tumor cells with PD-L1 protein expression. Percentage of tumor cells with PD-L1 expression was lower in patients with TT genotype of the rs822335 polymorphism compared to those with CC genotype (P=0.03). The present study observed significantly higher risk of death in patients treated with chemotherapy compared to those treated with immunotherapy (P<0.0001; hazard ratio=2.4768; 95% confidence interval, 2.0120–3.0490). The present study demonstrated a close relationship between PD-L1 copies number, genotype of rs822335 PD-L1 polymorphism and PD-L1 protein expression on tumor cells. However, the impact of CNV and SNPs of PD-L1 on overall survival of patients with NSCLC requires further investigation.

Systematic Investigation of mRNA N6-Methyladenosine Machinery in Primary Prostate Cancer

Background Appreciable findings have pointed out pivotal roles of N6-methyladenosine (m6A) machinery in cancer onset and progression. However, limited efforts have been directed towards relevant research in the prostate cancer area. Methods A PubMed search was conducted to acquire components of the mRNA m6A machinery. Multiomics integration was performed to systematically investigate the mRNA m6A machinery in primary prostate cancer. Furthermore, RNA interference assays of two prognostic m6A readers EIF3D and HNRNPA2B1 were conducted to explore m6A dependence of their functions in prostate cancer cell proliferation and migration. Results A total of 41 mRNA m6A regulators have been identified to date. A small degree of copy number aberrations and an extremely low frequency of somatic mutations were observed in the regulators across prostate tumors. Enrichment of CpG sites and extensive changes of DNA methylation in the m6A machinery were also found. Impact of copy number variation on m6A regulator expression was stronger than that of DNA methylation disturbance. Furthermore, our study identified a set of m6A regulators related to clinical features and/or survival which were largely m6A-binding proteins. The translation initiation factor subunit EIF3D and the splicing factor HNRNPA2B1 can be independent prognostic factors which may contribute to retardation and promotion of cancer progression, respectively, through affecting cancer-related processes such as cell cycle. Moreover, in vitro assays demonstrated that m6A impacted the EIF3D and HNRNPA2B1 roles in proliferation and migration of prostate cancer cells. Conclusions Our report systematically described molecular features of the mRNA m6A machinery and their potential roles in primary prostate cancer. Knowledge gained from this work may pave the way for further studies on the m6A system in prostate cancer.

Chromosomal instability in the prediction of pituitary neuroendocrine tumors prognosis

The purpose of this study was to analyze the impact of copy number variations (CNV) on sporadic pituitary neuroendocrine tumors (PitNETs) prognosis, to identify specific prognosis markers according to the known clinico-pathological classification. CGH array analysis was performed on 195 fresh-frozen PitNETs (56 gonadotroph, 11 immunonegative, 56 somatotroph, 39 lactotroph and 33 corticotroph), with 5 years post-surgery follow-up (124 recurrences), classified according to the five-tiered grading classification (invasion, Ki-67, mitotic index and p53 positivity). Effect of alterations on recurrence was studied using logistic regression models. Transcriptomic analysis of 32 lactotroph tumors was performed. The quantity of CNV was dependent on tumor type: higher in lactotroph (median(min–max) = 38% (0–97) of probes) compared to corticotroph (11% (0–77)), somatotroph (5% (0–99)), gonadotroph (0% (0–10)) and immunonegative tumors (0% (0–17). It was not predictive of recurrence in the whole cohort. In lactotroph tumors, genome instability, especially quantity of gains, significantly predicted recurrence independently of invasion and proliferation (p-value = 0.02, OR = 1.2). However, no specific CNV was found as a prognostic marker. Transcriptomic analysis of the genes included in the CNV and associated with prognosis didn’t show significantly overrepresented pathway. In somatotroph and corticotroph tumors, USP8 and GNAS mutations were not associated with genome disruption or recurrence respectively. To conclude, CGH array analysis showed genome instability was dependent on PitNET type. Lactotroph tumors were highly altered and the quantity of altered genome was associated with poorer prognosis though the mechanism is unclear, whereas gonadotroph and immunonegative tumors showed the same ‘quiet’ profile, leaving the mechanism underlying tumorigenesis open to question.

Functional annotation of rare structural variation in the human brain

Structural variants (SVs) contribute to many disorders, yet, functionally annotating them remains a major challenge. Here, we integrate SVs with RNA-sequencing from human post-mortem brains to quantify their dosage and regulatory effects. We show that genic and regulatory SVs exist at significantly lower frequencies than intergenic SVs. Functional impact of copy number variants (CNVs) stems from both the proportion of genic and regulatory content altered and loss-of-function intolerance of the gene. We train a linear model to predict expression effects of rare CNVs and use it to annotate regulatory disruption of CNVs from 14,891 independent genome-sequenced individuals. Pathogenic deletions implicated in neurodevelopmental disorders show significantly more extreme regulatory disruption scores and if rank ordered would be prioritized higher than using frequency or length alone. This work shows the deleteriousness of regulatory SVs, particularly those altering CTCF sites and provides a simple approach for functionally annotating the regulatory consequences of CNVs.

