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

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.

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

10.1101/2021.12.10.472168 ◽

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.

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Frequency of CDK2 , CCNE1 Copy Number Variation in Acral Melanoma and Implications for CDK Inhibitor in Targeted Therapy

10.21203/rs.2.23330/v1 ◽

2020 ◽

Author(s):

Xiaowen Wu ◽

Junya Yan ◽

Jiayi Yu ◽

Jinyu Yu ◽

Zhiyuan Cheng ◽

...

Keyword(s):

Cell Cycle ◽

Targeted Therapy ◽

Copy Number Variation ◽

Copy Number ◽

Melanoma Cells ◽

Copy Number Variations ◽

Gene Copy ◽

Cdk Inhibitor ◽

Acral Melanoma ◽

Number Variation

Abstract Background: Acral melanoma have a high frequency of cell cycle-related gene copy number variation. However, the status and clinical significance of CNVs of CDK 2 and CCNE1 have not been fully elucidated. Methods: A total of 490 acral melanoma samples were examined for CNVs of CDK 2 and CCNE1 using QuantiGenePlex DNA Assay. Correlations of CDK2 and CCNE1 CNVs to clinicopathologic features and prognosis of acral melanoma were evaluated.The sensitivity of cell lines and cell-derived xenograft (CDX) containing CCNE1 CNVs to CDK inhibitor AT7519,Dinaciclib and proteasome inhibitor Bortezomib were also analyzed. Results: Among the 490 samples,140 cases, 139 cases and 39 cases respectively showed CDK2 gain (28.5%), CCNE1 gain (28.3%) and CDK2 gain plus CCNE1 gain (8.0%).The median progression-free survival (PFS) time for acral patients with CCNE1 gain was significantly shorter than that for patients without CCNE1 gain (17.0 versus 27.0 months; P =0.002). Furthermore, CCNE1 gain was an independent prognostic factor for patients receiving chemotherapy. The pan-CDK inhibitor AT7519 could inhibit the cell proliferation, induce apoptosis and cause cell cycle arrest in G2 phase of acral melanoma cells and inhibit the tumor growth of CDX with CCNE1 gain. Dinaciclib and Bortezomib showed CCNE1 copy number independent inhibitory effects on the proliferation of melanoma cells. Conclusions: CDK2 and CCNE1 copy number variations were frequent in acral melanoma and CCNE1 gain may be a useful biomarker to predict the outcome of receiving chemotherapy in patients with acral melanoma. In addition, our study provides a basis for the use of CDK inhibitor in the treatment of acral melanoma. Keywords: acral melanoma, targeted therapy, CDK2 , CCNE1 , copy number variation

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Copy number variation analysis in Chinese children with complete atrioventricular canal and single ventricle

BMC Medical Genomics ◽

10.1186/s12920-021-01090-y ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Xingyu Zhang ◽

Bo Wang ◽

Guoling You ◽

Ying Xiang ◽

Qihua Fu ◽

...

Keyword(s):

Copy Number ◽

Trisomy 21 ◽

Single Ventricle ◽

Snp Array ◽

Copy Number Variations ◽

Chinese Children ◽

Atrioventricular Canal ◽

Genome Wide ◽

Number Variation ◽

Complete Atrioventricular

Abstract Background Congenital heart disease (CHD) is one of the most common birth defects. Copy number variations (CNVs) have been proved to be important genetic factors that contribute to CHD. Here we screened genome-wide CNVs in Chinese children with complete atrioventricular canal (CAVC) and single ventricle (SV), since there were scarce researches dedicated to these two types of CHD. Methods We screened CNVs in 262 sporadic CAVC cases and 259 sporadic SV cases respectively, using a customized SNP array. The detected CNVs were annotated and filtered using available databases. Results Among 262 CAVC patients, we identified 6 potentially-causative CNVs in 43 individuals (16.41%, 43/262), including 2 syndrome-related CNVs (7q11.23 and 8q24.3 deletion). Surprisingly, 90.70% CAVC patients with detected CNVs (39/43) were found to carry duplications of 21q11.2–21q22.3, which were recognized as trisomy 21 (Down syndrome, DS). In CAVC with DS patients, the female to male ratio was 1.6:1.0 (24:15), and the rate of pulmonary hypertension (PH) was 41.03% (16/39). Additionally, 6 potentially-causative CNVs were identified in the SV patients (2.32%, 6/259), and none of them was trisomy 21. Most CNVs identified in our cohort were classified as rare (< 1%), occurring just once among CAVC or SV individuals except the 21q11.2–21q22.3 duplication (14.89%) in CAVC cohort. Conclusions Our study identified 12 potentially-causative CNVs in 262 CAVC and 259 SV patients, representing the largest cohort of these two CHD types in Chinese population. The results provided strong correlation between CAVC and DS, which also showed sex difference and high incidence of PH. The presence of potentially-causative CNVs suggests the etiology of complex CHD is incredibly diverse, and CHD candidate genes remain to be discovered.

