Somatic Mosaicism in Bulls Estimated from Genome-Wide CNV Array and TSPY Gene Copy Numbers

2016 ◽  
Vol 149 (3) ◽  
pp. 176-181 ◽  
Author(s):  
Olutobi A. Oluwole ◽  
Tamas Revay ◽  
Kiana Mahboubi ◽  
Laura A. Favetta ◽  
W. Allan King
Keyword(s):  
Copy Number ◽  
De Novo ◽  
Somatic Mosaicism ◽  
Copy Number Variations ◽  
Tissue Type ◽  
Gene Copy ◽  
Copy Numbers ◽  
Genome Wide ◽  
Wide Range ◽  
Tspy Gene

Somatic mosaicism has become a focus in human research due to the implications of individual genetic variability in disease. Here, we assessed somatic copy number variations (CNVs) in Holstein bulls in 2 respects. We estimated genome-wide CNVs and assayed CNVs of the TSPY gene, the most variable bovine gene from the Y chromosome. Somatic tissues (blood, lung, heart, muscle, testis, and brain) of 4 bulls were arrayed on the Illumina Bovine SNP50k chip and qPCR tested for TSPY copy numbers. Our results showed extensive copy number divergence in tissues within the same animal as well as significant copy number alterations of TSPY. We detected a mean of 31 CNVs per animal among which 14 were of germline origin, as they were constantly present in all investigated tissues of the animal, while 18 were specific to 1 tissue. Thus, 57% of the total number of detected CNVs was the result of de novo somatic events. Further, TSPY copy number was found to vary significantly among tissues as well as among the same tissue type from different animals in a wide range from 7 to 224% of the calibrator. Our study shows significant autosomal and Y-chromosomal de novo somatic CNV in bulls.

scholarly journals Copy Number Variations of CEP63, FOSL2 and PAQR6 Serve as Novel Signatures for the Prognosis of Bladder Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhao Cai ◽  
Huang Chen ◽  
Jingqiao Bai ◽  
Yang Zheng ◽  
Jianhui Ma ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Prognostic Factors ◽  
High Risk ◽  
Copy Number ◽  
Copy Number Variations ◽  
Invasive Bladder Cancer ◽  
Gene Copy ◽  
Muscle Invasive Bladder Cancer ◽  
Copy Numbers ◽  
Muscle Invasive

BackgroundFinding effective prognostic signatures is of great urgency due to the high risk of recurrence and progression of bladder cancer (BC). Although a lot of genetic alterations are involved in the carcinogenesis, none of them were referred in the current risk group stratifications. In this study, we aimed to find significant copy number variations (CNVs) to predict prognosis for BC patients.MethodsCNVs with high aberration frequencies in BC were explored by array-based comparative genomic hybridization in 65 tumor samples. Candidates were validated in independent groups of BC tumor samples (n=219) and urine samples (n=123). 3D digital PCR was applied for detecting accurate gene copy numbers in BC urine. In order to explore the prognostic value of candidate CNVs, all enrolled patients were followed up for the disease-free survival (DFS). Cox proportional hazards regression analysis was performed to find the independent prognostic factors for DFS.ResultsCNVs of CEP63, FOSL2 and PAQR6 with high aberration frequencies (67.7%, 56.9% and 60.0%, respectively) were found in BC tumors. Copy numbers of CEP63, FOSL2 and PAQR6 were gained in 219 tumor samples. CNVs of CEP63 and FOSL2 were correlated with advanced tumor stage and high grade. Retrospective analysis (median follow-up time: 69 months) revealed that CNVs of CEP63 and FOSL2 were independent prognostic factors for DFS of non-muscle-invasive bladder cancer (NMIBC) patients, while CNVs of FOSL2 and PAQR6 were independent prognostic factors for DFS of muscle-invasive bladder cancer (MIBC) patients. Models for predicting DFS were constructed based on CNVs of three genes. Patients with high prognostic indexes tended to have poor DFS. Prognostic index can also help to identify those with worse outcomes among high risk NMIBC patients. Copy number gains of CEP63 and FOSL2 in urine were found to be significantly correlated with poor DFS of NMIBC patients.ConclusionsCNVs of CEP63, FOSL2 and PAQR6 were capable of predicting DFS and may serve as promising signatures for prognosis of BC.

