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Analysis of copy number variation in normal human population within a region containing complex segmental duplications on 22q11 using high resolution array-CGH
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2006 (English)In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 88, no 2, 152-162 p.Article in journal (Refereed) Published
Abstract [en]

A previously detected copy number polymorphism (Ep CNP) in patients affected with neuroectodermal tumors led us to investigate its frequency and length in the normal population. For this purpose, a program called Sequence Allocator was developed and applied for the construction of an array that consisted of unique and duplicated fragments, allowing the assessment of copy number variation within regions of segmental duplications. The average resolution of this array was 11 kb and we determined the size of the Ep CNP to be 290 kb. Analysis of normal controls identified 7.7 and 7.1% gains in peripheral blood and lymphoblastoid cell line (LCL) DNA, respectively, while deletions were found only in the LCL group (7.1%). This array platform allows the detection of DNA copy number variation within regions of pronounced genomic complexity, which constitutes an improvement over available technologies.

Place, publisher, year, edition, pages
2006. Vol. 88, no 2, 152-162 p.
Keyword [en]
Comparative genomic hybridization; Segmental duplications; Human chromosome 22; Copy number polymorphism; Human variation, Ependymoma, Neuroectodermal tumors, Low-copy repeats, CRYBB2, LRP5
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94128DOI: 10.1016/j.ygeno.2006.03.016OAI: oai:DiVA.org:uu-94128DiVA: diva2:167875
Available from: 2006-03-23 Created: 2006-03-23 Last updated: 2011-11-21Bibliographically approved
In thesis
1. Genetic and Epigenetic Variation in the Human Genome: Analysis of Phenotypically Normal Individuals and Patients Affected with Brain Tumors
Open this publication in new window or tab >>Genetic and Epigenetic Variation in the Human Genome: Analysis of Phenotypically Normal Individuals and Patients Affected with Brain Tumors
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Genetic and epigenetic variation is a key determinant of human diversity and has an impact on disease predisposition. Single nucleotide polymorphisms (SNPs) and copy number polymorphisms (CNPs) are the main forms of genetic variation. The challenge is to distinguish normal variations from disease-associated changes. Combination of genetic and epigenetic alterations, often together with an environmental component, can cause cancer. In paper I, we investigated possible alterations affecting the transcriptional regulation of PDGFRα in patients affected with central nervous system tumors by characterizing the haplotype combinations in the PDGFRA gene promoter. A specific over-representation of one haplotype (H2δ) in primitive neuroectodermal tumors and ependymomas was observed, suggesting a functional role for the ZNF148/PDGFRα pathway in the tumor pathogenesis. In paper II, 50 glioblastomas were analyzed for DNA copy number variation with a chromosome 22 tiling genomic array. While 20% of tumors displayed monosomy 22, copy number variations affecting a portion of chromosome 22 were found in 14% of cases. This implies the presence of genes involved in glioblastoma development on 22q. Paper III described the analysis of copy number variation of 37 ependymomas using the same array. We detected monosomy in 51.5% of the samples. In addition, we identified two overlapping germline deletions of 2.2 Mb and 320 kb (the latter designated as Ep CNP). In order to investigate whether Ep CNP was a common polymorphism in the normal population or had an association with ependymoma development, we constructed a high-resolution PCR product-based microarray covering this locus (paper IV). For this purpose, we developed a program called Sequence Allocator, which automates the process of array design. This approach allowed assessment of copy number variation within regions of segmental duplications. Our results revealed that gains or deletions were identical in size and encompassed 290 kb. Therefore, papers I-IV suggest that some SNPs and CNPs can be regarded as tumor-associated polymorphisms. Finally, paper V describes variation of DNA methylation among fully differentiated tissues by using an array covering ~9% of the human genome. Major changes in the overall methylation were also found in colorectal cancer cell lines lacking one or two DNA methyltransferases.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 68 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 122
Keyword
Molecular genetics, genetic variation, epigenetics, brain tumor, array-CGH, glioblastoma, ependymoma, microarray, methylation, Genetik
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-6629 (URN)91-554-6490-4 (ISBN)
Public defence
2006-04-13, Rudbecksalen, Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala, 09:15
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Available from: 2006-03-23 Created: 2006-03-23Bibliographically approved

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Dumanski, Jan P

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