Prevalence Of Copy Number Variations Research Articles

Genomic population structure and prevalence of copy number variations in South African Nguni cattle.

BackgroundCopy number variations (CNVs) are modifications in DNA structure comprising of deletions, duplications, insertions and complex multi-site variants. Although CNVs are proven to be involved in a variety of phenotypic discrepancies, the full extent and consequence of CNVs is yet to be understood. To date, no such genomic characterization has been performed in indigenous South African Nguni cattle. Nguni cattle are recognized for their ability to sustain harsh environmental conditions while exhibiting enhanced resistance to disease and parasites and are thought to comprise of up to nine different ecotypes.MethodsIllumina BovineSNP50 Beadchip data was utilized to investigate genomic population structure and the prevalence of CNVs in 492 South African Nguni cattle. PLINK, ADMIXTURE, R, gPLINK and Haploview software was utilized for quality control, population structure and haplotype block determination. PennCNV hidden Markov model identified CNVs and genes contained within and 10 Mb downstream from reported CNVs. PANTHER and Ensembl databases were subsequently utilized for gene annotation analyses.ResultsPopulation structure analyses on Nguni cattle revealed 5 sub-populations with a possible sub-structure evident at K equal to 8. Four hundred and thirty three CNVs that formed 334 CNVRs ranging from 30 kb to 1 Mb in size are reported. Only 231 of the 492 animals demonstrated CNVRs. Two hundred and eighty nine genes were observed within CNVRs identified. Of these 149, 28, 44, 2 and 14 genes were unique to sub-populations A, B, C, D and E respectively. Gene ontology analyses demonstrated a number of pathways to be represented by respective genes, including immune response, response to abiotic stress and biological regulation processess.ConclusionsCNVs may explain part of the phenotypic diversity and the enhanced adaptation evident in Nguni cattle. Genes involved in a number of cellular components, biological processes and molecular functions are reported within CNVRs identified. The significance of such CNVRs and the possible effect thereof needs to be ascertained and may hold interesting insight into the functional and adaptive consequence of CNVs in cattle.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-2122-z) contains supplementary material, which is available to authorized users.

Investigation of 15q11-q13, 16p11.2 and 22q13 CNVs in autism spectrum disorder Brazilian individuals with and without epilepsy.

Copy number variations (CNVs) are an important cause of ASD and those located at 15q11-q13, 16p11.2 and 22q13 have been reported as the most frequent. These CNVs exhibit variable clinical expressivity and those at 15q11-q13 and 16p11.2 also show incomplete penetrance. In the present work, through multiplex ligation-dependent probe amplification (MLPA) analysis of 531 ethnically admixed ASD-affected Brazilian individuals, we found that the combined prevalence of the 15q11-q13, 16p11.2 and 22q13 CNVs is 2.1% (11/531). Parental origin could be determined in 8 of the affected individuals, and revealed that 4 of the CNVs represent de novo events. Based on CNV prediction analysis from genome-wide SNP arrays, the size of those CNVs ranged from 206 kb to 2.27 Mb and those at 15q11-q13 were limited to the 15q13.3 region. In addition, this analysis also revealed 6 additional CNVs in 5 out of 11 affected individuals. Finally, we observed that the combined prevalence of CNVs at 15q13.3 and 22q13 in ASD-affected individuals with epilepsy (6.4%) was higher than that in ASD-affected individuals without epilepsy (1.3%; p<0.014). Therefore, our data show that the prevalence of CNVs at 15q13.3, 16p11.2 and 22q13 in Brazilian ASD-affected individuals is comparable to that estimated for ASD-affected individuals of pure or predominant European ancestry. Also, it suggests that the likelihood of a greater number of positive MLPA results might be found for the 15q13.3 and 22q13 regions by prioritizing ASD-affected individuals with epilepsy.

