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Copy Number Variation (copy + number_variation)

Distribution by Scientific Domains

Life Sciences	71%
Medical Sciences	28%

Selected Abstracts

Genetic variations associated with psoriasis and psoriatic arthritis found by genome-wide association

DERMATOLOGIC THERAPY, Issue 2 2010
Kristina Callis Duffin
ABSTRACT Psoriasis and psoriatic arthritis are immune disorders with a complex polygenic basis. HLA-Cw6, which lies in the major histocompatibility region on chromosome 6, is considered the major genetic determinant of psoriasis. Recent genome-wide association studies have identified new variants outside of the MHC with relevance to the immunology of psoriasis. Variants in or near genes that encode subunits of cytokines (IL12B, IL23A) or cytokine receptors (IL23R) are interesting given that the gene product of IL12B, p40, is the target of a recently approved monoclonal antibody therapy for psoriasis (ustekinumab). Association with psoriasis and psoriatic arthritis has been found in TNFAIP3 and TNFIP1, ubiquitin ligases in the NF-,B pathway, and IL13, a Th2 cytokine. Copy number variation of human beta-defensin and late cornified envelope genes also associate with psoriasis. Many of these genetic variations also associate with immune disorders considered psoriatic co-morbidities, including Crohn's disease and diabetes. [source]

MLPA as a screening method of aneuploidy and unbalanced chromosomal rearrangements in spontaneous miscarriages

PRENATAL DIAGNOSIS, Issue 8 2007
Dan Diego-Alvarez
Abstract Objective The present study aims to validate multiplex ligation-dependent probe amplification (MLPA) technique with subtelomeric probe mixes as a screening method to detect aneuploidy and unbalanced terminal chromosomal rearrangements in spontaneous abortions (SAs). Methods MLPA with P036B and P070 probe mixes was performed on 221 miscarriage DNA samples between the 5th and 24th week of gestation. Cytogenetic culture was attempted on 178 miscarriages. Karyotyped miscarriages served as controls in this blinded study. Results were confirmed by quantitative fluorescent-PCR (QF,PCR). Results Among the karyotyped miscarriages, MLPA was able to detect all the expected aneuploidies, as well as an unbalanced product from a reciprocal translocation, and revealed cryptic deletions and duplications not visible at the 550-band resolution level. In addition, chromosomal anomalies were found in ,37% of cases that failed to grow or could not be cultivated. As expected, ploidy changes were not detected. Copy number variation was found for target sequences of P036B (CYFIP1, MRPL41, CAB45) and P070 (DECR2, TNFRSF18) probe mixes. Conclusions We propose the use of MLPA with subtelomeric probe mixes as a reliable, rapid and economical first approach to detect aneuploidy and unbalanced terminal chromosomal rearrangements in SAs. Copyright © 2007 John Wiley & Sons, Ltd. [source]

High-resolution copy number arrays in cancer and the problem of normal genome copy number variation

GENES, CHROMOSOMES AND CANCER, Issue 11 2008
Kylie L. Gorringe
High-resolution techniques for analysis of genome copy number (CN) enable the analysis of complex cancer somatic genetics. However, the analysis of these data is difficult, and failure to consider a number of issues in depth may result in false leads or unnecessary rejection of true positives. First, segmental duplications may falsely generate CN breakpoints in aneuploid samples. Second, even when tumor data were each normalized to matching lymphocyte DNA, we still observed copy number polymorphisms masquerading as somatic alterations due to allelic imbalance. We investigated a number of different solutions and determined that evaluating matching normal DNA, or at least using locally derived normal baseline data, were preferable to relying on current online databases because of poor cross-platform compatibility and the likelihood of excluding genuine small somatic alterations. © 2008 Wiley-Liss, Inc. [source]

DNA copy number variation and loss of heterozygosity in relation to recurrence of and survival from head and neck squamous cell carcinoma: A review

HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 10 2008
Yu Chen PhD
Abstract Genetic aberrations, such as DNA copy number variation (CNV) and loss of heterozygosity (LOH), have been implicated in head and neck squamous cell carcinoma (HNSCC) initiation and progression. This review examines CNV and LOH as predictors of HNSCC recurrence and mortality. We searched PubMed for relevant publications and compared and discussed results from the articles. Certain CNV and LOH events have consistently been associated with HNSCC recurrence and survival. The recent high-resolution single nucleotide polymorphism (SNP) arrays have the potential to identify many more genetic changes and concurrent genome-wide CNV, copy-neutral and/or allelic imbalance LOH in HNSCC that may bear on prognosis. Our review confrms that outcome in HNSCC can be predicted to a considerable extent by the presence of tumor cell genetic aberrations. It points out the limitations of some methodologies that were used in the past and discusses the advantages and challenges of using genome-wide SNP arrays. © 2008 Wiley Periodicals, Inc. Head Neck 2008 [source]

