2012.9.25 Copy number variation detection via normalizing high-throughput sequencing data at a nucleotide level Speaker:Ruibin XI (School of Mathematical Sciences, PKU) Time:1:00pm, Se
Elia, J., Glessner, J.T., Wang, K., Takahashi, N., Shtir, C.J., Hadley, D., Sleiman, P.M.A., Zhang, H., Kim, C.E., Robison, R., Lyon, G.J., Flory, J.H., Bradfield, J.P., Imielinski, M., Hou, C., Frackelton, E.C., Chiavacci, R.M., Sakurai, T., Rabin, C., Middleton, F.A., Thomas, K.A., Garris, M., Mentch, F., Freitag, C.M., Steinhausen, H.-C., Todorov, A.A., Reif, A., Rothenberger, A., Franke, B., Mick, E.O., Roeyers, H., Buitelaar, J., Lesch, K.-P., Banaschewski, T., Ebstein, R.P., Mulas, F., Oades, R.D., Sergeant, J., Sonuga-Barke, E., Renner, T.J., Romanos, M., Romanos, J., Warnke, A., Walitza, S., Meyer, J., Pálmason, H., Seitz, C., Loo, S.K., Smalley, S.L., Biederman, J., Kent, L., Asherson, P., Anney, R.J.L., Gaynor, J.W., Shaw, P., Devoto, M., White, P.S., Grant, S.F.A., Buxbaum, J.D., Rapoport, J.L., Williams, N.M., Nelson, S.F., Faraone, S.V., Hakonarson, H. (2012-01). Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit ...
The strong association of de novo CNVs with ASD is consistent with such mutations being a primary cause in most cases rather than merely contributory. A further line of evidence to support this claim is the higher proportion of females among cases with de novo mutations, where the genders of patients consisted of 9 males and 5 females (1.8:1) compared with 163 males and 32 females (5:1) in our overall sample. This reduced gender ratio suggests that de novo CNVs that are detectable by our method have increased penetrance and, thus, contribute to disease more equally in females and males.. A lower rate of de novo mutation in multiplex families is also consistent with a causal role for the mutations reported in this study. An alternative hypothesis is that de novo CNVs are associated with autism indirectly, the consequence of a "fragile-genome disorder" in which many lesions in addition to the ones we detected occur due to an unknown environmental or heritable factor. We regard this alternative as ...
From a number of genome-wide association studies it was shown that de novo and/or rare copy number variants (CNVs) are found at an increased frequency in neuropsychiatric diseases. In this study we examined the prevalence of CNVs in six genomic regions (1q21.1, 2p16.3, 3q29, 15q11.2, 15q13.3, and 16p11.2) previously implicated in neuropsychiatric diseases. Hereto, a cohort of four neuropsychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, and intellectual disability) and control individuals from three different populations was used in combination with Multilpex Amplicon Quantifiaction (MAQ) assays, capable of high resolution (kb range) and custom-tailored CNV detection. Our results confirm the etiological candidacy of the six selected CNV regions for neuropsychiatric diseases. It is possible that CNVs in these regions can result in disturbed brain development and in this way lead to an increased susceptibility for different neuropsychiatric disorders, dependent on ...
Background: Congenital malformations are present in approximately 2-3% of liveborn babies and 20% of stillborn fetuses. The mechanisms underlying the majority of sporadic and isolated congenital malformations are poorly understood, although it is hypothesized that the accumulation of rare genetic, genomic and epigenetic variants converge to deregulate developmental networks. Methodology/Principal Findings: We selected samples from 95 fetuses with congenital malformations not ascribed to a specific syndrome (68 with isolated malformations, 27 with multiple malformations). Karyotyping and Multiplex Ligation-dependent Probe Amplification (MLPA) discarded recurrent genomic and cytogenetic rearrangements. DNA extracted from the affected tissue (46%) or from lung or liver (54%) was analyzed by molecular karyotyping. Validations and inheritance were obtained by MLPA. We identified 22 rare copy number variants (CNV) [,100 kb, either absent (n = 7) or very uncommon (n = 15, ,1/2,000) in the control ...
The first estimation of how genomic copy number variation (CNV) can influence anesthetic sensitivity and the magnitude of this influence can be gauged by a new study
This study reports a family trio-based study performed to identify rare CNVs in patients with sporadic, nonsyndromic cardiac OFT defects of 3 different types, respectively CoA, TGA, and ToF. The family trio design allowed us to identify 8 (11.3%) de novo rare CNVs and 63 (88.7%) inherited ones. De novo CNVs were significantly more frequent in patients with CoA (4.1%) and ToF (6.6%) compared with patients with TGA (no CNV in 159 patients; P=0.002). This difference indicates that novel genetic events are less frequent in the pathogenesis of TGA than in that of ToF and CoA. Thus, TGA could result from a genetic predisposition related to many low impact, mostly inherited, variants associated to environmental factors. The frequency of de novo CNVs identified in patients with ToF (6.6%) is broadly similar to previously reported frequencies11,21 considering the differences in the arrays and analysis pipelines between the studies. For example, Greenway et al11 reported 10% of de novo CNVs in their ToF ...