Distribution, functional impact, and origin mechanisms of copy number variation in the barley genome

BackgroundThere is growing evidence for the prevalence of copy number variation (CNV) and its role in phenotypic variation in many eukaryotic species. Here we use array comparative genomic hybridization to explore the extent of this type of structural variation in domesticated barley cultivars and wild barleys.ResultsA collection of 14 barley genotypes including eight cultivars and six wild barleys were used for comparative genomic hybridization. CNV affects 14.9% of all the sequences that were assessed. Higher levels of CNV diversity are present in the wild accessions relative to cultivated barley. CNVs are enriched near the ends of all chromosomes except 4H, which exhibits the lowest frequency of CNVs. CNV affects 9.5% of the coding sequences represented on the array and the genes affected by CNV are enriched for sequences annotated as disease-resistance proteins and protein kinases. Sequence-based comparisons of CNV between cultivars Barke and Morex provided evidence that DNA repair mechanisms of double-strand breaks via single-stranded annealing and synthesis-dependent strand annealing play an important role in the origin of CNV in barley.ConclusionsWe present the first catalog of CNVs in a diploid Triticeae species, which opens the door for future genome diversity research in a tribe that comprises the economically important cereal species wheat, barley, and rye. Our findings constitute a valuable resource for the identification of CNV affecting genes of agronomic importance. We also identify potential mechanisms that can generate variation in copy number in plant genomes.

An exome sequencing pipeline for identifying and genotyping common CNVs associated with disease with application to psoriasis

Motivation: Despite the prevalence of copy number variation (CNV) in the human genome, only a handful of confirmed associations have been reported between common CNVs and complex disease. This may be partially attributed to the difficulty in accurately genotyping CNVs in large cohorts using array-based technologies. Exome sequencing is now widely being applied to case–control cohorts and presents an exciting opportunity to look for common CNVs associated with disease.Results: We developed ExoCNVTest: an exome sequencing analysis pipeline to identify disease-associated CNVs and to generate absolute copy number genotypes at putatively associated loci. Our method re-discovered the LCE3B_LCE3C CNV association with psoriasis (P-value = 5 × 10e−6) while controlling inflation of test statistics (λ < 1). ExoCNVTest-derived absolute CNV genotypes were 97.4% concordant with PCR-derived genotypes at this locus.Availability and implementation: ExoCNVTest has been implemented in Java and R and is freely available from www1.imperial.ac.uk/medicine/people/l.coin/.Contact: wangj@genomics.org.cn or Lachlan.J.M.Coin@genomics.org.cn

Rare Copy Number Variants Disrupt Genes Regulating Vascular Smooth Muscle Cell Adhesion and Contractility in Sporadic Thoracic Aortic Aneurysms and Dissections

Conclusion: Rare copy number variants that disrupt smooth muscle cell (SMC) adhesion or contraction contribute to familial and sporadic thoracic aortic aneurysm (TAA) disease. Summary: A family history of similar disease is present in 20% of patients with TAAs or dissections. The phenotype is inherited as an autosomal-dominant, with variable expression and incomplete penetrance (Milewicz DM et al [Am J Cardiol 1998;82:474-9]). Genes have been identified that contribute to familial TAA and dissection. They encode SMC-specific isoforms of actin and myosin, regulate expression of contractile proteins by vascular SMCs, or involve mutations of SMC adhesive or cytoskeletal proteins (Grainger DJ et al [J Cell Sci 1998;111:2977-88]; Sheen VL [Neurology 2005;64:254-62]). The authors hypothesized that variations in modifying genes influence an individual's susceptibility to TAA or dissection. Variations in copy numbers of genes, so-called copy number variation (CNV), can increase the risk for certain diseases. The authors hypothesized CNVs result in structural variance of the aortic wall that contributes to risk for TAAA and dissection, and given the pathogenesis of TAA, it is also likely these genes involve vascular SMC contractility. This was a genome-wide analysis of genes that potentially contribute to TAA or dissection in 548 cases of sporadic TAA or dissection. Compared with controls, 47 CNV regions were identified that were enriched or unique to patients with TAA or dissection. The CNVs effected genes that regulated SMC adhesion or contractility or that interacted with SMC isoforms of α-actin and β-myosin. Both cause familial TAA or dissection when altered. There was also replication of rare CNVs in an independent cohort of sporadic TAAs or dissections (n = 387) and in a cohort of inherited TAAs (n = 88). The prevalence of CNVs was higher in patients with familial TAAs or dissection than in those with sporadic TAAs or dissection (P = .03). Comment: Genetic and environmental factors are both important in aneurysm disease. Gene products that relay environmental signals affecting genes that regulate SMC function would seem to be ideal candidates to modify the pathogenesis of aneurysm disease. The authors' findings are consistent with a genetic model where CNV mutations contribute to aneurysm causation or predisposition. If such variants could be tested for clinically, patients with appropriate environmental factors placing them at risk for aneurysm disease could have their potential risk of aneurysm development identified with genetic testing.

