scholarly journals Influences of rare copy number variation on human complex traits

2021 ◽  
Author(s):  
Margaux Louise Anna Hujoel ◽  
Maxwell A Sherman ◽  
Alison R Barton ◽  
Ronen E Mukamel ◽  
Vijay G. Sankaran ◽  
...  
Keyword(s):  
Copy Number Variation ◽  
Complex Traits ◽  
Copy Number ◽  
Target Genes ◽  
Snp Array ◽  
Regulatory Elements ◽  
Detection Sensitivity ◽  
Allelic Series ◽  
Number Variation ◽  
Human Complex

The human genome contains hundreds of thousands of regions exhibiting copy number variation (CNV). However, the phenotypic effects of most such polymorphisms are unknown because only larger CNVs (spanning tens of kilobases) have been ascertainable from the SNP-array data generated by large biobanks. We developed a new computational approach that leverages abundant haplotype-sharing in biobank cohorts to more sensitively detect CNVs co-inherited within extended SNP haplotypes. Applied to UK Biobank, this approach achieved 6-fold increased CNV detection sensitivity compared to previous analyses, accounting for approximately half of all rare gene inactivation events produced by genomic structural variation. This extensive CNV call set enabled the most comprehensive analysis to date of associations between CNVs and 56 quantitative traits, identifying 269 independent associations (P < 5 x 10-8) - involving 97 loci - that rigorous statistical fine-mapping analyses indicated were likely to be causally driven by CNVs. Putative target genes were identifiable for nearly half of the loci, enabling new insights into dosage-sensitivity of these genes and implicating several novel gene-trait relationships. CNVs at several loci created extended allelic series including deletions or duplications of distal enhancers that associated with much stronger phenotypic effects than SNPs within these regulatory elements. These results demonstrate the ability of haplotype-informed analysis to empower structural variant detection and provide insights into the genetic basis of human complex traits.

scholarly journals Copy Number Variation of TLR-7 Gene and its Association with the Development of Systemic Lupus Erythematosus in Female Patients from Yucatan Mexico

2014 ◽  
Vol 6 ◽  
pp. GEG.S16707 ◽  
Author(s):  
Guillermo Valencia Pacheco ◽  
Darig Cámara Cruz ◽  
Lizbeth J. González Herrera ◽  
Gerardo J. Pérez Mendoza ◽  
Guadalupe I. Adrián Amaro ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Copy Number Variation ◽  
Lupus Erythematosus ◽  
Copy Number ◽  
Target Genes ◽  
Quantitative Polymerase Chain Reaction ◽  
Systemic Autoimmune Disease ◽  
Systemic Lupus ◽  
Number Variation ◽  
Polymerase Chain

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies against self-antigens, which occurs most often in women between 15 and 40 years of age. The innate immunity is involved in the pathogenesis of SLE through TLR-7. Genetic factors such as copy number variation (CNV) of target genes may contribute to disease development, but this possible risk has not yet been studied in SLE patients from Yucatan, Mexico. The CNV of TLR-7 gene was determined by quantitative polymerase chain reaction assay using TaqMan probes in 80 SLE women and 150 control subjects. The results showed that 10% of SLE patients exhibited more than two copies of TLR-7 gene, whereas no mRNA overexpression was detected. These data suggested that increased CNV of the TLR-7 gene in Yucatan SLE women can be a risk factor for this disease.

scholarly journals Transcriptomics & copy number variation of radiotoxicity points to altered mitochondrial and DNA repair mechanisms

2020 ◽  
Author(s):  
Gita A Pathak ◽  
Renato Polimanti ◽  
Talisa K Silzer ◽  
Frank R Wendt ◽  
Ranajit Chakraborty ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Repair ◽  
Copy Number Variation ◽  
Whole Blood ◽  
Copy Number ◽  
Radiation Treatment ◽  
Snp Array ◽  
Prostate Tissue ◽  
Repair Mechanisms ◽  
Number Variation

Abstract Proctitis is an inflammation of the rectum and may be induced by radiation treatment for cancer. We investigated proctitis as a radiotoxic endpoint in prostate cancer patients who received radiotherapy (n=222). We analyzed the copy number variation and SNP-derived transcriptomic profiles of whole-blood and prostate tissue associated with proctitis. The SNP and copy number data were genotyped on Affymetrix® Genome-wide Human SNP Array 6.0. Following QC measures, the genotypes were used to obtain gene expression by leveraging GTEx, a reference dataset for gene expression association based on genotype and RNA-seq information for prostate (n= 132) and whole-blood tissue (n=369). In prostate tissue, 62 genes were significantly associated with proctitis, and 98 genes in whole-blood tissue. Six genes - CABLES2, ATP6AP1L, IFIT5, ATRIP, TELO2 , and PARD6G were common to both tissues. The copy number analysis identified seven regions associated with proctitis, one of which ( ALG1L2) was also associated with proctitis based on transcriptomic profiles in the whole-blood tissue. The genes identified via transcriptomics and copy number variation association were further investigated for enriched pathways and gene ontology. Some of the enriched processes were DNA repair, mitochondrial apoptosis regulation, cell-to-cell signaling interaction processes for renal and urological system, and organismal injury.