Results The large majority of these CNVs (76%, p=1.14×10−8) originated on the paternal allele. This paternal bias was independent of CNV length and CNV type. Interestingly, the paternal bias was less pronounced for CNVs flanked by segmental duplications (64%), suggesting that molecular mechanisms involved in the formation of rare de novo CNVs may be dependent on the parent-of-origin. In addition, a significantly increased paternal age was only observed for those CNVs which were not flanked by segmental duplications (p=0.02). ...
The AluScan platform, comprising the usage of inter-Alu PCR with multiple Alu-based PCR primers to generate a huge range of amplicons for next-generation sequencing, enables the facile capture of Alu-proximal sequences that are widespread throughout the human genome. It makes possible a rapid scan of mutations and alterations in diverse genomic regions including exons, introns and other non-coding regions employing only ~0.1 μg DNA samples [11].. The results in Figures 2 and 4 showed that the distribution of t-values obtained from AluScan sequences conformed closely to a normal distribution, and the read-depths of a test AluScan sample were closely correlated with those of a paired control AluScan or a reference template constructed from the AluScans of reference samples. These findings established the validity of the AluScanCNV package for calling CNVs from AluScan sequences, which was further confirmed by the properties of the AluScan-derived CNVs identified in various cancer samples.. In ...
Schizophrenia (SCZ) is a common, complex and severe psychiatric disorder associated with many different genetic and environmental risk factors. Evidence from genetic studies has revealed the role of genome structural variations, specifically copy number variants (CNVs), in the etiology of SCZ. Nevertheless, the occurrence of CNVs and their relation to SCZ has remained relatively unstudied in the diverse Han Chinese population. We used a case/control paradigm, including 476 cases and 1023 controls. All samples were genotyped using the Axiom® Exome Genotyping Arrays. Four CNVs, including two deletions and two duplications, were detected in this study. Notably, the 16p11.2 duplication from 29.3 Mb to 29.6 Mb was detected in four cases (0.84%) and one control (0.098%) (p = 0.0377). The results highlight the potential role of these deletions and duplications in the development of SCZ. Clearly, larger sample sized studies are needed for a careful localization of these CNVs and to possibly detect more
Cancer genomes frequently contain somatic copy number alterations (SCNA) that can significantly perturb the expression level of affected genes and thus disrupt pathways controlling normal growth. In melanoma, many studies have focussed on the copy number and gene expression levels of the BRAF, PTEN and MITF genes, but little has been done to identify new genes using these parameters at the genome-wide scale. Using karyotyping, SNP and CGH arrays, and RNA-seq, we have identified SCNA affecting gene expression (SCNA-genes) in seven human metastatic melanoma cell lines. We showed that the combination of these techniques is useful to identify candidate genes potentially involved in tumorigenesis. Since few of these alterations were recurrent across our samples, we used a protein network-guided approach to determine whether any pathways were enriched in SCNA-genes in one or more samples. From this unbiased genome-wide analysis, we identified 28 significantly enriched pathway modules. Comparison with two
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TY - JOUR. T1 - Loss of maternal ANNEXIN A10 via a 34-kb deleted-type copy number variation is associated with embryonic mortality in Japanese Black cattle. AU - Sasaki, Shinji. AU - Ibi, Takayuki. AU - Akiyama, Takayuki. AU - Fukushima, Moriyuki. AU - Sugimoto, Yoshikazu. PY - 2016/11/24. Y1 - 2016/11/24. N2 - Background: Conception is a fundamental trait for successful cattle reproduction. However, conception rates in Japanese Black cattle have been gradually declining over the last two decades. Although conception failures are mainly caused by embryonic mortality, the role of maternal genetic factors in the process remains unknown. Copy number variation (CNV), defined as large-scale genomic structural variants, contributes to several genetic disorders. To identify CNV associated with embryonic mortality in Japanese Black cattle, we evaluated embryonic mortality as a categorical trait with a threshold model and conducted a genome-wide CNV association study for embryonic mortality using 791 ...
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Our analysis of genome-wide chromosomal copy number of pancreatic cancer precursor neoplasms from patients with a family history of pancreatic cancer reveals that most low-grade precursor lesions do not harbor any detectable somatic chromosomal copy number alterations. Analysis of these lesions for KRAS codon 12/13 mutations revealed that approximately 95% of familial PanIN lesions harbored KRAS mutations. These 2 findings, a very high prevalence of mutant KRAS lesions and the paucity of somatic chromosomal copy number alterations in early familial precursor lesions, support the hypothesis that many familial PanINs are not initiated tumor suppressor gene inactivation. Although there are other mechanisms by which germ line tumor suppressor gene mutations can promote tumorigenesis besides the "second-hit" provided by copy number loss (such as haploinsufficiency from a germ line mutation or "second-hit" inactivation by intragenic mutation or promoter methylation), our results raise the possibility ...
