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Association of Activating KIR Copy Number Variation of NK Cells with Containment of SIV Replication in Rhesus Monkeys  [PDF]
Ina Hellmann,So-Yon Lim,Rebecca S. Gelman,Norman L. Letvin
PLOS Pathogens , 2011, DOI: 10.1371/journal.ppat.1002436
Abstract: While the contribution of CD8+ cytotoxic T lymphocytes to early containment of HIV-1 spread is well established, a role for NK cells in controlling HIV-1 replication during primary infection has been uncertain. The highly polymorphic family of KIR molecules expressed on NK cells can inhibit or activate these effector cells and might therefore modulate their activity against HIV-1-infected cells. In the present study, we investigated copy number variation in KIR3DH loci encoding the only activating KIR receptor family in rhesus monkeys and its effect on simian immunodeficiency virus (SIV) replication during primary infection in rhesus monkeys. We observed an association between copy numbers of KIR3DH genes and control of SIV replication in Mamu-A*01– rhesus monkeys that express restrictive TRIM5 alleles. These findings provide further evidence for an association between NK cells and the early containment of SIV replication, and underscore the potential importance of activating KIRs in stimulating NK cell responses to control SIV spread.
Variation in chromosome copy number influences the virulence of Cryptococcus neoformans and occurs in isolates from AIDS patients
Guanggan Hu, Joyce Wang, Jaehyuk Choi, Won Jung, Iris Liu, Anastasia P Litvintseva, Tihana Bicanic, Rajeev Aurora, Thomas G Mitchell, John R Perfect, James W Kronstad
BMC Genomics , 2011, DOI: 10.1186/1471-2164-12-526
Abstract: In an initial set of strains, melanin production was correlated with monosomy at chromosome 13, and disomic variants were less melanized and attenuated for virulence in mice. After growth in culture or passage through mice, subsequent strains were identified that varied in melanin formation and exhibited copy number changes for other chromosomes. The correlation between melanin and disomy at chromosome 13 was observed for some but not all strains. A survey of environmental and clinical isolates maintained in culture revealed few occurrences of disomic chromosomes. However, an examination of isolates that were freshly collected from the cerebrospinal fluid of AIDS patients and minimally cultured provided evidence for infections with multiple strains and copy number variation.Overall, these results suggest that the genome of C. neoformans exhibits a greater degree of plasticity than previously appreciated. Furthermore, the expression of an essential virulence factor and the severity of disease are associated with genome variation. The occurrence of chromosomal variation in isolates from AIDS patients, combined with the observed influence of disomy on virulence, indicates that genome plasticity may have clinical relevance.The adaptation of pathogens to the host environment is a critical determinant of the outcome of disease. Well-documented examples include antigenic variation in parasites and fungi to evade adaptive immune responses, viral evasion of immune detection, and phase variation in bacterial pathogens [1-5]. For fungi that attack humans, accumulating evidence indicates that genomic plasticity also contributes to adaptation to the host. For example, surveys of clinical isolates of Candida albicans reveal extensive variation in karyotypes and chromosome copy number, and genomic changes have been shown to arise during infection [6-11]. Furthermore, aneuploidy is common in laboratory strains of C. albicans, and this trait, along with isochromosome formation, is a
Copy Number Variation of the Beta Defensin Gene Cluster on Chromosome 8p Influences the Bacterial Microbiota within the Nasopharynx of Otitis-Prone Children  [PDF]
Eric A. Jones, Anchasa Kananurak, Charles L. Bevins, Edward J. Hollox, Lauren O. Bakaletz
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098269
Abstract: As there is increasing evidence that aberrant defensin expression is related to susceptibility for infectious disease and inflammatory disorders, we sought to determine if copy number of the beta-defensin gene cluster located on chromosome 8p23.1 (DEFB107, 106, 105, 104, 103, DEFB4 and SPAG11), that shows copy number variation as a block, was associated with susceptibility to otitis media (OM). The gene DEFB103 within this complex encodes human beta defensin-3 (hBD-3), an antimicrobial peptide (AP) expressed by epithelial cells that line the mammalian airway, important for defense of mucosal surfaces and previously shown to have bactericidal activity in vitro against multiple human pathogens, including the three that predominate in OM. To this end, we conducted a retrospective case-control study of 113 OM prone children and 267 controls aged five to sixty months. We identified the copy number of the above defined beta-defensin gene cluster (DEFB-CN) in each study subject by paralogue ratio assays. The mean DEFB-CN was indistinguishable between subjects classified as OM prone based on a recent history of multiple episodes of OM and control subjects who had no history of OM (4.4±0.96 versus 4.4±1.08, respectively: Odds Ratio [OR]: 1.16 (95% CI: 0.61, 2.20). Despite a lack of direct association, we observed a statistically significant correlation between DEFB-CN and nasopharyngeal bacterial colonization patterns. Collectively, our findings suggested that susceptibility to OM might be mediated by genetic variation among individuals, wherein a DEFB-CN less than 4 exerts a marked influence on the microbiota of the nasopharynx, specifically with regard to colonization by the three predominant bacterial pathogens of OM.