scholarly journals SNP array mapping of chromosome 20p deletions: Genotypes, phenotypes, and copy number variation

2009 ◽  
Vol 30 (3) ◽  
pp. 371-378 ◽  
Author(s):  
Binita M. Kamath ◽  
Brian D. Thiel ◽  
Xiaowu Gai ◽  
Laura K. Conlin ◽  
Pedro S. Munoz ◽  
...  
Keyword(s):  
Copy Number Variation ◽  
Copy Number ◽  
Snp Array ◽  
Number Variation

Evaluation of chemokine-ligand pathways in pretreatment tumor biopsies as predictive biomarker of response to adoptive therapy in metastatic melanoma patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8576-8576 ◽  
Author(s):  
Davide Bedognetti ◽  
Sara Tomei ◽  
Tara L Spivey ◽  
Valeria De Giorgi ◽  
Maria Libera Ascierto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Copy Number Variation ◽  
Copy Number ◽  
Target Genes ◽  
Adoptive Therapy ◽  
Over Expression ◽  
Number Variation ◽  
Pre Treatment ◽  
Tumor Biopsies

8576 Background: Adoptive therapy with tumor infiltrating lymphocytes (TILs) induces objective responses (OR) in approximately 50% of patients with metastatic melanoma. The recruitment of TILs through CXCR3/CCR5-ligand chemokines is believed critical for immune-mediated rejection. Here, we investigated the predictive role of a gene-signature based on CXCR3/CCR5-ligand chemokine transcripts in pre-treatment melanoma biopsies, its biological role and its relation with CCR5-Δ32 polymorphism, which encodes a protein not expressed on cell surface. Methods: Expression of CXCR3/CXCR3-ligand transcripts (i.e CXCL9, 10, 11) and CCR5/CCR5-ligand transcripts (i.e. CCL3, 4, 5) were assessed in 113 pre-treatment tumor biopsies from patients enrolled in adoptive therapy trials: 24 patients achieved a complete remission (CR), 34 a partial remission (PR), and 55 did not respond (NR). Copy number variation and gene expression profile of these target genes were assessed in 15 biopsy-derived cell lines. CCR5-Δ32 was assessed by sequencing germinal DNA. Results: CXCL9, 10 and 11 and CCL5 clustered together and were selected for hierarchical clustering analysis based on the mean-centered gene expression values. A signature characterized by the over-expression of these genes was associated with the likelihood to achieve a clinical response (OR rate: PR+CR: 65% vs 38%, High vs Low, respectively, P=0.015). Neither correlation between the copy number variation and the gene-expression of the corresponding genes, nor correlation between the transcripts of the investigated genes between tumor biopsies and the matched cell lines was detected. Transcript expression of the target genes did not differ between CCR5-Δ32 (n =20) and wild type patients (n=93). Conclusions: Coordinate over-expression of CXCR3/CCR5 ligands in pre-treatment tumor samples was associated with responsiveness to treatment. However, the lack of correlation between in vivo and ex vivo data suggest the inflammatory status characterized by the up-regulation of these inflammatory chemokine genes is an in vivo multifactorial phenomenon.

scholarly journals Software comparison for evaluating genomic copy number variation for Affymetrix 6.0 SNP array platform

2011 ◽  
Vol 12 (1) ◽  
Author(s):  
Jeanette E Eckel-Passow ◽  
Elizabeth J Atkinson ◽  
Sooraj Maharjan ◽  
Sharon LR Kardia ◽  
Mariza de Andrade
Keyword(s):  
Copy Number Variation ◽  
Copy Number ◽  
Snp Array ◽  
Array Platform ◽  
Genomic Copy Number ◽  
Software Comparison ◽  
Genomic Copy ◽  
Number Variation ◽  
Genomic Copy Number Variation

scholarly journals Assessment of copy number variation using the Illumina Infinium 1M SNP-array: a comparison of methodological approaches in the Spanish Bladder Cancer/EPICURO study

2011 ◽  
Vol 32 (2) ◽  
pp. 240-248 ◽  
Author(s):  
Gaëlle Marenne ◽  
Benjamín Rodríguez-Santiago ◽  
Montserrat García Closas ◽  
Luis Pérez-Jurado ◽  
Nathaniel Rothman ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Copy Number Variation ◽  
Copy Number ◽  
Snp Array ◽  
Number Variation ◽  
Methodological Approaches

scholarly journals Genome-wide detection of CNV regions and their potential association with growth and fatness traits in Duroc pigs