Lesch, K P; Selch, S; Renner, T J; Jacob, C; Nguyen, T T; Hahn, T; Romanos, M; Walitza, S; Shoichet, S; Dempfle, A; Heine, M; Boreatti-Hümmer, A; Romanos, J; Gross-Lesch, S; Zerlaut, H; Wultsch, T; Heinzel, S; Fassnacht, M; Fallgatter, A; Allolio, B; Schäfer, H; Warnke, A; Reif, A; Ropers, H H; Ullmann, R (2011). Genome-wide copy number variation analysis in attention-deficit/hyperactivity disorder: association with neuropeptide Y gene dosage in an extended pedigree. Molecular Psychiatry, 16(5):491-503.. Romanos, M; Freitag, C; Jacob, C; Craig, D W; Dempfle, A; Nguyen, T T; Halperin, R; Walitza, S; Renner, T J; Seitz, C; Romanos, J; Palmason, H; Reif, A; Heine, M; Windemuth-Kieselbach, C; Vogler, C; Sigmund, J; Warnke, A; Schäfer, H; Meyer, J; Stephan, D A; Lesch, K P (2008). Genome-wide linkage analysis of ADHD using high-density SNP arrays: novel loci at 5q13.1 and 14q12. Molecular Psychiatry, 13(5):522-530.. Lesch, K P; Timmesfeld, N; Renner, T J; Halperin, R; Röser, C; Nguyen, T T; ...
The recent genome-wide allele-specific copy number variation data enable us to explore two types of genomic information including chromosomal genotype variations as well as DNA copy number variations. For a cancer study, it is common to collect data for paired normal and tumor samples. Then, two types of paired data can be obtained to study a disease subject. However, there is a lack of methods for a simultaneous analysis of these four sequences of data. In this study, we propose a statistical framework based on the change-point analysis approach. The validity and usefulness of our proposed statistical framework are demonstrated through the simulation studies and applications based on an experimental data set.
We conducted a genome-wide scan for large CNVs (≥100 kb) in a case-control dataset of Caribbean Hispanic origin that was previously investigated in a SNP-based GWAS (Lee JH et al. 2010). To generate results with high confidence, we focused on CNVs that were identified by at least two algorithms. We detected 1774 stringent CNVs (Table S4). First, we tested the hypothesis that rare CNVs (≤1%) with a potentially strong impact on AD risk in individual patients might contribute to the overall disease risk, as was previously observed in other common neuropsychiatric disorders (Kirov et al. 2009; Zhang et al. 2009; Glessner et al. 2010). However, the burden analyses of rare CNVs did not find significant differences between cases and controls in CNV rate, total or average CNV size, or the number of genes affected by CNVs.. In addition, we conducted a case-control analysis of large genic CNVs, including common variants, using PLINK regional analysis. The only nominally significant result that ...
Copy number analysis usually refers to the process of analyzing data produced by a test for DNA copy number variation in patients sample. Such analysis helps detect chromosomal copy number variation that may cause or may increase risks of various critical disorders. Copy number variation can be detected with various types of tests such as fluorescent in situ hybridization, comparative genomic hybridization and with high-resolution array-based tests based on array comparative genomic hybridization (or aCGH), SNP array technologies and high resolution microarrays that include copy number probes as well an SNPs. Array-based methods have been accepted as the most efficient in terms of their resolution and high-throughput nature and the highest coverage (choose an array with over 2 million probes) and they are also referred to as Virtual Karyotype. Data analysis for an array-based DNA copy number test can be very challenging though due to very high volume of data that come out of an array platform. ...
