| 1. |
- Soranzo, Nicole, et al.
(författare)
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A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:11, s. 38-1182
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Tidskriftsartikel (refereegranskat)abstract
- The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.
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| 2. |
- 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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| 3. |
- 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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| 4. |
- Erdogan, F, et al.
(författare)
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Impact of low copy repeats on the generation of balanced and unbalanced chromosomal aberrations in mental retardation
- 2006
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Ingår i: Cytogenetic and Genome Research. - : S. Karger AG. - 1424-859X .- 1424-8581. ; 115:3-4, s. 247-253
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Tidskriftsartikel (refereegranskat)abstract
- Low copy repeats (LCRs) are stretches of duplicated DNA that are more than 1 kb in size and share a sequence similarity that exceeds 90%. Non-allelic homologous recombination (NAHR) between highly similar LCRs has been implicated in numerous genomic disorders. This study aimed at defining the impact of LCRs on the generation of balanced and unbalanced chromosomal rearrangements in mentally retarded patients. A cohort of 22 patients, preselected for the presence of submicroscopic imbalances, was analysed using submegabase resolution tiling path array CGH and the results were compared with a set of 41 patients with balanced translocations and breakpoints that were mapped to the BAC level by FISH. Our data indicate an accumulation of LCRs at breakpoints of both balanced and unbalanced rearrangements. LCRs with high sequence similarity in both breakpoint regions, suggesting NAHR as the most likely cause of rearrangement, were observed in 6/22 patients with chromosomal imbalances, but not in any of the balanced translocation cases studied. In case of chromosomal imbalances, the likelihood of NAHR seems to be inversely related to the size of the aberration. Our data also suggest the presence of additional mechanisms coinciding with or dependent on the presence of LCRs that may induce an increased instability at these chromosomal sites.
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| 5. |
- Galizia, C. G., et al.
(författare)
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Relationship of visual and olfactory signal parameters in a food-deceptive flower mimicry system
- 2005
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Ingår i: Behavioral Ecology. - : Oxford University Press (OUP). - 1045-2249 .- 1465-7279. ; 16:1, s. 159-168
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Tidskriftsartikel (refereegranskat)abstract
- Pollinators such as bees are attracted to flowers by their visual display and their scent. Although most flowers reinforce visits by providing pollen and/or nectar, there are species-notably from the orchid family-that do not but do resemble rewarding species. These mimicry relationships provide ideal opportunities for investigating the evolution of floral signals and their impact on pollinator behavior. Here, we have reanalyzed a case of specialized food mimicry between the orchid Orchis israelitica and its model, the lily Bellevalia flexuosa. Based on current knowledge of insect sensory physiology, we were able to characterize both the visual and olfactory signals of model and mimic, as well as of two phylogenetically related orchids. By using a color vision model, we mapped each species' visual signals to the perceptual space of honeybees and found an apparent shift of the mimic's visual signals towards the model. We confirm that visual mimicry is present. We analyzed the flower odors by using gas chromatography/mass spectroscopy. We related these signals to the perceptual space of the pollinators by testing the scent extracts physiologically, using in vivo brain imaging. We found no evidence of olfactory mimicry. The results indicate that evolutionary pressure acts on the visual, but not olfactory, traits of O. israelitica toward a higher similarity to its model. Apparently, odor mismatch does not prevent a bee from landing on a flower that has the expected visual display. The results therefore argue for the dominance of visual stimuli in short-distance flower choice. The orchid may still depend on long-distance olfactory attraction originating from neighboring model plants.
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| 6. |
- Herlin, G, et al.
(författare)
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Quantitative assessment of 99mTc-depreotide uptake in patients with non-small-cell lung cancer: immunohistochemical correlations
- 2009
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Ingår i: Acta radiologica (Stockholm, Sweden : 1987). - : SAGE Publications. - 1600-0455 .- 0284-1851. ; 50:8, s. 902-908
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Tidskriftsartikel (refereegranskat)abstract
- Background: Somatostatin receptor (SSTR) scintigraphy with 99mTc-depreotide is used for differential diagnosis of solitary pulmonary nodules. The method is based on SSTR expression in cancer tissue. Purpose: To estimate the expression of SSTRs in non-small-cell lung cancer (NSCLC) in vitro, and to determine the correlation between 99mTc-depreotide uptake in vivo and different tumor characteristics determined in vitro, such as tumor grade, and presence of SSTR2, MIB-1, and p53. Material and Methods: A total of 127 patients with lung lesions detected on computed tomography (CT) were investigated with SSTR scintigraphy after injection of 740 MBq 99mTc-depreotide. This study includes 19 patients with NSCLC with histologically proven diagnosis. The quantitative evaluation of 99mTc-depreotide was performed using region-of-interest analysis and includes tumor counts/cm3, background counts/cm3, and the ratio between tumor and background counts. Results: 99mTc-depreotide uptake was found in all NSCLC tumors, which expressed SSTR2 defined in vitro by immunochemical methods. SSTR2 expression was negatively correlated to the degree of the tumor's differentiation ( P<0.05). 99mTc-depreotide uptake in tumor cells did not correlate with tumor grade, or SSTR2, MIB-1, or p53 expression. Conclusion: There is an expression of SSTRs in NSCLC. The degree of tumor differentiation correlates negatively with SSTR2 measured in vitro and positively with MIB-1 expression in tumor tissue. No correlation was found between 99mTc-depreotide uptake and possible prognostic factors such as MIB-1 and p53 expression in tumor cells in NSCLC. Lastly, no correlation was found between 99mTc-depreotide uptake and tumor grade or SSTR2 expression.