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Rapid Diagnosis of Imprinting Disorders Involving Copy Number Variation and Uniparental Disomy Using Genome-Wide SNP Microarrays

Cytogenetic and Genome Research ◽

10.1159/000435847 ◽

2015 ◽

Vol 146 (1) ◽

pp. 9-18 ◽

Cited By ~ 10

Author(s):

Weiqiang Liu ◽

Rui Zhang ◽

Jun Wei ◽

Huimin Zhang ◽

Guojiu Yu ◽

...

Keyword(s):

Copy Number ◽

Snp Array ◽

Uniparental Disomy ◽

Copy Number Variations ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Imprinting Disorders ◽

Genome Wide ◽

Number Variation ◽

Efficient Alternative

Imprinting disorders, such as Beckwith-Wiedemann syndrome (BWS), Prader-Willi syndrome (PWS) and Angelman syndrome (AS), can be detected via methylation analysis, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), or other methods. In this study, we applied single nucleotide polymorphism (SNP)-based chromosomal microarray analysis to detect copy number variations (CNVs) and uniparental disomy (UPD) events in patients with suspected imprinting disorders. Of 4 patients, 2 had a 5.25-Mb microdeletion in the 15q11.2q13.2 region, 1 had a 38.4-Mb mosaic UPD in the 11p15.4 region, and 1 had a 60-Mb detectable UPD between regions 14q13.2 and 14q32.13. Although the 14q32.2 region was classified as normal by SNP array for the 14q13 UPD patient, it turned out to be a heterodisomic UPD by short tandem repeat marker analysis. MS-MLPA analysis was performed to validate the variations. In conclusion, SNP-based microarray is an efficient alternative method for quickly and precisely diagnosing PWS, AS, BWS, and other imprinted gene-associated disorders when considering aberrations due to CNVs and most types of UPD.

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Copy Number Variation of UGT 2B Genes in Indian Families Using Whole Genome Scans

Journal of Nucleic Acids ◽

10.1155/2016/1648527 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7

Author(s):

Avinash M. Veerappa ◽

Prakash Padakannaya ◽

Nallur B. Ramachandra

Keyword(s):

Copy Number ◽

Gene Deletion ◽

Indian Population ◽

Snp Array ◽

Copy Number Variations ◽

Genome Scans ◽

Genome Wide ◽

Disease Associations ◽

Number Variation

Background and Objectives. Uridine diphospho-glucuronosyltransferase 2B (UGT2B) is a family of genes involved in metabolizing steroid hormones and several other xenobiotics. These UGT2B genes are highly polymorphic in nature and have distinct polymorphisms associated with specific regions around the globe. Copy number variations (CNVs) status of UGT2B17 in Indian population is not known and their disease associations have been inconclusive. It was therefore of interest to investigate the CNV profile of UGT2B genes.Methods. We investigated the presence of CNVs in UGT2B genes in 31 members from eight Indian families using Affymetrix Genome-Wide Human SNP Array 6.0 chip.Results. Our data revealed >50% of the study members carried CNVs in UGT2B genes, of which 76% showed deletion polymorphism. CNVs were observed more in UGT2B17 (76.4%) than in UGT2B15 (17.6%). Molecular network and pathway analysis found enrichment related to steroid metabolic process, carboxylesterase activity, and sequence specific DNA binding.Interpretation and Conclusion. We report the presence of UGT2B gene deletion and duplication polymorphisms in Indian families. Network analysis indicates the substitutive role of other possible genes in the UGT activity. The CNVs of UGT2B genes are very common in individuals indicating that the effect is neutral in causing any suspected diseases.

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Identification of Copy Number Variation Among Nonsyndromic Cleft Lip and or Without Cleft Palate With Hypodontia: A Genome-Wide Association Study

Frontiers in Physiology ◽

10.3389/fphys.2021.637306 ◽

2021 ◽

Vol 12 ◽

Author(s):

Norliana Ghazali ◽

Normastura Abd Rahman ◽

Azlina Ahmad ◽

Sarina Sulong ◽

Thirumulu Ponnuraj Kannan

Keyword(s):