Pregnancy complications could lead to maternal and fetal morbidity and mortality. Early diagnosing and managing complications have been associated with good outcomes. The placenta was an important organ for development of pregnancy complications. Thus, non-invasive prenatal testing technologies could detect genetic variations, such as aneuploidies and sub-chromosomal copy number variations, reflecting defective placenta by maternal plasma cffDNAs. Maternal cffDNAs had been proved to derive from trophoblast cells of placenta. In order to find out the relationship between genetic variations and pregnancy complications, we reviewed NIPT results for subchromosomal copy number variations in a cohort of 3890 pregnancies without complications and 441 pregnancies with pregnancy complications including gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), preterm prelabor rupture of membranes (PPROM) and placenta implantation abnormalities (PIA). For GDMs, we identified three CNV regions
TY - JOUR. T1 - Glutathione S-transferase copy number variation alters lung gene expression. AU - Butler, M. W.. AU - Hackett, N. R.. AU - Salit, J.. AU - Strulovici-Barel, Y.. AU - Omberg, L.. AU - Mezey, J.. AU - Crystal, Ronald. PY - 2011/7/1. Y1 - 2011/7/1. N2 - The glutathione S-transferase (GST) enzymes catalyse the conjugation of xenobiotics to glutathione. Based on reports that inherited copy number variations (CNVs) modulate some GST gene expression levels, and that the small airway epithelium (SAE) and alveolar macrophages (AMs) are involved early in the pathogenesis of smoking-induced lung disease, we asked: do germline CNVs modulate GST expression levels in SAE and AMs? Microarrays were used to survey GST gene expression and determine CNVs genotypes in SAE and AMs obtained by bronchoscopy from current smokers and nonsmokers. 26% of subjects were null for both GSTM1 alleles, with reduced GSTM1 mRNA levels seen in both SAE and AMs. 30% of subjects had homozygous deletions of GSTT1, ...
MiRNA-mediated gene regulation is complex and genomic variations, such as CNVs and SNPs, which can modulate miRNA expression, add to this complexity. The miRNA-CNV relationship has been rarely studied and predominantly involved polymorphic CNVs found in control cohorts [9, 10].. Our study is novel in its comparison of miRNA content in different classes of CNVs detected in a cohort of subjects with ID relative to cognitively typical subjects. We found a significant increase in the number of miRNAs in de novo and DECIPHER CNVs versus common CNVs (weighted median 0.6 and 0.8 versus 0.0, P , 0.05). In addition, the miRNAs in de novo CNVs were more likely to have expression in brain-related tissues or cell lines compared to the miRNAs from common CNV groups. Our collective findings suggest that miRNAs from de novo and putatively pathogenic CNVs could contribute to ID etiopathogenesis, in addition to coding genes integral to CNVs.. Similar to the increase in the number of miRNAs in de novo and ...
Structural variation is thought to play a major etiological role in the development of autism spectrum disorders (ASDs), and numerous studies documenting the relevance of copy number variants (CNVs) in ASD have been published since 2006. To determine if large ASD families harbor high-impact CNVs that may have broader impact in the general ASD population, we used the Affymetrix genome-wide human SNP array 6.0 to identify 153 putative autism-specific CNVs present in 55 individuals with ASD from 9 multiplex ASD pedigrees. To evaluate the actual prevalence of these CNVs as well as 185 CNVs reportedly associated with ASD from published studies many of which are insufficiently powered, we designed a custom Illumina array and used it to interrogate these CNVs in 3,000 ASD cases and 6,000 controls. Additional single nucleotide variants (SNVs) on the array identified 25 CNVs that we did not detect in our family studies at the standard SNP array resolution. After molecular validation, our results demonstrated
Environmental risk factors have been shown to alter DNA copy number variations (CNVs). Recently, CNVs have been described to arise after low-dose ionizing radiation in vitro and in vivo. Development of cost- and size-effective laser-driven electron accelerators (LDEAs), capable to deliver high energy beams in pico- or femtosecond durations requires examination of their biological effects. Here we studied in vitro impact of LDEAs radiation on known CNV hotspots in human peripheral blood lymphocytes on single cell level. Here CNVs in chromosomal regions 1p31.1, 7q11.22, 9q21.3, 10q21.1 and 16q23.1 earlier reported to be sensitive to ionizing radiation were analyzed using molecular cytogenetics. Irradiation of cells with 0.5, 1.5 and 3.0 Gy significantly increased signal intensities in all analyzed chromosomal regions compared to controls. The latter is suggested to be due to radiation-induced duplication or amplification of CNV stretches. As significantly lower gains in mean fluorescence intensities were
Although both intragenic deletions and duplications can lead to out-of-frame defects and gene haploinsufficiency, frequency of intragenic deletions appears to be higher than duplications. A study with targeted exon-level CNV analysis in 3018 patients with suspected Mendelian disorders illustrated a CNV detection rate of 3.3% of which 96 were deletions and only 2 were duplications.48 Recent data from WES have also indicated the enrichment of 1-30 kb deletions in individuals with ASD.7 Accordingly, 12 of our 41 confirmed rare small deletions (29%) were pathogenic, but only 2 of 17 confirmed rare duplications (12%) were categorised as such, but the difference did not reach statistical significance.. With reference to inheritance pattern (figure 4B), 24% of confirmed small CNVs were de novo or likely de novo, but only 57% of these were considered disease causing. Rare CNVs occurring de novo are more likely to be pathogenic, and consensus guidelines suggest de novo CNVs to be considered for causality ...