scholarly journals Association of Copy Number Variations in Autism Spectrum Disorders: A Systematic Review

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Elif Funda Sener
Keyword(s):  
Autism Spectrum Disorders ◽  
Complex Traits ◽  
Copy Number ◽  
De Novo ◽  
Genome Structure ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Repetitive Behaviors ◽  
Wide Range ◽  
Spectrum Disorders

Autism spectrum disorders (ASDs) are characterized by language impairments, social deficits, and repetitive behaviors. The onset of symptoms occurs by the age of 3 and shows a lifelong persistence. Genetics plays a major role in the etiology of ASD. Except genetics, several potential risk factors (environmental factors and epigenetics) may contribute to ASD. Copy number variations (CNVs) are the most widespread structural variations in the human genome. These variations can alter the genome structure either by deletion or by duplication. CNVs can be de novo or inherited. Chromosomal rearrangements have been detected in 5–10% of the patients with ASD and recently copy number changes ranging from a few kilobases (kb) to several megabases (Mb) in size have been reported. Recent data have also revealed that submicroscopic CNVs can have a role in ASD, and de novo CNVs seem to be a more common risk factor in sporadic compared with inherited forms of ASD. CNVs are being implicated as a contributor to the pathophysiology of complex neurodevelopmental disorders and they can affect a wide range of human phenotypes including mental retardation (MR), autism, neuropsychiatric disorders, and susceptibility to other complex traits such as HIV, Crohn’s disease, and psoriasis. This review emphasizes the major CNVs reported to date in ASD.

Mapping of genome-wide copy number variations in the Iranian indigenous cattle using a dense SNP data set

2018 ◽  
Vol 58 (7) ◽  
pp. 1192 ◽  
Author(s):  
K. Karimi ◽  
A. Esmailizadeh ◽  
D. D. Wu ◽  
C. Gondro
Keyword(s):  
Copy Number ◽  
Copy Number Variations ◽  
Indigenous Cattle ◽  
Data Set ◽  
Single Nucleotide ◽  
Snp Data ◽  
Genome Wide ◽  
A Genome ◽  
Wide Range ◽  
Environmental Responses

The objective of this study was to present the first map of the copy number variations (CNVs) in Iranian indigenous cattle based on a high-density single nucleotide polymorphism (SNP) dataset. A total of 90 individuals were genotyped using the Illumina BovineHD BeadChip containing 777 962 SNPs. The QuantiSNP algorithm was used to perform a genome-wide CNV detection across autosomal genome. After merging the overlapping CNV, a total of 221 CNV regions were identified encompassing 36.4 Mb or 1.44% of the bovine autosomal genome. The length of the CNV regions ranged from 3.5 to 2252.8 Kb with an average of 163.8 Kb. These regions included 147 loss (66.52%) and 74 gain (33.48%) events containing a total of 637 annotated Ensembl genes. Gene ontology analysis revealed that most of genes in the CNV regions were involved in environmental responses, disease susceptibility and immune system functions. Furthermore, 543 of these genes corresponded to the human orthologous genes, which involved in a wide range of biological functions. Altogether, 73% of the 221 CNV regions overlapped either completely or partially with those previously reported in other cattle studies. Moreover, novel CNV regions involved several quantitative trait loci (QTL)-related to adaptative traits of Iranian indigenous cattle. These results provided a basis to conduct future studies on association between CNV regions and phenotypic variations in the Iranian indigenous cattle.

scholarly journals Reducing False Positives in CRISPR/Cas9 Screens from Copy Number Variations