Copy number amplification of androgen receptor in cell-free DNA is a potential prognostic factor in patients with CRPC.

180 Background: A circulating cell-free DNA (cfDNA) has been suggested as a potential biomarker for castration-resistant prostate cancer (CRPC). However, clinical implication of the parameters in cfDNA remains unclear. We aimed to investigate the impact of copy number variation (CNV) of androgen-receptor amplification (AR-amp) in cfDNA on prognosis in patients with CRPC. Methods: We retrospectively evaluated AR-amp in cfDNA in 154 patients with prostate cancer between April 2018 and September 2019. We compared AR-amp between the patients with CRPC and non-CRPC. An optimal cutoff point was defined using receiver operating characteristic (ROC) curve. The effect of AR-amp on prognosis was evaluated between the CRPC patients with AR-amp high and low. Results: The median age and initial PSA was 75 years and 34 ng/mL, respectively. The number of patients with abiraterone acetate, enzalutamide, docetaxel, cabazitaxel was 24, 15, 21, and 2, respectively. No significant association was observed between the AR-amp and serum prostate-specific antigen (PSA) level at AR-amp measurement. Of 154, 73 (47%) patients developed to CRPC. The AR-amp was significantly higher in the patients with CRPC than that in the non-CRPC (1.07 vs. 0.97, respectively, P&lt;0.001). The cutoff value of AR-amp was defined 1.16 with area under the ROC curve of 0.672. Overall survival was significantly shorter in the patients with AR-amp low (≤1.16, n=46) than that with AR-amp high (&gt;1.16, n=27) (8.9 vs. 9.6 months, respectively, P &lt; 0.001). The AR-amp was not significantly different between the pre- and post-docetaxel status in patients with CRPC. Conclusions: AR-amp in cfDNA might be a potential biomarker for poor prognosis in patients with CRPC who were treated with life-prolonging therapies.

Association of Rare Recurrent Copy Number Variants With Congenital Heart Defects Based on Next-Generation Sequencing Data From Family Trios.

Congenital heart defects (CHDs) are a common birth defect, affecting approximately 1% of newborn children in the United States. As previously reported, a significant number of CHDs are potentially attributed to altered copy number variants (CNVs). However, as many genomic variants are rare, a large-scale CNV triad study is necessary to characterize the genetic architecture of CHD. We used whole-exome sequencing (WES) data generated by the Pediatric Cardiac Genomics Consortium (PCGC), including a discovery dataset of 2,103 individuals from 760 nuclear family trios and an independent replication set of 4,808 individuals from 1,712 trios. The candidate targets uncovered were further validated through different platforms, including the Omni single-nucleotide polymorphism (SNP) array chip in 1,860 individuals and the whole-genome sequencing (WGS) data in 33 trios. The genes harboring CNVs of interest were then investigated for expression alternations based on cardiac tissue RNA-Seq data. We identified multiple CNVs in the WES data that associated with specific sub-phenotypes of CHD in approximately 2,400 families, including 98 de novo CNV regions. We identified five CNV loci harboring LIMS1, GCC2, RANBP2, TTC3, and MAP3K7CL, respectively, where those genes are highly expressed in human heart and/or mouse embryo heart at 15 days. Five novel CNV loci were uncovered, demonstrating altered expression of the respective candidate genes involved. To our knowledge, this is the largest trio-based WES study of CHD and, in addition to uncovering novel CHD targets, presents an extensive resource with the potential to provide important insights to the architecture and impact of CNVs in CHD.

Association study of copy number variants in CCL3L1, FCGR3A and FCGR3B genes with risk of ankylosing spondylitis in a West Algerian population.

Numerous single nucleotide polymorphisms (SNPs) were explored in the Algerian population to evaluate associated ankylosing spondylitis (AS) genetic risk factors, but no study has identified the impact of copy number variations (CNVs). The aim of the study was to determine whether CNVs of CCL3L1, FCGR3A and FCGR3B genes were also associated with the susceptibility of AS disease in Algerian population. The data set of the current study is composed of 81 patients with AS and 119 healthy controls. All samples were genotyped by digital droplet PCR (ddPCR). Chi-square test and OR calculation were used to evaluate association between CNVs and AS and the risk associated with copy numbers (CN). In results, FCGR3A CN less than two copies (<2) was significantly increased in spondylitis patients (p=.0001, OR=7.74 [2.32-25.74]). Additionally, FCGR3A CN<2 copies association was present only in HLA-B27 (-) patients. We have concluded that FCGR3A deletions have an independent effect on AS regarding HLA-B27 status. This is the first study that investigated the CCL3L1 CNVs in relation to AS risk disease. It reveals that CCL3L1 and FCGR3B CNVs may not be involved in susceptibility to AS risk in the Algerian population.