High-resolution mapping of the 8p23.1 beta-defensin cluster reveals strictly concordant copy number variation of all genes,

HUMAN MUTATION, Issue 10 2008
Marco Groth
Abstract One unexpected feature of the human genome is the high structural variability across individuals. Frequently, large regions of the genome show structural polymorphisms and many vary in their abundance. However, accurate methods for the characterization and typing of such copy number variations (CNV) are needed. The defensin cluster at the human region 8p23.1 is one of the best studied CNV regions due to its potential clinical relevance for innate immunity, inflammation, and cancer. The region can be divided into two subclusters, which harbor predominantly either alpha- or beta-defensin genes. Previous studies assessing individual copy numbers gave different results regarding whether the complete beta-defensin cluster varies or only particular genes therein. We applied multiplex ligation-dependent probe amplification (MLPA) to measure defensin locus copy numbers in 42 samples. The data show strict copy number concordance of all 10 loci typed within the beta-defensin cluster in each individual, while seven loci within the alpha-defensin cluster are consistently found as single copies per chromosome. The exception is DEFA3, which is located within the alpha-defensin cluster and was found to also differ in copy number interindividually. Absolute copy numbers ranged from two to nine for the beta-defensin cluster and zero to four for DEFA3. The CNV-typed individuals, including HapMap samples, are publicly available and may serve as a universal reference for absolute copy number determination. On this basis, MLPA represents a reliable technique for medium- to high-throughput typing of 8p23.1 defensin CNV in association studies for diverse clinical phenotypes. Hum Mutat 0,1,8, 2008. © 2008 Wiley-Liss, Inc. [source]

Identification of genetic aberrations on chromosome 22 outside the NF2 locus in schwannomatosis and neurofibromatosis type 2,

HUMAN MUTATION, Issue 6 2005
Patrick G. Buckley
Abstract Schwannomatosis is characterized by multiple peripheral and cranial nerve schwannomas that occur in the absence of bilateral 8th cranial nerve schwannomas. The latter is the main diagnostic criterion of neurofibromatosis type 2 (NF2), which is a related but distinct disorder. The genetic factors underlying the differences between schwannomatosis and NF2 are poorly understood, although available evidence implicates chromosome 22 as the primary location of the gene(s) of interest. To investigate this, we comprehensively profiled the DNA copy number in samples from sporadic and familial schwannomatosis, NF2, and a large cohort of normal controls. Using a tiling-path chromosome 22 genomic array, we identified two candidate regions of copy number variation, which were further characterized by a PCR-based array with higher resolution. The latter approach allows the detection of minute alterations in total genomic DNA, with as little as 1.5,kb per measurement point of nonredundant sequence on the array. In DNA derived from peripheral blood from a schwannomatosis patient and a sporadic schwannoma sample, we detected rearrangements of the immunoglobulin lambda (IGL) locus, which is unlikely to be due to a B-cell specific somatic recombination of IGL. Analysis of normal controls indicated that these IGL rearrangements were restricted to schwannomatosis/schwannoma samples. In the second candidate region spanning GSTT1 and CABIN1 genes, we observed a frequent copy number polymorphism at the GSTT1 locus. We further describe missense mutations in the CABIN1 gene that are specific to samples from schwannomatosis and NF2 and make this gene a plausible candidate for contributing to the pathogenesis of these disorders. Hum Mutat 26(6), 540,549, 2005. © 2005 Wiley-Liss, Inc. [source]

Evolutionary history of the ancient cutinase family in five filamentous Ascomycetes reveals differential gene duplications and losses and in Magnaporthe grisea shows evidence of sub- and neo-functionalization