2018 ◽  
Author(s):  
Alexander Wu ◽  
Tengfei Xiao ◽  
Teng Fei ◽  
X. Shirley Liu ◽  
Wei Li
Keyword(s):  
Copy Number ◽  
Sliding Window ◽  
Copy Number Variations ◽  
False Positives ◽  
Screening Experiments ◽  
Copy Numbers ◽  
Cas9 Nuclease ◽  
Wide Range ◽  
Window Approach ◽  
Genomic Regions

AbstractCRISPR/Cas9 knockout screens have been widely used to interrogate gene functions across a wide range of cell systems. However, the screening outcome is biased in amplified genomic regions, due to the ability of the Cas9 nuclease to induce multiple double-stranded breaks and strong DNA damage responses at these regions. We developed algorithms to correct biases associated with copy number variations (CNV), even when the CNV profiles are unknown. We demonstrated that our methods effectively reduced false positives in amplified regions while preserving signals of true positives. In addition, we developed a sliding window approach to estimate regions of high copy numbers for cases in which CNV information is not available. These copy number estimations can subsequently be used to effectively correct CNV-related biases in CRISPR screening experiments. Our approach is integrated into the existing MAGeCK/MAGeCK-VISPR analysis pipelines and provides a convenient framework to improve the precision of CRISPR screening results.

scholarly journals The population genetics of adaptation through copy-number variation in a fungal plant pathogen

2021 ◽  
Author(s):  
Luzia Stalder ◽  
Ursula Oggenfuss ◽  
Norfarhan Mohd-Assaad ◽  
Daniel Croll
Keyword(s):  
Copy Number Variation ◽  
Fungal Pathogen ◽  
Copy Number ◽  
Copy Number Variations ◽  
Temperature Adaptation ◽  
Gene Copy ◽  
Gene Duplications ◽  
Genome Wide ◽  
A Genome ◽  
Number Variation

ABSTRACTMicrobial pathogens can rapidly adapt to changing environments such as the application of pesticides or host resistance. Copy number variations (CNV) are a major source of adaptive genetic variation for recent adaptation. Here, we analyze how a major fungal pathogen of barley, Rhynchosporium commune, has adapted to host environment, fungicide and temperature challenges. We screen the genomes of 126 isolates sampled across a worldwide set of populations and identify a total of 7’879 gene duplications and 116 gene deletions. Most gene duplications result from segmental chromosomal duplications. We find that genes showing recent gains or losses are enriched in functions related to host exploitation (i.e. effectors and cell wall degrading enzymes). We perform a phylogeny-informed genome-wide association study (GWAS) and identify 191 copy-number variants associated with different pathogenesis and temperature related traits, including a large segmental duplication of CYP51A that has contributed to the emergence of azole resistance. Additionally, we use a genome-wide SNP dataset to replicate the GWAS and contrast it with the CNV-focused analysis. We find that frequencies of adaptive CNV alleles show high variation among populations for traits under strong selection such as fungicide resistance. In contrast, adaptive CNV alleles underpinning temperature adaptation tend to be near fixation. Finally, we show that transposable elements are important drivers of recent gene copy-number variation. Loci showing signatures of recent positive selection are enriched in miniature inverted repeat transposons. Our findings show how extensive segmental duplications create the raw material for recent adaptation in global populations of a fungal pathogen.

scholarly journals Low α-defensin gene copy number increases the risk for IgA nephropathy and renal dysfunction

2016 ◽  
Vol 8 (345) ◽  
pp. 345ra88-345ra88 ◽  
Author(s):  
Zhen Ai ◽  
Ming Li ◽  
Wenting Liu ◽  
Jia-Nee Foo ◽  
Omniah Mansouri ◽  
...  
Keyword(s):  
Renal Dysfunction ◽  
Copy Number ◽  
Fixed Effects ◽  
Disease Risk ◽  
Strong Association ◽  
Copy Number Variations ◽  
Gene Copy ◽  
Copy Numbers ◽  
Southern Chinese ◽  
Increased Risk

