| 1. |
- Andersson, Robin, et al.
(författare)
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A Segmental Maximum A Posteriori Approach to Genome-wide Copy Number Profiling
- 2008
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 24:6, s. 751-758
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- MOTIVATION: Copy number profiling methods aim at assigning DNA copy numbers to chromosomal regions using measurements from microarray-based comparative genomic hybridizations. Among the proposed methods to this end, Hidden Markov Model (HMM)-based approaches seem promising since DNA copy number transitions are naturally captured in the model. Current discrete-index HMM-based approaches do not, however, take into account heterogeneous information regarding the genomic overlap between clones. Moreover, the majority of existing methods are restricted to chromosome-wise analysis. RESULTS: We introduce a novel Segmental Maximum A Posteriori approach, SMAP, for DNA copy number profiling. Our method is based on discrete-index Hidden Markov Modeling and incorporates genomic distance and overlap between clones. We exploit a priori information through user-controllable parameterization that enables the identification of copy number deviations of various lengths and amplitudes. The model parameters may be inferred at a genome-wide scale to avoid overfitting of model parameters often resulting from chromosome-wise model inference. We report superior performances of SMAP on synthetic data when compared with two recent methods. When applied on our new experimental data, SMAP readily recognizes already known genetic aberrations including both large-scale regions with aberrant DNA copy number and changes affecting only single features on the array. We highlight the differences between the prediction of SMAP and the compared methods and show that SMAP accurately determines copy number changes and benefits from overlap consideration.
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| 2. |
- Benetkiewicz, Magdalena, et al.
(författare)
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Chromosome 22 array-CGH profiling of breast cancer delimited minimal common regions of genomic imbalances and revealed frequent intra-tumoral genetic heterogeneity
- 2006
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Ingår i: International Journal of Oncology. - 1019-6439 .- 1791-2423. ; 29:4, s. 935-945
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a common malignancy and the second most frequent cause of death among women. Our aim was to perform DNA copy number profiling of 22q in breast tumors using a methodology which is superior, as compared to the ones applied previously. We studied 83 biopsies from 63 tumors obtained from 60 female patients. A general conclusion is that multiple distinct patterns of genetic aberrations were observed, which included deletion(s) and/or gain(s), ranging in size from affecting the whole chromosome to only a few hundred kb. Overall, the analysis revealed genomic imbalances of 22q in 22% (14 out of 63) of tumors. The predominant profile (11%) was monosomy 22. The smallest identified candidate region, in the vicinity of telomere of 22q, encompasses approximately 220 kb and was involved in all but one of the tumors with aberrations on chromosome 22. This segment is dense in genes and contains 11 confirmed and one predicted gene. The availability of multiple biopsies from a single tumor provides an excellent opportunity for analysis of possible intra-tumor differences in genetic profiles. In 15 tumors we had access to two or three biopsies derived from the same lesion and these were studied independently. Four out of 15 (26.6%) tumors displayed indications of clonal intra-tumor genotypic differences, which should be viewed as a high number, considering that we studied in detail only a single human chromosome. Our results open up several avenues for continued genetic research of breast cancer.
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| 3. |
- Bruder, Carl E G, et al.
(författare)
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Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles
- 2008
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 82:3, s. 763-71
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Tidskriftsartikel (refereegranskat)abstract
- The exploration of copy-number variation (CNV), notably of somatic cells, is an understudied aspect of genome biology. Any differences in the genetic makeup between twins derived from the same zygote represent an irrefutable example of somatic mosaicism. We studied 19 pairs of monozygotic twins with either concordant or discordant phenotype by using two platforms for genome-wide CNV analyses and showed that CNVs exist within pairs in both groups. These findings have an impact on our views of genotypic and phenotypic diversity in monozygotic twins and suggest that CNV analysis in phenotypically discordant monozygotic twins may provide a powerful tool for identifying disease-predisposition loci. Our results also imply that caution should be exercised when interpreting disease causality of de novo CNVs found in patients based on analysis of a single tissue in routine disease-related DNA diagnostics.
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| 4. |
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| 5. |
- Buckley, Patrick G., et al.
(författare)
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Identification of genetic aberrations on chromosome 22 outside the NF2 locus in schwannomatosis and neurofibromatosis type 2
- 2005
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 26:6, s. 540-9
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Tidskriftsartikel (refereegranskat)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.
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| 6. |
- De Bustos, Cecilia, et al.
(författare)
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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
- 2006
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Ingår i: Genomics. - : Elsevier BV. - 0888-7543 .- 1089-8646. ; 88:2, s. 152-162
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- de Ståhl, Teresita Díaz, et al.