DNA copy number variations (CNVs) are an important component of genetic variation, affecting a greater fraction of the genome than single nucleotide polymorphisms (SNPs). The advent of high-resolution SNP arrays has made it possible to identify CNVs. Characterization of widespread constitutional (germline) CNVs has provided insight into their role in susceptibility to a wide spectrum of diseases, and somatic CNVs can be used to identify regions of the genome involved in disease phenotypes. The role of CNVs as risk factors for cancer is currently underappreciated. However, the genomic instability and structural dynamism that characterize cancer cells would seem to make this form of genetic variation particularly intriguing to study in cancer. Here, we provide a detailed overview of the current understanding of the CNVs that arise in the human genome and explore the emerging literature that reveals associations of both constitutional and somatic CNVs with a wide variety of human cancers.
Researchers have identified the deletion of a genomic region on chromosome 17 as a significant risk factor for autism spectrum disorders (ASD) and schizophrenia. A mutation of one of the genes in the deleted interval already is a known cause of renal cysts and diabetes syndrome (RCAD). The research, by an international collaboration of scientists led by Emory University, will be published in the American Journal of Human Genetics. Lead author of the study is Daniel Moreno-De-Luca, MD, MSc, Emory postdoctoral fellow in the Department of Human Genetics. Senior authors at Emory include David H. Ledbetter, PhD and Christa L. Martin, PhD.. Scientists have known that autism and schizophrenia are strongly influenced by genetic mutations. Although they have shown that rare copy number variations insertions or deletions of genomic material play a common and overlapping role in the two disorders, they had not previously identified this specific copy number variation (CNV), which confers very high risk. ...
Perennial, clonally propagated plants provide a challenge and an opportunity for functional gene discovery. Meiotic recombination-based genetic analysis and breeding are hampered by the long generation cycle. On the other hand, clonal propagation enables the production of many individuals with identical genotypes and economic exploitation of plants without the need for sexual reproduction. In collaboration with Andrew Groover at US Forest Service, Davis we are studying the effect of genomic copy number variation on poplar hybrid performance. We are studying both variation induced by hybridization and by ionizing radiation, the latter applied to pollen during interspecific hybridization. ...
Perennial, clonally propagated plants provide a challenge and an opportunity for functional gene discovery. Meiotic recombination-based genetic analysis and breeding are hampered by the long generation cycle. On the other hand, clonal propagation enables the production of many individuals with identical genotypes and economic exploitation of plants without the need for sexual reproduction. In collaboration with Andrew Groover at US Forest Service, Davis we are studying the effect of genomic copy number variation on poplar hybrid performance. We are studying both variation induced by hybridization and by ionizing radiation, the latter applied to pollen during interspecific hybridization. ...
DNA copy number variants represent the greatest source of genetic variability in humans [1] and are the underlying cause of many human diseases. Array CGH is recognized as a first-tier test for DNA copy number variants (CNV) [2] and accordingly, many laboratories have already established their pipelines for pre-processing of array CGH data and CNV calling. In many cases these pipelines are based on software packages provided by the companies selling DNA microarrays or scanners such as BlueFuse [3], CytoSure [4] or CytoGenomics [5]. Yet, the scope of these tools is focused on the identification of CNVs and their evaluation in the context of gene content and frequency of a given variant in the healthy population. Comparative analysis, which integrates data obtained from multiple patients, or other experiment types are hardly supported, in particular when they are based on different array platforms or NGS technology.. Such kind of meta-analysis needs the implementation of additional commercial or ...
TY - JOUR. T1 - Olfactory copy number association with age at onset of Alzheimer disease. AU - Shaw, C. A.. AU - Li, Y.. AU - Wiszniewska, J.. AU - Chasse, S.. AU - Zaidi, S. N.Y.. AU - Jin, W.. AU - Dawson, B.. AU - Wilhelmsen, K.. AU - Lupski, J. R.. AU - Belmont, J. W.. AU - Doody, R. S.. AU - Szigeti, K.. PY - 2011/4/12. Y1 - 2011/4/12. N2 - Objectives: Copy number variants (CNVs) have been recognized as a source of genetic variation that contributes to disease phenotypes. Alzheimer disease (AD) has high heritability for occurrence and age at onset (AAO). We performed a cases-only genome-wide CNV association study for age at onset of AD. Methods: The discovery case series (n = 40 subjects with AD) was evaluated using array comparative genome hybridization (aCGH). A replication case series (n = 507 subjects with AD) was evaluated using Affymetrix array (n = 243) and multiplex ligation-dependent probe amplification (n = 264). Hazard models related onset age to CNV. Results: The discovery ...