Copy number variation in the bovine genome
Jo?o Fadista, Bo Thomsen, Lars-Erik Holm, Christian Bendixen
BMC Genomics , 2010, DOI: 10.1186/1471-2164-11-284
Abstract: We designed and used a set of NimbleGen CGH arrays that tile across the assayable portion of the cattle genome with approximately 6.3 million probes, at a median probe spacing of 301 bp. This study reports the highest resolution map of copy number variation in the cattle genome, with 304 CNV regions (CNVRs) being identified among the genomes of 20 bovine samples from 4 dairy and beef breeds. The CNVRs identified covered 0.68% (22 Mb) of the genome, and ranged in size from 1.7 to 2,031 kb (median size 16.7 kb). About 20% of the CNVs co-localized with segmental duplications, while 30% encompass genes, of which the majority is involved in environmental response. About 10% of the human orthologous of these genes are associated with human disease susceptibility and, hence, may have important phenotypic consequences.Together, this analysis provides a useful resource for assessment of the impact of CNVs regarding variation in bovine health and production traits.Cattle, part of the Cetartiodactyl order of eutherian mammals [1], is an important source of human nutrition worldwide as well as the most studied ruminant model of metabolism, reproduction, and disease [2]. Following the milestone publication of the cattle genome assembly along with annotation of functional elements and variation [2,3], we are now enabled to search for genomic regions that impact the genetic variation of important phenotypic traits.Genomic structural variation, including insertions, duplications, deletions, inversions and translocations of DNA, has long been known to be present in animal genomes [4,5] but had predominantly been assumed to be to rare events and often associated with disease. This notion changed in 2004 when two groups of researchers published the first genome-wide maps of copy number variation in seemingly healthy individuals [6,7]. Copy number variant (CNV) is described as a segment of DNA > = 1 kb that is copy number variable when compared with a reference genome [8]. Before these
Copy number variation goes clinical
Cédric Le Caignec, Richard Redon
Genome Biology , 2009, DOI: 10.1186/gb-2009-10-1-301
Abstract: Since its development in the late 1990s, microarray-based comparative genomic hybridization (aCGH) has been widely used to screen for copy-number changes at high resolution across whole genomes. It has quickly become a reference method for the diagnosis of patients with severe developmental defects and has been instrumental in the discovery of a new abundant source of polymorphism in the human genome, called DNA copy number variation (CNV). Here we report some highlights of the First Golden Helix Symposium, focusing on the latest advances in the rapidly evolving field of research on CNV.Chromosomal imbalances are a major known cause of learning disability and developmental defects. A standard karyotype can only detect chromosomal imbalances (deletions and duplications) larger than 5 Mb, whereas aCGH is able to detect cryptic chromosomal imbalances that are not detectable by standard cytogenetic analysis. Since the recent implementation of aCGH in clinical diagnosis, large numbers of patients have been tested worldwide and genomic copy number alterations have been detected in around 10-15% of such patients with apparently normal karyotypes.Pawel Stankiewicz (Baylor College of Medicine, Houston, USA) reported a large study in which more than 18,500 patients with mental retardation with or without anatomical malformations have been screened by aCGH. DNA samples from patients were analyzed using custom bacterial artificial chromosome (BAC) arrays until March 2007, when BACs were replaced by oligonucleotides. Overall, chromosomal imbalances with clinical significance were identified in 14% of the patients. This enormous dataset led to the discovery of several recurrent genomic disorders, in particular, microdeletions and microduplications on chromosome 1q21.1 in a series of individuals with developmental delay and neuropsychiatric abnormalities. The 1q21.1 microdeletions found in the Baylor study can be de novo, or be inherited from a mildly affected parent, or be inheri
CCL3L1 Copy Number Variation and Susceptibility to HIV-1 Infection: A Meta-Analysis  [PDF]
SiJie Liu,Lei Yao,DongLin Ding,HuanZhang Zhu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015778
Abstract: Although several studies have investigated whether CCL3L1 copy number variation (CNV) influences the risk of HIV-1 infection, there are still no clear conclusions. Therefore, we performed a meta-analysis using two models to generate a more robust estimate of the association between CCL3L1 CNV and susceptibility to HIV-1 infection.