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yibin Qiu ◽  
Rongrong Ding ◽  
Zhanwei Zhuang ◽  
Jie Wu ◽  
Ming Yang ◽  
...  
Keyword(s):  
Copy Number Variation ◽  
Complex Traits ◽  
Copy Number ◽  
Association Studies ◽  
Average Daily Gain ◽  
Genome Wide Association Studies ◽  
Potential Candidate ◽  
Genome Wide ◽  
Number Variation ◽  
Genetic Mechanisms

Abstract Background In the process of pig breeding, the average daily gain (ADG), days to 100 kg (AGE), and backfat thickness (BFT) are directly related to growth rate and fatness. However, the genetic mechanisms involved are not well understood. Copy number variation (CNV), an important source of genetic diversity, can affect a variety of complex traits and diseases and has gradually been thrust into the limelight. In this study, we reported the genome-wide CNVs of Duroc pigs using SNP genotyping data from 6627 animals. We also performed a copy number variation region (CNVR)-based genome-wide association studies (GWAS) for growth and fatness traits in two Duroc populations. Results Our study identified 953 nonredundant CNVRs in U.S. and Canadian Duroc pigs, covering 246.89 Mb (~ 10.90%) of the pig autosomal genome. Of these, 802 CNVRs were in U.S. Duroc pigs with 499 CNVRs were in Canadian Duroc pigs, indicating 348 CNVRs were shared by the two populations. Experimentally, 77.8% of nine randomly selected CNVRs were validated through quantitative PCR (qPCR). We also identified 35 CNVRs with significant association with growth and fatness traits using CNVR-based GWAS. Ten of these CNVRs were associated with both ADG and AGE traits in U.S. Duroc pigs. Notably, four CNVRs showed significant associations with ADG, AGE, and BFT, indicating that these CNVRs may play a pleiotropic role in regulating pig growth and fat deposition. In Canadian Duroc pigs, nine CNVRs were significantly associated with both ADG and AGE traits. Further bioinformatic analysis identified a subset of potential candidate genes, including PDGFA, GPER1, PNPLA2 and BSCL2. Conclusions The present study provides a necessary supplement to the CNV map of the Duroc genome through large-scale population genotyping. In addition, the CNVR-based GWAS results provide a meaningful way to elucidate the genetic mechanisms underlying complex traits. The identified CNVRs can be used as molecular markers for genetic improvement in the molecular-guided breeding of modern commercial pigs.

scholarly journals The distribution and impact of common copy-number variation in the genome of the domesticated apple, Malus x domestica Borkh.

2015 ◽  
Author(s):  
James Boocock ◽  
David Chagné ◽  
Tony R Merriman ◽  
Mik Black
Keyword(s):  
Copy Number Variation ◽  
Copy Number ◽  
Snp Array ◽  
Malus X Domestica ◽  
R Genes ◽  
Variable Regions ◽  
Exact Test ◽  
Apple Genome ◽  
Number Variation ◽  
Ngs Data

BackgroundCopy number variation (CNV) is a common feature of eukaryotic genomes, and a growing body of evidence suggests that genes affected by CNV are enriched in processes that are associated with environmental responses. Here we use next generation sequence (NGS) data to detect copy-number variable regions (CNVRs) within the Malus x domestica genome, as well as to examine their distribution and impact.MethodsCNVRs were detected using NGS data derived from 30 accessions of M. x domestica analysed using the read-depth method, as implemented in the CNVrd2 software. To improve the reliability of our results, we developed a quality control and analysis procedure that involved checking for organelle DNA, not repeat masking, and the determination of CNVR identity using a permutation testing procedure.ResultsOverall, we identified 876 CNVRs, which spanned 3.5% of the apple genome. To verify that detected CNVRs were not artefacts, we analysed the B- allele-frequencies (BAF) within a SNP array dataset derived from a screening of 185 individual apple accessions and found the CNVRs were enriched for SNPs having aberrant BAFs (P < 1e-13, Fisher?s Exact test). Putative CNVRs overlapped 845 gene models and were enriched for resistance (R) genes (P < 1e-22, Fisher?s exact test). Of note is a cluster of resistance genes on chromosome 2 near a region containing multiple major gene loci conferring resistance to apple scab.ConclusionWe present the first analysis and catalogue of CNVRs in the M. x domestica genome. The enrichment of the CNVRs with R genes and their overlap with gene loci of agricultural significance draw attention to a form of unexplored genetic variation in apple. This research will underpin further investigation of the role that CNV plays within the apple genome.  

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