Although a major source of genetic variation, copy number variations (CNVs) and their involvement in disease development have not been well studied. Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. We performed association analysis of the DEFA1A3 CNV locus in two independent IgAN cohorts of southern Chinese Han (total of 1189 cases and 1187 controls). We discovered three independent copy number associations within the locus: DEFA1A3 [P = 3.99 × 10−9; odds ratio (OR), 0.88], DEFA3 (P = 6.55 × 10−5; OR, 0.82), and a noncoding deletion variant (211bp) (P = 3.50 × 10−16; OR, 0.75) (OR per copy, fixed-effects meta-analysis). While showing strong association with an increased risk for IgAN (P = 9.56 × 10−20), low total copy numbers of the three variants also showed significant association with renal dysfunction in patients with IgAN (P = 0.03; hazards ratio, 3.69; after controlling for the effects of known prognostic factors) and also with increased serum IgA1 (P = 0.02) and galactose-deficient IgA1 (P = 0.03). For replication, we confirmed the associations of DEFA1A3 (P = 4.42 × 10−4; OR, 0.82) and DEFA3 copy numbers (P = 4.30 × 10−3; OR, 0.74) with IgAN in a Caucasian cohort (531 cases and 198 controls) and found the 211bp variant to be much rarer in Caucasians. We also observed an association of the 211bp copy number with membranous nephropathy (P = 1.11 × 10−7; OR, 0.74; in 493 Chinese cases and 500 matched controls), but not with diabetic kidney disease (in 806 Chinese cases and 786 matched controls). By explaining 4.96% of disease risk and influencing renal dysfunction in patients with IgAN, the DEFA1A3 CNV locus may be a potential therapeutic target for developing treatments for this disease.

scholarly journals Genome-Wide Analysis of Copy Number Variations in Normal Population Identified by SNP Arrays

2009 ◽  
Vol 2 (1) ◽  
pp. 54-65 ◽  
Author(s):  
Jian Wang ◽  
Tsz-Kwong Man ◽  
Kwong Kwok Wong ◽  
Pulivarthi H. Rao ◽  
Hon-Chiu Eastwood Leung ◽  
...  
Keyword(s):  
Copy Number Variation ◽  
Human Genome ◽  
Copy Number ◽  
Repetitive Sequences ◽  
Snp Array ◽  
Copy Number Variations ◽  
Gene Copy ◽  
Chemical Stimulus ◽  
Genome Wide ◽  
Number Variation

Gene copy number change is an essential characteristic of many types of cancer. However, it is important to distinguish copy number variation (CNV) in the human genome of normal individuals from bona fide abnormal copy number changes of genes specific to cancers. Based on Affymetrix 50K single nucleotide polymorphism (SNP) array data, we identified genome-wide copy number variations among 104 normal subjects from three ethnic groups that were used in the HapMap project. Our analysis revealed 155 CNV regions, of which 37% were gains and 63% were losses. About 21% (30) of the CNV regions are concordant with earlier reports. These 155 CNV regions are located on more than 100 cytobands across all 23 chromosomes. The CNVs range from 68bp to 18 Mb in length, with a median length of 86 Kb. Eight CNV regions were selected for validation by quantitative PCR. Analysis of genomic sequences within and adjacent to CNVs suggests that repetitive sequences such as long interspersed nuclear elements (LINEs) and long terminal repeats (LTRs) may play a role in the origin of CNVs by facilitating non-allelic homologous recombination. Thirty-two percent of the CNVs identified in this study are associated with segmental duplications. CNVs were not preferentially enriched in gene-encoding regions. Among the 364 genes that are completely encompassed by these 155 CNVs, genes related to olfactory sensory, chemical stimulus, and other physiological responses are significantly enriched. A statistical analysis of CNVs by ethnic group revealed distinct patterns regarding the CNV location and gain-to-loss ratio. The CNVs reported here will help build a more comprehensive map of genomic variations in the human genome and facilitate the differentiation between copy number variation and somatic changes in cancers. The potential roles of certain repeat elements in CNV formation, as corroborated by other studies, shed light on the origin of CNVs and will improve our understanding of the mechanisms of genomic rearrangements in the human genome.