Copy number variation in African Americans
Joseph P McElroy, Matthew R Nelson, Stacy J Caillier, Jorge R Oksenberg
BMC Genetics , 2009, DOI: 10.1186/1471-2156-10-15
Abstract: Employing a SNP platform with greater than 500,000 SNPs, a first-generation CNV map of the African American genome was generated using DNA from 385 healthy African American individuals, and compared to a sample of 435 healthy White individuals. A total of 1362 CNVs were identified within African Americans, which included two CNV regions that were significantly different in frequency between African Americans and Whites (17q21 and 15q11). In addition, a duplication was identified in 74% of DNAs derived from cell lines that was not present in any of the whole blood derived DNAs.The Affymetrix 500 K array provides reliable CNV mapping information. However, using cell lines as a source of DNA may introduce artifacts. The duplication identified in high frequency in Whites and low frequency in African Americans on chromosome 17q21 reflects haplotype specific frequency differences between ancestral groups. The generation of the CNV map will be a valuable tool for identifying disease associated CNVs in African Americans.Duplications or deletions of genomic segments generate copy number variants (CNVs) that can range is size from one thousand to several million base pairs, and may affect one or more genes. More nucleotides appear to be affected by CNVs than by single nucleotide polymorphisms (SNPs) [1]. Current annotated CNVs cover about 28.8% of the genome, and, to date, over 5600 non-overlapping human CNV loci have been identified http://projects.tcag.ca/variation webcite; Database of Genomic Variants) [2]. CNVs are a major source of human genetic diversity, and have been shown to influence rare genomic disorders [3] as well as complex traits and diseases [4].In addressing the role of CNVs in disease, it is important to understand their distribution in the population at large [5]. Several studies have attempted to characterize CNVs in the general population using data from the International HapMap Consortium [1,6-8], and other reference groups [2,5,9-11], and have confirme
Copy Number Variation in the Horse Genome  [PDF]
Sharmila Ghosh,Zhipeng Qu,Pranab J. Das,Erica Fang,Rytis Juras,E. Gus Cothran,Sue McDonell,Daniel G. Kenney,Teri L. Lear,David L. Adelson,Bhanu P. Chowdhary,Terje Raudsepp
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004712
Abstract: We constructed a 400K WG tiling oligoarray for the horse and applied it for the discovery of copy number variations (CNVs) in 38 normal horses of 16 diverse breeds, and the Przewalski horse. Probes on the array represented 18,763 autosomal and X-linked genes, and intergenic, sub-telomeric and chrY sequences. We identified 258 CNV regions (CNVRs) across all autosomes, chrX and chrUn, but not in chrY. CNVs comprised 1.3% of the horse genome with chr12 being most enriched. American Miniature horses had the highest and American Quarter Horses the lowest number of CNVs in relation to Thoroughbred reference. The Przewalski horse was similar to native ponies and draft breeds. The majority of CNVRs involved genes, while 20% were located in intergenic regions. Similar to previous studies in horses and other mammals, molecular functions of CNV-associated genes were predominantly in sensory perception, immunity and reproduction. The findings were integrated with previous studies to generate a composite genome-wide dataset of 1476 CNVRs. Of these, 301 CNVRs were shared between studies, while 1174 were novel and require further validation. Integrated data revealed that to date, 41 out of over 400 breeds of the domestic horse have been analyzed for CNVs, of which 11 new breeds were added in this study. Finally, the composite CNV dataset was applied in a pilot study for the discovery of CNVs in 6 horses with XY disorders of sexual development. A homozygous deletion involving AKR1C gene cluster in chr29 in two affected horses was considered possibly causative because of the known role of AKR1C genes in testicular androgen synthesis and sexual development. While the findings improve and integrate the knowledge of CNVs in horses, they also show that for effective discovery of variants of biomedical importance, more breeds and individuals need to be analyzed using comparable methodological approaches.
Copy Number Variation across European Populations  [PDF]
Wanting Chen,Caroline Hayward,Alan F. Wright,Andrew A. Hicks,Veronique Vitart,Sara Knott,Sarah H. Wild,Peter P. Pramstaller,James F. Wilson,Igor Rudan,David J. Porteous
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0023087
Abstract: Genome analysis provides a powerful approach to test for evidence of genetic variation within and between geographical regions and local populations. Copy number variants which comprise insertions, deletions and duplications of genomic sequence provide one such convenient and informative source. Here, we investigate copy number variants from genome wide scans of single nucleotide polymorphisms in three European population isolates, the island of Vis in Croatia, the islands of Orkney in Scotland and the South Tyrol in Italy. We show that whereas the overall copy number variant frequencies are similar between populations, their distribution is highly specific to the population of origin, a finding which is supported by evidence for increased kinship correlation for specific copy number variants within populations.
Elusive Copy Number Variation in the Mouse Genome  [PDF]
Avigail Agam,Binnaz Yalcin,Amarjit Bhomra,Matthew Cubin,Caleb Webber,Christopher Holmes,Jonathan Flint,Richard Mott
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012839
Abstract: Array comparative genomic hybridization (aCGH) to detect copy number variants (CNVs) in mammalian genomes has led to a growing awareness of the potential importance of this category of sequence variation as a cause of phenotypic variation. Yet there are large discrepancies between studies, so that the extent of the genome affected by CNVs is unknown. We combined molecular and aCGH analyses of CNVs in inbred mouse strains to investigate this question.
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