| 1. |
- Jallow, Muminatou, et al.
(författare)
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Genome-wide and fine-resolution association analysis of malaria in West Africa.
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; , s. 657-665
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Tidskriftsartikel (refereegranskat)abstract
- We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 x 10(-7) to P = 4 x 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.
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| 2. |
- Richards, Stephen, et al.
(författare)
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The genome of the model beetle and pest Tribolium castaneum.
- 2008
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Ingår i: Nature. - 1476-4687. ; 452:7190, s. 949-55
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Tidskriftsartikel (refereegranskat)abstract
- Tribolium castaneum is a representative of earth’s most numerous eukaryotic order, a powerful model organism for the study of generalized insect development, and also an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved an ability to interact with a diverse chemical environment as evidenced by large expansions in odorant and gustatory receptors, as well as p450 and other detoxification enzymes. Developmental patterns in Tribolium are more representative of other arthropods than those found in Drosophila, a fact represented in gene content and function. For one, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, and some are expressed in the growth zone crucial for axial elongation in short germ development. Systemic RNAi in T. castaneum appears to use mechanisms distinct from those found in C. elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.
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| 3. |
- Mangano, Valentina D, et al.
(författare)
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Lack of association of Interferon Regulatory Factor 1 with severe malaria in affected child‐parental trio studies across three African populations
- 2009
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:1, s. e4206-
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Tidskriftsartikel (refereegranskat)abstract
- Interferon Regulatory Factor 1 (IRF-1) is a member of the IRF family of transcription factors, which have key and diverse roles in the gene-regulatory networks of the immune system. IRF-1 has been described as a critical mediator of IFN-gamma signalling and as the major player in driving TH1 type responses. It is therefore likely to be crucial in both innate and adaptive responses against intracellular pathogens such as Plasmodium falciparum. Polymorphisms at the human IRF1 locus have been previously found to be associated with the ability to control P. falciparum infection in populations naturally exposed to malaria. In order to test whether genetic variation at the IRF1 locus also affects the risk of developing severe malaria, we performed a family-based test of association for 18 Single Nucleotide Polymorphisms (SNPs) across the gene in three African populations, using genotype data from 961 trios consisting of one affected child and his/her two parents (555 from The Gambia, 204 from Kenya and 202 from Malawi). No significant association with severe malaria or severe malaria subphenotypes (cerebral malaria and severe malaria anaemia) was observed for any of the SNPs/haplotypes tested in any of the study populations. Our results offer no evidence that the molecular pathways regulated by the transcription factor IRF-1 are involved in the immune-based pathogenesis of severe malaria.
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| 4. |
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| 5. |
- Bading, James R., et al.
(författare)
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Quantitative serial imaging of an I-124 anti-CEA monoclonal antibody in tumor-bearing mice
- 2008
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Ingår i: Cancer Biotherapy & Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 23:4, s. 399-409
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The 4.2-day half-life I-124 favors its use for positron emission tomography (PET) of monoclonal antibodies (mAbs). However, high positron energy and beta(+)-associated cascade gamma rays pose image resolution and background noise problems for I-124. This study evaluated quantitative PET of an I-124 mAb in tumor-bearing mice. Methods: An R4 microPET (TM) (Siemens/CTIMI, Knoxville, TN) was used with standard energy and coincidence timing windows (350-750 keV and 6 ns, respectively), delayed random coincidence subtraction, iterative image reconstruction, and no attenuation or scatter correction. Image resolution, contrast, and response linearity were compared for I-124 and F-18, using phantoms. Nude mice bearing human colon tumors (LS-174T) were injected intravenously with a chimeric I-124 anti-CEA mAb (cT84.66) and imaged serially 1 hour to 7 clays postinjection. Venous blood was sampled to validate image-derived blood curves. Mice were sacrificed after the final scan, and the biodistribution of I-124 was measured by direct tissue assay. Images were converted to units of kBq/g for each tissue of interest by comparing the final scans with the direct assays. Results: Measured resolution (FWHM) 0-16 mm from? the scanner axis was. 2.3-2.7 mm for I-124 versus 1.9-2.0 mm for F-18. Due to true coincidence e vents between annihilation photons and cascade gamma rays, background was greater for I-124 than F-18, but the signal-to-background ratio was still more than 20, and I-124 image intensities varied linearly with activity concentration. Tissue-based calibration worked well (i.e., PET blood curves agreed with direct measurements within 12% at all time points), while calibration, based on a cylindrical phantom approximating the mouse body, yielded tumor quantitation that was 46%-66% low, compared with direct assay. Conclusions: Images of quantitative accuracy sufficient for biodistribution. measurements can be obtained from tumor-bearing mice by using I-124 anti-CEA mAbs with standard. microPET acquisition and processing techniques, provided the calibration is based on the direct assay of excised tissue samples.
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| 6. |
- Wood, Laura D, et al.
(författare)
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The genomic landscapes of human breast and colorectal cancers.
- 2007
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 318:5853, s. 1108-1113
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Tidskriftsartikel (refereegranskat)abstract
- Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes. To catalog the genetic changes that occur during tumorigenesis, we isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene "mountains" and a much larger number of gene "hills" that are mutated at low frequency. We describe statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. These results have implications for understanding the nature and heterogeneity of human cancers and for using personal genomics for tumor diagnosis and therapy.
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