Genomic instability is a hallmark of cancer resulting in widespread somatic copy number alterations. We integrated a genome-scale shRNA viability screen and copy number profiles from 179 cancer cell lines to perform an unbiased analysis of copy-number associated gene-dependency interactions. We found most copy-number associated gene dependencies result from losses of genetic material rather than gains. Strikingly, the most enriched class of these dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes. Hemizygous loss of CYCLOPS genes sensitizes cancer cells to their further suppression. One of the "top hits" from the analysis was the pre-mRNA splicing factor SF3B1, which is also frequently mutated in cancer. We then sought to evaluate SF3B1 as a CYCLOPS gene. Cancer cells with hemizygous SF3B1 copy-loss were uniquely sensitive to partial SF3B1 suppression by RNAi compared to cells with normal SF3B1 gene dosage. Mechanistically, cancer cells ...
Highlights:. BRCA1 and BRCA2 analysis by Karyo. BRCA1 and BRCA2 are analyzed using CE-IVD kits in our Next Generation Sequencing platform. Full coverage can be obtained by ordering addition large rearrangement analysis of the two genes by means of MLPA analysis.. Human Breast Cancer Panel by Karyo. 19 genes associated with human breast cancer are analyzed using Next Generation Sequencing. The probes are designed to enrich for all the coding exons and splicing sites of these 19 genes. Copy number variation analysis is also included.. The analyzed genes are: AR, ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, DIRAS3, HER2, NBN, PALB2, PTEN, RAD50, RAD51, STK11, TP53, CASP8 και TGFB1.. Exome Analysis - Breast Cancer associated. Hereditary Breast and Ovarian Cancer predominately caused by mutations in genes BRCA1&2 accounts for 5-10% of cases. There is an additional 20-25% with family history present but negative for BRCA1&2 mutations termed Familial Breast Cancer. Modern science has identified ...
About a decade ago the first large catalogs of copy number variants (CNVs) in the human genome were presented [1, 2]. Numerous studies later, CNVs are known to contribute to the genomic variation to a larger extent than single nucleotide polymorphisms (SNPs) in terms of number of nucleotide differences [3, 4]. CNVs are defined as DNA segments of variable length, up to several megabases (Mb), that varies in copy numbers in comparison to a reference genome [5]. The different types of CNVs include deletions and duplications, while consequences of CNVs include e.g. altered gene dosage and regulation, changed gene structure and unmasking of recessive alleles [5]. The effect of CNVs varies from being benign or neutral, to having subtle effects on disease predisposition or directly causing disease. The contribution and importance of CNVs for phenotypic diversity and disease susceptibility has been repeatedly shown in human and several complex diseases such as psoriasis, Crohns disease, type 2 ...
Hepatocellular carcinoma (HCC) is the most commonly diagnosed form of liver cancer with high morbidity and mortality. Copy number variation analysis (CNV) of human HCC revealed that over 50% of the HCC samples examined had CNV in the gene leukocyte specific protein-1 (LSP1). LSP1, a F-actin binding protein, is expressed in hematopoietic cells and interacts with Kinase Suppressor of Ras (KSR), a scaffold for the ERK/MAPK pathway. The expression of LSP1 in liver and its role in normal hepatocellular function and carcinogenesis remains unknown. Therefore, LSP1 mRNA and protein levels were analyzed in normal hepatocytes in culture, rat liver following partial hepatectomy (PHx), and hepatoma cell lines. In culture and after PHx, LSP1 increased after the termination of hepatocyte proliferation and migration. To investigate LSP1 function in HCC, shRNA was utilized to stably knock down LSP1 expression in the JM1 rat hepatoma cell line. Loss of LSP1 in JM1 cells resulted in dramatic upregulation of ...
The inaugural Glioma Club, a brain tumour conference for scientists and medical staff, is being held today (Thursday 23 September) at Barts and The London Medical School. , Mark Caulfield, Graham Hitman, Philip Howard, Toby Johnson, Abiodun Onipinla and Patricia Munroe, CNVs, DNA
Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of 270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many ...
Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, Stütz AM, Korshunov A, Reimand J, Schumacher SE, Beroukhim R, Ellison DW, Marshall CR, Lionel AC, Mack S, Dubuc A, Yao Y, Ramaswamy V, Luu B, Rolider A, Cavalli FM, Wang X, Remke M, Wu X, Chiu RY, Chu A, Chuah E, Corbett RD, Hoad GR, Jackman SD, Li Y, Lo A, Mungall KL, Nip KM, Qian JQ, Raymond AG, Thiessen NT, Varhol RJ, Birol I, Moore RA, Mungall AJ, Holt R, Kawauchi D, Roussel MF, Kool M, Jones DT, Witt H, Fernandez-L A, Kenney AM, Wechsler-Reya RJ, Dirks P, Aviv T, Grajkowska WA, Perek-Polnik M, Haberler CC, Delattre O, Reynaud SS, Doz FF, Pernet-Fattet SS, Cho BK, Kim SK, Wang KC, Scheurlen W, Eberhart CG, Fèvre-Montange M, Jouvet A, Pollack IF, Fan X, Muraszko KM, Gillespie GY, Di Rocco C, Massimi L, Michiels EM, Kloosterhof NK, French PJ, Kros JM, Olson JM, Ellenbogen RG, Zitterbart K, Kren L, Thompson RC, Cooper MK, Lach B, McLendon RE, Bigner DD, Fontebasso A, Albrecht S, Jabado N, Lindsey JC, Bailey S, Gupta N, Weiss ...
