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Number Variation (number + variation)

Distribution by Scientific Domains

Life Sciences	76%
Medical Sciences	23%

Kinds of Number Variation

copy number variation

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]

How Drosophila change their combs: the Hox gene Sex combs reduced and sex comb variation among Sophophora species

EVOLUTION AND DEVELOPMENT, Issue 1 2008
Neel B. Randsholt
SUMMARY Identification of the events responsible for rapid morphological variation during evolution can help understand how developmental processes are changed by genetic modifications and thus produce diverse body features and shapes. Sex combs, a sexually dimorphic structure, show considerable variation in morphology and numbers among males from related species of Sophophora, a subgenus of Drosophila. To address which evolutionary changes in developmental processes underlie this diversity, we first analyzed the genetic network that controls morphogenesis of a single sex comb in the model D. melanogaster. We show that it depends on positive and negative regulatory inputs from proximo-distal identity specifying genes, including dachshund, bric à brac, and sex combs distal. All contribute to spatial regulation of the Hox gene Sex combs reduced (Scr), which is crucial for comb formation. We next analyzed the expression of these genes in sexually dimorphic species with different comb numbers. Only Scr shows considerable expression plasticity, which is correlated with comb number variation in these species. We suggest that differences in comb numbers reflect changes of Scr expression in tarsus primordia, and discuss how initial comb formation could have occurred in an ancestral Sophophora fly following regulatory modifications of developmental programs both parallel to and downstream of Scr. [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]

Phylogeography and environmental correlates of a cap on reproduction: teat number in a small marsupial, Antechinus agilis

MOLECULAR ECOLOGY, Issue 5 2007
J. BECKMAN
Abstract Natural selection should optimize litter size in response to the distribution and abundance of resources during breeding. In semelparous, litter-bearing antechinuses, teat number limits litter size. Consequently adaptation has been inferred in explaining intraspecific, geographic variability in teat number for several Antechinus spp. The phylogeography of teat number variation and associated genetic divergence were assessed in A. agilis using nine microsatellites and mitochondrial cytochrome b sequence data. Six-teat Otway Range animals were divergent in microsatellite allele identity and frequencies: samples from three Otway six-teat sites demonstrated significantly greater similarity genetically to those from six-teat animals ,250 km to the west, than to nearby Otway 10-teat samples, or to the six-teat animals at Wilsons Promontory. Gene flow between Otway phenotypes appears to have been limited for sufficient time to enable different microsatellite alleles to evolve. Nonetheless, nuclear genetic evidence suggested only incomplete reproductive isolation, and mitochondrial DNA (mtDNA) haplotypes showed no association with teat number. Other populations across the range were no more genetically differentiated from one another than expected from geographic separation. Principal components and distance-based redundancy analyses found an association between environmental variables and geographic distribution of A. agilis teat number , six-teat animals inhabit more temperate forests, whilst those with more teats experience greater seasonality. The apparent restricted breeding between phenotypically distinct animals, together with phylogenetically separate groups of six-teat animals in different locations with similar environments, are consistent with the hypothesis that adaptation to different habitats drives teat number variation in A. agilis. [source]

Evolutionary history of the European whitefish Coregonus lavaretus (L.) species complex as inferred from mtDNA phylogeography and gill-raker numbers

MOLECULAR ECOLOGY, Issue 14 2005
K. ØSTBYE
Abstract We compared mitochondrial DNA and gill-raker number variation in populations of the European whitefish Coregonus lavaretus (L.) species complex to illuminate their evolutionary history, and discuss mechanisms behind diversification. Using single-strand conformation polymorphism (SSCP) and sequencing 528 bp of combined parts of the cytochrome oxidase b (cyt b) and NADH dehydrogenase subunit 3 (ND3) mithochondrial DNA (mtDNA) regions, we documented phylogeographic relationships among populations and phylogeny of mtDNA haplotypes. Demographic events behind geographical distribution of haplotypes were inferred using nested clade analysis (NCA) and mismatch distribution. Concordance between operational taxonomical groups, based on gill-raker numbers, and mtDNA patterns was tested. Three major mtDNA clades were resolved in Europe: a North European clade from northwest Russia to Denmark, a Siberian clade from the Arctic Sea to southwest Norway, and a South European clade from Denmark to the European Alps, reflecting occupation in different glacial refugia. Demographic events inferred from NCA were isolation by distance, range expansion, and fragmentation. Mismatch analysis suggested that clades which colonized Fennoscandia and the Alps expanded in population size 24 500,5800 years before present, with minute female effective population sizes, implying small founder populations during colonization. Gill-raker counts did not commensurate with hierarchical mtDNA clades, and poorly with haplotypes, suggesting recent origin of gill-raker variation. Whitefish designations based on gill-raker numbers were not associated with ancient clades. Lack of congruence in morphology and evolutionary lineages implies that the taxonomy of this species complex should be reconsidered. [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]

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]

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]

A study of the diversity and geographical variation in numbers of leg-bearing segments in centipedes (Chilopoda: Geophilomorpha) in north-western Europe

BIOLOGICAL JOURNAL OF THE LINNEAN SOCIETY, Issue 4 2010
STYLIANOS M. SIMAIAKIS
Five species of geophilomorphs, Strigamia maritima (Leach, 1817), Geophilus flavus (De Geer, 1778), Geophilus truncorum Bergsøe and Meinert, 1866, Geophilus proximus C. L. Koch, 1847, and Pachymerium ferrugineum (C. L. Koch, 1835), from various sample sites in north-western Europe were examined for numbers of leg-bearing segments. Where data was adequate, mean segment numbers were correlated with latitudinal gradients for each species. Solely in S. maritima and some populations of P. ferrugineum did the results show a highly significant geographic pattern towards more leg-bearing segments in southern populations of both sexes. As concerns G. proximus, we presented for the first time a remarkable geographic shift towards an increased number of pairs of legs in northern populations. Contrary to the conventional geographic pattern, we found that G. flavus and G. truncorum did not exhibit a north,south increase or decrease in segment number. Although there was no general/universal evidence supporting the occurrence of a significant regression slope between mean segment number and latitude/temperature, more information shows that the overall region-to-region segment variation was highly significant in both sexes. In S. maritima and P. ferrugineum mean segment number was correlated with the north,south temperature cline. The same was not observed in G. proximus. Parthenogenesis in G. proximus, and a series of ecological characteristics such as habitat preferences, spatial distribution, and fragmented populations could explain the presence or absence of a geographic patterning of segment number variation along a latitudinal cline. © 2010 The Linnean Society of London, Biological Journal of the Linnean Society, 2010, 100, 899,909. [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]