NEW PHYTOLOGIST, Issue 3 2008
Pari Skamnioti
Summary ,,The cuticle is the first barrier for fungi that parasitize plants systematically or opportunistically. Here, the evolutionary history is reported of the multimembered cutinase families of the plant pathogenic Ascomycetes Magnaporthe grisea, Fusarium graminearum and Botrytis cinerea and the saprotrophic Ascomycetes Aspergillus nidulans and Neurospora crassa. ,,Molecular taxonomy of all fungal cutinases demonstrates a clear division into two ancient subfamilies. No evidence was found for lateral gene transfer from prokaryotes. The cutinases in the five Ascomycetes show significant copy number variation, they form six clades and their extreme sequence diversity is highlighted by the lack of consensus intron. The average ratio of gene duplication to loss is 2 : 3, with the exception of M. grisea and N. crassa, which exhibit extreme family expansion and contraction, respectively. ,,Detailed transcript profiling in vivo, categorizes the M. grisea cutinases into four regulatory patterns. Symmetric or asymmetric expression profiles of phylogenetically related cutinase genes suggest subfunctionalization and neofunctionalization, respectively. ,,The cutinase family-size per fungal species is discussed in relation to genome characteristics and lifestyle. The ancestry of the cutinase gene family, together with the expression divergence of its individual members provides a first insight into the drivers for niche differentiation in fungi. [source]

What a difference copy number variation makes

BIOESSAYS, Issue 4 2007
Hildegard Kehrer-Sawatzki
DNA copy number variation (CNV) represents a considerable source of human genetic diversity. Recently,1 a global map of copy number variation in the human genome has been drawn up which reveals not only the ubiquity but also the complexity of this type of variation. Thus, two human genomes may differ by more than 20 Mb and it is likely that the full extent of CNV still remains to be discovered. Nearly 3000 genes are associated with CNV. This high degree of variability with regard to gene copy number between two individuals challenges definitions of normality. Many CNVs are located in regions of complex genomic structure and this currently limits the extent to which these variants can be genotyped by using tagging SNPs. However, some CNVs are already amenable to genome-wide association studies so that their influence on human phenotypic diversity and disease susceptibility may soon be determined. BioEssays 29:311,313, 2007. © 2007 Wiley Periodicals, Inc. [source]

Association test of multiallelic gene copy numbers in family trios

GENETIC EPIDEMIOLOGY, Issue 1 2010
Sadeep Shrestha
Abstract While recent genomic surveys reveal growing numbers of di-allelic copy number variations, it is genes with multiallelic (>2) copy numbers that have shown association with distinct phenotypes. Current high-throughput laboratory methods are restricted to enumerating total gene copy numbers (GCNs) per individual and not the "genotype," i.e. gene copy per chromosome. Thus, association studies of multiallelic GCNs have been limited to comparison of median copies in different groups. Our new nonparametric statistical approach is based on GCN information within a trio-based study design. We present theoretical derivation of the statistics and results of simulation studies that show robustness of our approach and power under several genetic models. Genet. Epidemiol. 34:2,6, 2010. © 2009 Wiley-Liss, Inc. [source]

High-resolution mapping of the 8p23.1 beta-defensin cluster reveals strictly concordant copy number variation of all genes,

Detection of pathogenic gene copy number variations in patients with mental retardation by genomewide oligonucleotide array comparative genomic hybridization,,

HUMAN MUTATION, Issue 11 2007
Yao-Shan Fan
Abstract Genomic imbalance is a major cause of developmental disorders. Microarray-based comparative genomic hybridization (aCGH) has revealed frequent imbalances associated with clinical syndromes, but also a large number of copy number variations (CNVs), which have complicated the interpretation of results. We studied 100 consecutive patients with unexplained mental retardation and a normal karyotype using several platforms of CGH arrays. A genomewide array with 44,290 oligonucleotide probes (OaCGH44K) detected imbalances in 15% of cases studied with sizes ranged from 459,kb to 19,Mb while revealing a small number of CNVs (0.72/individual). Another platform with ,240,000 oligonucleotide probes (OaCGH244K) revealed a large number of CNVs (20/individual) in selected cases and their normal parents. We used a comprehensive approach for interpreting the results of aCGH, including consideration of the size, inheritance and gene content of CNVs, and consultation with an online Database of Genomic Variants (DGV) and Online Mendelian Inheritance in Men (OMIM) for information on the genes involved. Our study suggests that genomewide oligonucleotide arrays such as the OaCGH44K platform can be used as a powerful diagnostic tool for detection of genomic imbalances associated with unexplained mental retardation or syndromic autism spectrum disorders. It is interesting to note that a small number of common variants were revealed by OaCGH244K in some study subjects but not in their parents and that some inherited CNVs had altered breakpoints. Further investigations on these alterations may provide useful information for understanding the mechanism of CNVs. Hum Mutat 28(11),1124,1132, 2007. © 2007 Wiley-Liss, Inc. [source]