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| 7. |
- Mantripragada, K K, et al.
(författare)
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Identification of novel deletion breakpoints bordered by segmental duplications in the NF1 locus using high resolution array-CGH.
- 2006
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Ingår i: Journal of medical genetics. - : BMJ. - 1468-6244 .- 0022-2593. ; 43:1, s. 28-38
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Segmental duplications flanking the neurofibromatosis type 1 (NF1) gene locus on 17q11 mediate most gene deletions in NF1 patients. However, the large size of the gene and the complexity of the locus architecture pose difficulties in deletion analysis. We report the construction and application of the first NF1 locus specific microarray, covering 2.24 Mb of 17q11, using a non-redundant approach for array design. The average resolution of analysis for the array is approximately 12 kb per measurement point with an increased average resolution of 6.4 kb for the NF1 gene. METHODS: We performed a comprehensive array-CGH analysis of 161 NF1 derived samples and identified heterozygous deletions of various sizes in 39 cases. The typical deletion was identified in 26 cases, whereas 13 samples showed atypical deletion profiles. RESULTS: The size of the atypical deletions, contained within the segment covered by the array, ranged from 6 kb to 1.6 Mb and their breakpoints could be accurately determined. Moreover, 10 atypical deletions were observed to share a common breakpoint either on the proximal or distal end of the deletion. The deletions identified by array-CGH were independently confirmed using multiplex ligation-dependent probe amplification. Bioinformatic analysis of the entire locus identified 33 segmental duplications. CONCLUSIONS: We show that at least one of these segmental duplications, which borders the proximal breakpoint located within the NF1 intron 1 in five atypical deletions, might represent a novel hot spot for deletions. Our array constitutes a novel and reliable tool offering significantly improved diagnostics for this common disorder.
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| 8. |
- Menzel, Annette, et al.
(författare)
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European phenological response to climate change matches the warming pattern
- 2006
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Ingår i: Global Change Biology. - 1354-1013 .- 1365-2486. ; 12:10, s. 1969-1976
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Tidskriftsartikel (refereegranskat)abstract
- Global climate change impacts can already be tracked in many physical and biological systems; in particular, terrestrial ecosystems provide a consistent picture of observed changes. One of the preferred indicators is phenology, the science of natural recurring events, as their recorded dates provide a high-temporal resolution of ongoing changes. Thus, numerous analyses have demonstrated an earlier onset of spring events for mid and higher latitudes and a lengthening of the growing season. However, published single-site or single-species studies are particularly open to suspicion of being biased towards predominantly reporting climate change-induced impacts. No comprehensive study or meta-analysis has so far examined the possible lack of evidence for changes or shifts at sites where no temperature change is observed. We used an enormous systematic phenological network data set of more than 125000 observational series of 542 plant and 19 animal species in 21 European countries (1971-2000). Our results showed that 78% of all leafing, flowering and fruiting records advanced (30% significantly) and only 3% were significantly delayed, whereas the signal of leaf colouring/fall is ambiguous. We conclude that previously published results of phenological changes were not biased by reporting or publication predisposition: the average advance of spring/summer was 2.5 days decade -1 in Europe. Our analysis of 254 mean national time series undoubtedly demonstrates that species' phenology is responsive to temperature of the preceding months (mean advance of spring/summer by 2.5 days °C -1, delay of leaf colouring and fall by 1.0 day °C -1). The pattern of observed change in spring efficiently matches measured national warming across 19 European countries (correlation coefficient r = -0.69, P < 0.001).
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| 9. |
- Menzel, Andreas, et al.
(författare)
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On a computational orientation-distribution-function-based remodelling framework
- 2007
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Ingår i: Proceedings of the 20th Nordic Seminar on Computational Mechanics.
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Konferensbidrag (refereegranskat)abstract
- In this contribution, we apply the framework of orientation distribution functions (odf) to the modelling of adapting anisotropic biological tissues. Remodelling phenomena are thereby incorporated by means of an evolution equation for a generalised structural tensor so that the underlying odf evolves according to the local loading conditions.
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| 10. |
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