Copy Number Variation ◽

Cleft Palate ◽

Copy Number ◽

Cleft Lip ◽

Genome Wide Association Study ◽

Quantitative Polymerase Chain Reaction ◽

Copy Number Variations ◽

Genome Wide ◽

A Genome ◽

Number Variation

Nonsyndromic cleft lip and or without cleft palate (NSCL/P) with the hypodontia is a common developmental abnormality in humans and animals. This study identified the genetic aberration involved in both NSCL/P and hypodontia pathogenesis. A cross-sectional study using genome-wide study copy number variation-targeted CytoScan 750K array carried out on salivary samples from 61 NSCL/P and 20 noncleft with and without hypodontia Malay subjects aged 7–13 years old. Copy number variations (CNVs) of SKI and fragile histidine triad (FHIT) were identified in NSCL/P and noncleft children using quantitative polymerase chain reaction (qPCR) as a validation analysis. Copy number calculated (CNC) for each gene determined with Applied Biosystems CopyCaller Software v2.0. The six significant CNVs included gains (12q14.3, 15q26.3, 1p36.32, and 1p36.33) and losses (3p14.2 and 4q13.2) in NSCL/P with hypodontia patients compared with the NSCL/P only. The genes located in these regions encoded LEMD3, IGF1R, TP73, SKI, FHIT, and UGT2β15. There were a significant gain and loss of both SKI and FHIT copy number in NSCL/P with hypodontia compared with the noncleft group (p < 0.05). The results supported that CNVs significantly furnish to the development of NSCL/P with hypodontia.

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Genome-wide patterns of copy number variation in the diversified chicken genomes using next-generation sequencing

10.1101/002006 ◽

2014 ◽

Author(s):

Guoqiang Yi ◽

Lujiang Qu ◽

Jianfeng Liu ◽

Yiyuan Yan ◽

Guiyun Xu ◽

...

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Association Studies ◽

False Negative ◽

Gene Copy ◽

Comparative Genomic ◽

Mineral Density ◽

Validation Rate ◽

Genome Wide ◽

Number Variation

Copy number variation (CNV) is important and widespread in the genome, and is a major cause of disease and phenotypic diversity. Herein, we perform genome-wide CNV analysis in 12 diversified chicken genomes based on whole genome sequencing. A total of 9,025 CNV regions (CNVRs) covering 100.1 Mb and representing 9.6% of the chicken genome are identified, ranging in size from 1.1 to 268.8 kb with an average of 11.1 kb. Sequencing-based predictions are confirmed at high validation rate by two independent approaches, including array comparative genomic hybridization (aCGH) and quantitative PCR (qPCR). The Pearson?s correlation values between sequencing and aCGH results range from 0.395 to 0.740, and qPCR experiments reveal a positive validation rate of 91.71% and a false negative rate of 22.43%. In total, 2,188 predicted CNVRs (24.2%) span 2,182 RefSeq genes (36.8%) associated with specific biological functions. Besides two previously accepted copy number variable genesEDN3andPRLR, we also find some promising genes with potential in phenotypic variants.FZD6andLIMS1, two genes related to diseases susceptibility and resistance are covered by CNVRs. Highly duplicatedSOCS2may lead to higher bone mineral density. Entire or partial duplication of some genes likePOPDC3andLBFABPmay have great economic importance in poultry breeding. Our results based on extensive genetic diversity provide the first individualized chicken CNV map and genome-wide gene copy number estimates and warrant future CNV association studies for important traits of chickens.

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Complement C4 Gene Copy Number Variation Genotyping by High Resolution Melting PCR

International Journal of Molecular Sciences ◽

10.3390/ijms21176309 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6309

Author(s):

Claudia P. Jaimes-Bernal ◽

Monte Trujillo ◽

Francisco José Márquez ◽

Antonio Caruz

Keyword(s):

High Resolution ◽

Copy Number Variation ◽

Copy Number ◽

High Resolution Melting ◽

Gene Copy Number ◽

Copy Number Variations ◽

Gene Copy ◽

Complement C4 ◽

Gene Copy Number Variation ◽

Number Variation

Background: Complement C4 gene copy number variation plays an important role as a determinant of genetic susceptibility to common diseases, such as systemic lupus erythematosus, schizophrenia, rheumatoid arthritis, and infectious diseases. This study aimed to develop an assay for the quantification of copy number variations in the C4 locus. Methods: the assay was based on a gene ratio analysis copy enumeration (GRACE) PCR combined with high resolution melting (HRM) PCR. The test was optimized using samples of a known genotype and validated with 72 DNA samples from healthy blood donors. Results: to validate the assay, standard curves were generated by plotting the C4/RP1 ratio values against copy number variation (CNV) for each gene, using genomic DNA with known C4 CNV. The range of copy numbers in control individuals was comparable to distributions observed in previous studies of European descent. Conclusions: the method herein described significantly simplifies C4 CNV diagnosis to validate the assay.

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