Polar bear evolution is marked by rapid changes in gene copy number in response to dietary shift

Polar bear (Ursus maritimus) and brown bear (Ursus arctos) are recently diverged species that inhabit vastly differing habitats. Thus, analysis of the polar bear and brown bear genomes represents a unique opportunity to investigate the evolutionary mechanisms and genetic underpinnings of rapid ecological adaptation in mammals. Copy number (CN) differences in genomic regions between closely related species can underlie adaptive phenotypes and this form of genetic variation has not been explored in the context of polar bear evolution. Here, we analyzed the CN profiles of 17 polar bears, 9 brown bears, and 2 black bears (Ursus americanus). We identified an average of 318 genes per individual that showed evidence of CN variation (CNV). Nearly 200 genes displayed species-specific CN differences between polar bear and brown bear species. Principal component analysis of gene CN provides strong evidence that CNV evolved rapidly in the polar bear lineage and mainly resulted in CN loss. Olfactory receptors composed 47% of CN differentiated genes, with the majority of these genes being at lower CN in the polar bear. Additionally, we found significantly fewer copies of several genes involved in fatty acid metabolism as well as AMY1B, the salivary amylase-encoding gene in the polar bear. These results suggest that natural selection shaped patterns of CNV in response to the transition from an omnivorous to primarily carnivorous diet during polar bear evolution. Our analyses of CNV shed light on the genomic underpinnings of ecological adaptation during polar bear evolution.

Robust pathway-based multi-omics data integration using directed random walks for survival prediction in multiple cancer studies

BackgroundIntegrating the rich information from multi-omics data has been a popular approach to survival prediction and bio-marker identification for several cancer studies. To facilitate the integrative analysis of multiple genomic profiles, several studies have suggested utilizing pathway information rather than using individual genomic profiles.MethodsWe have recently proposed an integrative directed random walk-based method utilizing pathway information (iDRW) for more robust and effective genomic feature extraction. In this study, we applied iDRW to multiple genomic profiles for two different cancers, and designed a directed gene-gene graph which reflects the interaction between gene expression and copy number data. In the experiments, the performances of the iDRW method and four state-of-the-art pathway-based methods were compared using a survival prediction model which classifies samples into two survival groups.ResultsThe results show that the integrative analysis guided by pathway information not only improves prediction performance, but also provides better biological insights into the top pathways and genes prioritized by the model in both the neuroblastoma and the breast cancer datasets. The pathways and genes selected by the iDRW method were shown to be related to the corresponding cancers.ConclusionsIn this study, we demonstrated the effectiveness of a directed random walk-based multi-omics data integration method applied to gene expression and copy number data for both breast cancer and neuroblastoma datasets. We revamped a directed gene-gene graph considering the impact of copy number variation on gene expression and redefined the weight initialization and gene-scoring method. The benchmark result for iDRW with four pathway-based methods demonstrated that the iDRW method improved survival prediction performance and jointly identified cancer-related pathways and genes for two different cancer datasets.ReviewersThis article was reviewed by Helena Molina-Abril and Marta Hidalgo.

Copy Number Variants Account for a Tiny Fraction of Undiagnosed Myopathic Patients.

Next-generation sequencing (NGS) technologies have led to an increase in the diagnosis of heterogeneous genetic conditions. However, over 50% of patients with a genetically inherited disease are still without a diagnosis. In these cases, different hypotheses are usually postulated, including variants in novel genes or elusive mutations. Although the impact of copy number variants (CNVs) in neuromuscular disorders has been largely ignored to date, missed CNVs are predicted to have a major role in disease causation as some very large genes, such as the dystrophin gene, have prone-to-deletion regions. Since muscle tissues express several large disease genes, the presence of elusive CNVs needs to be comprehensively assessed following an accurate and systematic approach. In this multicenter cohort study, we analyzed 234 undiagnosed myopathy patients using a custom array comparative genomic hybridization (CGH) that covers all muscle disease genes at high resolution. Twenty-two patients (9.4%) showed non-polymorphic CNVs. In 12 patients (5.1%), the identified CNVs were considered responsible for the observed phenotype. An additional ten patients (4.3%) presented candidate CNVs not yet proven to be causative. Our study indicates that deletions and duplications may account for 5–9% of genetically unsolved patients. This strongly suggests that other mechanisms of disease are yet to be discovered.