(författare)
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Profiling of copy number variations (CNVs) in healthy individuals from three ethnic groups using a human genome 32 K BAC-clone-based array
- 2008
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 29:3, s. 398-408
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Tidskriftsartikel (refereegranskat)abstract
- To further explore the extent of structural large-scale variation in the human genome, we assessed copy number variations (CNVs) in a series of 71 healthy subjects from three ethnic groups. CNVs were analyzed using comparative genomic hybridization (CGH) to a BAC array covering the human genome, using DNA extracted from peripheral blood, thus avoiding any culture-induced rearrangements. By applying a newly developed computational algorithm based on Hidden Markov modeling, we identified 1,078 autosomal CNVs, including at least two neighboring/overlapping BACs, which represent 315 distinct regions. The average size of the sequence polymorphisms was approximately 350 kb and involved in total approximately 117 Mb or approximately 3.5% of the genome. Gains were about four times more common than deletions, and segmental duplications (SDs) were overrepresented, especially in larger deletion variants. This strengthens the notion that SDs often define hotspots of chromosomal rearrangements. Over 60% of the identified autosomal rearrangements match previously reported CNVs, recognized with various platforms. However, results from chromosome X do not agree well with the previously annotated CNVs. Furthermore, data from single BACs deviating in copy number suggest that our above estimate of total variation is conservative. This report contributes to the establishment of the common baseline for CNV, which is an important resource in human genetics.
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| 8. |
- Descartes, Maria, et al.
(författare)
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Distal 22q11.2 microduplication encompassing the BCR gene
- 2008
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Ingår i: American journal of medical genetics. Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 146A:23, s. 3075-3081
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Tidskriftsartikel (refereegranskat)abstract
- Chromosome 22 band q11.2 has been recognized to be highly susceptible to subtle microdeletions and microduplications, which have been attributed to the presence of several large segmental duplications; also known as low copy repeats (LCRs). These LCRs function as mediators of non-allelic homologous recombination (NAHR), which results in these chromosomal rearrangements as a result of unequal crossover. The four centromeric LCRs at proximal 22q11.2 have been previously implicated in recurrent chromosomal rearrangements including the DiGeorge/Velocardiofacial syndrome (DG/VCFs) microdeletion and its reciprocal microduplication. Recently, we and others have demonstrated that the four telomeric LCRs at distal 22q11.2 are causally implicated in a newly recognized recurrent distal 22q11.2 microdeletion syndrome in the region immediately telomeric to the DG/VCFs typically deleted region. Here we report on the clinical, cytogenetic, and array CGH studies of a 4.5-year-old girl with history of failure to thrive, developmental delay (DD), and relative macrocephaly. She carries a paternally inherited approximately 2.1 Mb microduplication at distal 22q11.2, which spans approximately 34 annotated genes, and is flanked by two of the four telomeric 22q11.2 LCRs. We conclude that the four telomeric LCRs at distal 22q11.2 can mediate both deletions and duplications in this genomic region. Both deletions and duplication of this region present with subtle clinical features including mild to moderate mental retardation, DD, and mild dysmorphic features.
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| 9. |
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| 10. |
- Hansson, Caisa M., et al.
(författare)
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Comprehensive genetic and epigenetic analysis of sporadic meningioma for macro-mutations on 22q and micro-mutations within the NF2 locus
- 2007
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 8, s. 16-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Meningiomas are the most common intracranial neoplasias, representing a clinically and histopathologically heterogeneous group of tumors. The neurofibromatosis type 2 (NF2) tumor suppressor is the only gene known to be frequently involved in early development of meningiomas. The objective of this study was to identify genetic and/or epigenetic factors contributing to the development of these tumors. A large set of sporadic meningiomas were analyzed for presence of 22q macro-mutations using array-CGH in order to identify tumors carrying gene dosage aberrations not encompassing NF2. The NF2 locus was also comprehensively studied for point mutations within coding and conserved non-coding sequences. Furthermore, CpG methylation within the NF2 promoter region was thoroughly analyzed. Results: Monosomy 22 was the predominant finding, detected in 47% of meningiomas. Thirteen percent of the tumors contained interstitial/ terminal deletions and gains, present singly or in combinations. We defined at least two minimal overlapping regions outside the NF2 locus that are small enough (∼550 kb and ∼250 kb) to allow analysis of a limited number of candidate genes. Bialleinactivationo the NF2 gne was detected in 36% of meningiomas. Among the monosomy 22 cases, no additional NF2 mutations could be identified in 35% (17 out of 49) of tumors. Furthermore, the majority of tumors (9 out of 12) with interstitial/terminal deletions did not have any detectable NF2 mutations. Methylation within the NF2 promoter region was only identified at a single CpG site in one tumor sample. Conclusion: We confirmed previous findings of pronounced differences in mutation frequency between different histopathological subtypes. There is a higher frequency of biallelic NF2 inactivation in fibroblastic (52%) compared to meningothelial (18%) tumors. The presence of macro-mutations on 22q also shows marked differences between fibroblastic (86%) and meningothelial (39%) subtypes. Thus, inactivation of NF2, often combined with the presence of macro-mutation on 22q, is likely not as important for the development of the meningothelial subtype, as opposed to the fibroblastic form. Analysis of 40 CpG sites distributed within 750 bp of the promoter region suggests that NF2 promoter methylation does not play a major role in meningioma development.
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