CCL3 is a ligand for the HIV-1 co-receptor CCR5. There have recently been conflicting reports in the literature concerning whether CCL3-like gene (CCL3L) copy number variation (CNV) is associated with resistance to HIV-1 acquisition and with both viral load and disease progression following infection with HIV-1. An association has also been reported between CCL3L CNV and clinical sequelae of the simian immunodeficiency virus (SIV) infection in vivo in rhesus monkeys. The present study was initiated to explore the possibility of an association of CCL3L CNV with the control of virus replication and AIDS progression in a carefully defined cohort of SIVmac251-infected, Indian-origin rhesus monkeys. Although we demonstrated extensive variation in copy number of CCL3L in this cohort of monkeys, CCL3L CNV was not significantly associated with either peak or set-point plasma SIV RNA levels in these monkeys when MHC class I allele Mamu-A*01 was included in the models or progression to AIDS in these ...
Microdeletion and other copy number variations contribute to human genetic diversity - and many complex neurodevelopmental and psychiatric disorders.
TY - JOUR. T1 - Refining analyses of copy number variation identifies specific genes associated with developmental delay. AU - Coe, Bradley P.. AU - Witherspoon, Kali. AU - Rosenfeld, Jill A.. AU - Van Bon, Bregje W.M.. AU - Vulto-Van Silfhout, Anneke T.. AU - Bosco, Paolo. AU - Friend, Kathryn L.. AU - Baker, Carl. AU - Buono, Serafino. AU - Vissers, Lisenka E.L.M.. AU - Schuurs-Hoeijmakers, Janneke H.. AU - Hoischen, Alex. AU - Pfundt, Rolph. AU - Krumm, Nik. AU - Carvill, Gemma L.. AU - Li, Deana. AU - Amaral, David. AU - Brown, Natasha. AU - Lockhart, Paul J.. AU - Scheffer, Ingrid E.. AU - Alberti, Antonino. AU - Shaw, Marie. AU - Pettinato, Rosa. AU - Tervo, Raymond. AU - De Leeuw, Nicole. AU - Reijnders, Margot R.F.. AU - Torchia, Beth S.. AU - Peeters, Hilde. AU - Thompson, Elizabeth. AU - ORoak, Brian J.. AU - Fichera, Marco. AU - Hehir-Kwa, Jayne Y.. AU - Shendure, Jay. AU - Mefford, Heather C.. AU - Haan, Eric. AU - Gécz, Jozef. AU - De Vries, Bert B.A.. AU - Romano, Corrado. AU - ...
40. Glessner,J.T., Wang,K., Cai,G., Korvatska,O., Kim,C.E., Wood,S., Zhang,H., Estes,A., Brune,C.W., Bradfield,J.P., Imielinski,M., Frackelton,E.C., Reichert,J., Crawford,E.L., Munson,J., Sleiman,P.M., Chiavacci,R., Annaiah,K., Thomas,K., Hou,C., Glaberson,W., Flory,J., Otieno,F., Garris,M., Soorya,L., Klei,L., Piven,J., Meyer,K.J., Anagnostou,E., Sakurai,T., Game,R.M., Rudd,D.S., Zurawiecki,D., McDougle,C.J., Davis,L.K., Miller,J., Posey,D.J., Michaels,S., Kolevzon,A., Silverman,J.M., Bernier,R., Levy,S.E., Schultz,R.T., Dawson,G., Owley,T., McMahon,W.M., Wassink,T.H., Sweeney,J.A., Nurnberger,J.I., Coon,H., Sutcliffe,J.S., Minshew,N.J., Grant,S.F., Bucan,M., Cook,E.H., Buxbaum,J.D., Devlin,B., Schellenberg,G.D., Hakonarson,H. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature. 459: 569-573. 5/ 28/ 2009. ...
Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, Zhang H, Estes A, Brune CW, Bradfield JP, Imielinski M, Frackelton EC, Reichert J, Crawford EL, Munson J, Sleiman PM, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J, Meyer KJ, Anagnostou E, Sakurai T, Game RM, Rudd DS, Zurawiecki D, McDougle CJ, Davis LK, Miller J, Posey DJ, Michaels S, Kolevzon A, Silverman JM, Bernier R, Levy SE, Schultz RT, Dawson G, Owley T, McMahon WM, Wassink TH, Sweeney JA, Nurnberger JI, Coon H, Sutcliffe JS, Minshew NJ, Grant SF, Bucan M, Cook EH, Buxbaum JD, Devlin B, Schellenberg GD, Hakonarson H. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature. 2009 May 28; 459(7246):569-73 ...