scholarly journals X-CNV: genome-wide prediction of the pathogenicity of copy number variations

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Li Zhang ◽  
Jingru Shi ◽  
Jian Ouyang ◽  
Riquan Zhang ◽  
Yiran Tao ◽  
...  
Keyword(s):  
Ethnic Groups ◽  
Copy Number ◽  
Association Studies ◽  
Gene Copy Number ◽  
Copy Number Variations ◽  
Gene Copy ◽  
Computational Framework ◽  
Genome Wide ◽  
Pathogenicity Prediction ◽  
A Genome

Abstract Background Gene copy number variations (CNVs) contribute to genetic diversity and disease prevalence across populations. Substantial efforts have been made to decipher the relationship between CNVs and pathogenesis but with limited success. Results We have developed a novel computational framework X-CNV (www.unimd.org/XCNV), to predict the pathogenicity of CNVs by integrating more than 30 informative features such as allele frequency (AF), CNV length, CNV type, and some deleterious scores. Notably, over 14 million CNVs across various ethnic groups, covering nearly 93% of the human genome, were unified to calculate the AF. X-CNV, which yielded area under curve (AUC) values of 0.96 and 0.94 in training and validation sets, was demonstrated to outperform other available tools in terms of CNV pathogenicity prediction. A meta-voting prediction (MVP) score was developed to quantitively measure the pathogenic effect, which is based on the probabilistic value generated from the XGBoost algorithm. The proposed MVP score demonstrated a high discriminative power in determining pathogenetic CNVs for inherited traits/diseases in different ethnic groups. Conclusions The ability of the X-CNV framework to quantitatively prioritize functional, deleterious, and disease-causing CNV on a genome-wide basis outperformed current CNV-annotation tools and will have broad utility in population genetics, disease-association studies, and diagnostic screening.

scholarly journals Combination of Genome-Wide Polymorphisms and Copy Number Variations of Pharmacogenes in Koreans

2021 ◽  
Vol 11 (1) ◽  
pp. 33
Author(s):  
Nayoung Han ◽  
Jung Mi Oh ◽  
In-Wha Kim
Keyword(s):  
Copy Number ◽  
Genome Wide Association Study ◽  
Copy Number Gain ◽  
Copy Number Variations ◽  
Gene Gain ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Haplotype Blocks ◽  
Genome Wide ◽  
Control And Prevention

For predicting phenotypes and executing precision medicine, combination analysis of single nucleotide variants (SNVs) genotyping with copy number variations (CNVs) is required. The aim of this study was to discover SNVs or common copy CNVs and examine the combined frequencies of SNVs and CNVs in pharmacogenes using the Korean genome and epidemiology study (KoGES), a consortium project. The genotypes (N = 72,299) and CNV data (N = 1000) were provided by the Korean National Institute of Health, Korea Centers for Disease Control and Prevention. The allele frequencies of SNVs, CNVs, and combined SNVs with CNVs were calculated and haplotype analysis was performed. CYP2D6 rs1065852 (c.100C>T, p.P34S) was the most common variant allele (48.23%). A total of 8454 haplotype blocks in 18 pharmacogenes were estimated. DMD ranked the highest in frequency for gene gain (64.52%), while TPMT ranked the highest in frequency for gene loss (51.80%). Copy number gain of CYP4F2 was observed in 22 subjects; 13 of those subjects were carriers with CYP4F2*3 gain. In the case of TPMT, approximately one-half of the participants (N = 308) had loss of the TPMT*1*1 diplotype. The frequencies of SNVs and CNVs in pharmacogenes were determined using the Korean cohort-based genome-wide association study.

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