Duplication of amyloid precursor protein (APP), but not prion protein (PRNP) gene is a significant cause of early onset dementia in a large UK series.

Amyloid precursor protein gene (APP) duplications have been identified in screens of selected probands with early onset familial Alzheimer's disease (FAD). A causal role for copy number variation (CNV) in the prion protein gene (PRNP) in prion dementias is not known. We aimed to determine the prevalence of copy number variation in APP and PRNP in a large referral series, test a screening method for detection of the same, and expand knowledge of clinical phenotype. We used a 3-tiered screening assay for APP and PRNP duplication (exonic real-time quantitative polymerase chain reaction [exon-qPCR], fluorescent microsatellite quantitative PCR [fm-q-PCR], and Illumina array [Illumina Inc., San Diego, CA, USA]) for analysis of a heterogeneous referral series comprising 1531 probands. Five of 1531 probands screened showed APP duplication, a similar prevalence to APP missense mutation. Real-time quantitative PCR and fluorescent microsatellite quantitative PCR were similar individually but are theoretically complementary; we used Illumina arrays as our reference assay. Two of 5 probands were from an autosomal dominant early onset Alzheimer's disease (familial Alzheimer's disease) pedigree. One extensive, noncontiguous duplication on chromosome 21 was consistent with an unbalanced translocation not including the Down's syndrome critical region. Seizures were prominent in the other typical APP duplications. A range of imaging, neuropsychological, cerebrospinal fluid, and pathological findings are reported that extend the known phenotype. APP but not PRNP duplication is a significant cause of early onset dementia in the UK. The recognized phenotype may be expanded to include the possibility of early seizures and apparently sporadic disease which, in part, may be due to different mutational mechanisms. The pros and cons of our screening method are discussed.

Accurate, high-throughput typing of copy number variation using paralogue ratios from dispersed repeats

Recent work has demonstrated an unexpected prevalence of copy number variation in the human genome, and has highlighted the part this variation may play in predisposition to common phenotypes. Some important genes vary in number over a high range (e.g. DEFB4, which commonly varies between two and seven copies), and have posed formidable technical challenges for accurate copy number typing, so that there are no simple, cheap, high-throughput approaches suitable for large-scale screening. We have developed a simple comparative PCR method based on dispersed repeat sequences, using a single pair of precisely designed primers to amplify products simultaneously from both test and reference loci, which are subsequently distinguished and quantified via internal sequence differences. We have validated the method for the measurement of copy number at DEFB4 by comparison of results from >800 DNA samples with copy number measurements by MAPH/REDVR, MLPA and array-CGH. The new Paralogue Ratio Test (PRT) method can require as little as 10 ng genomic DNA, appears to be comparable in accuracy to the other methods, and for the first time provides a rapid, simple and inexpensive method for copy number analysis, suitable for application to typing thousands of samples in large case-control association studies.