NEW YORK (GenomeWeb News) - A subset of genomic disorders stemming from rare copy number variants involve one or more additional CNVs that combine to contribute to the variability observed in these conditions, according to a study appearing online last night in the New England Journal of Medi
Advances in genetics and genomics have improved our understanding of autism spectrum disorders. As many genes have been implicated, we look to points of convergence among these genes across biological systems to better understand and treat these disorders.
Copy numbers. When we discuss structural genomic variants in the human genome on the Channelopathist blog, we usually refer to regions where simple deletions or duplications exert a pathogenic effect. However, there are also genes that are highly copy number variable, sometimes present at 80 copies or more. Copy numbers of a few of these genes have expanded during human evolution recently, turning these genes into potential candidate genes for human disease. A recent paper in PLOS Genetics now examines the role of DUF1220, which encodes a protein domain of the NBPF genes. This domain shows an unusually broad range of copy number variation in the human genome. Interestingly, this gene resides right next to the 1q21.1 region that is implicated in various neurodevelopmental disorders.. Lineage and breakpoints. When gene expression in humans and chimpanzees was compared for the first time in 2005 and when the first chromosomes of the chimpanzee genome were first sequenced, I was a little ...
Chronic lymphocytic leukemia (CLL) is the most frequent type of leukemia in the elderly and is accompanied by the accumulation of malignant monoclonal B-cells in the bone marrow, peripheral blood or lymph nodes which harbor various genetic aberrations. Genomic instability is an important characteristic of leukemia cells and plays a role both in its development as well as in the response to therapy. Somatic copy number changes in distinct genes are associated with the development of specific leukemias. Copy number variations are important diagnostic tools and help in classifying the disease and guiding the therapy. Current strategies for the detection of chromosomal aberrations in CLL are laborious and time consuming. Using multiplex ligation dependent probe amplification (MLPA) copy number changes at multiple loci can be detected simultaneously in a single simple PCR reaction. In this study, we investigated the copy number alterations in several key genes in CLL by MLPA.. DNA was isolated from ...
Copy number variations (CNVs) and polymorphisms (CNPs) have only recently gained the genetic communitys attention. Conservative estimates have shown that CNVs and CNPs might affect more than 10% of the genome and that they may be at least as important as single nucleotide polymorphisms in assessing human variability. Widely used tools for CNP analysis have been implemented in Birdsuite and PLINK for the purpose of conducting genetic association studies based on the unpartitioned total number of CNP copies provided by the intensities from Affymetrixs Genome-Wide Human SNP Array. Here, we are interested in partitioning copy number variations and polymorphisms in extended pedigrees for the purpose of linkage analysis on familial data. We have developed CNGen, a new software for the partitioning of copy number polymorphism using the integrated genotypes from Birdsuite with the Affymetrix platform. The algorithm applied to familial trios or extended pedigrees can produce partitioned copy number genotypes
Copy number variants (CNVs) on the Breakpoint 1 to Breakpoint 2 region Ki8751 at 15q11. of publically obtainable expression data identified a relationship between expression of mRNA and FOXP2 in mind. We suggest that changed medication dosage through aberrant patterning from the lh.SMG may donate to language-related Mouse monoclonal to CD11b.4AM216 reacts with CD11b, a member of the integrin a chain family with 165 kDa MW. which is expressed on NK cells, monocytes, granulocytes and subsets of T and B cells. It associates with CD18 to form CD11b/CD18 complex.The cellular function of CD11b is on neutrophil and monocyte interactions with stimulated endothelium; Phagocytosis of iC3b or IgG coated particles as a receptor; Chemotaxis and apoptosis. Ki8751 issues connected with BP1-2 CNVs. Even more generally this process may be useful in clarifying the contribution Ki8751 of individual genes at CNV risk loci. Introduction Rare multi-gene copy number variants (CNVs) are well established to increase ...
The fraction of genomic variation attributable to copy number variants (CNVs) is larger than single nucleotide polymorphisms (SNPs) and yet the full extent of such structural variation is still relatively unexplored [1, 2]. CNVs involve duplications, deletions or insertions of DNA segments up to several megabases in length and are responsible for significant phenotypic variation [3]. In humans, the frequency distribution of CNVs shows signals of purifying selection, suggesting that a significant proportion of CNVs have harmful phenotypic effects [1]. CNVs are associated with a number of genetic disorders, including Crohns disease [4], psoriasis [5], osteoporosis [6], glomerulonephritis [7] and systemic lupus erythematosus [8]. However, there are also a small number of examples of CNVs that may be beneficial, such as adaptive variation in copy number of the amylase gene in response to diet [9], and variation in HIV/AIDS susceptibility [10].. A variety of mechanisms are thought to give rise to ...