| 1. |
- Jallow, Muminatou, et al.
(author)
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Genome-wide and fine-resolution association analysis of malaria in West Africa.
- 2009
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; , s. 657-665
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Journal article (peer-reviewed)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. |
- Hung, Rayjean J, et al.
(author)
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A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25
- 2008
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In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 452:7187, s. 633-637
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Journal article (peer-reviewed)abstract
- Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.
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| 3. |
- Gan, Lu, et al.
(author)
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Capsid Conformational Sampling in HK97 Maturation Visualized by X-Ray Crystallography and Cryo-EM
- 2006
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In: Structure. - : Elsevier BV. - 0969-2126 .- 1878-4186. ; 14:11, s. 1655-1665
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Journal article (peer-reviewed)abstract
- Maturation of the bacteriophage HK97 capsid from a precursor (Prohead II) to the mature state (Head II) involves a 60 angstrom radial expansion. The mature particle is formed by 420 copies of the major capsid protein organized on a T = 7 laevo, lattice with each subunit covalently crosslinked to two neighbors. Well-characterized pH 4 expansion intermediates make HK97 valuable for investigating quaternary structural dynamics. Here, we use X-ray crystallography and cryo-EM to demonstrate that in the final transition in maturation (requiring neutral pH), pentons in Expansion Intermediate IV (EI-IV) reversibly sample 14 angstrom translations and 6 degrees rotations relative to a fixed hexon lattice. The limit of this trajectory corresponds to the Head II conformation that is secured at this extent only by the formation of the final class of covalent crosslinks. Mutants that cannot crosslink or EI-IV particles that have been rendered incapable of forming the final crosslink remain in the EI-IV state.
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| 4. |
- Parra Barraza, Rodrigo, 1974, et al.
(author)
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Multiwavelength radio observations of the compact starburst in Arp 220
- 2006
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In: Proceedings of Science. - 1824-8039. ; 36
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Conference paper (peer-reviewed)abstract
- We report the first detection at multiple radio wavelengths (13, 6, and 3.6 cm) of 18 compact sources within both nuclei of the Ultra Luminous Infra-Red Galaxy (ULIRG) Arp 220. In just over half of the sources we find that the observed spectra are consistent with the standard model of powerful Type IIn supernovae interacting with their pre-explosion stellar wind. The rate of appearance of new radio sources ascribed to these supernova events suggests that a large fraction of core-collapse supernovae in Arp 220 are highly luminous, possibly implying a radically different stellar initial mass function (IMF) or stellar evolution compared to galactic disks. A second group of sources, consisting of the brightest and longest monitored sources at 18 cm, do not easily fit the radio supernova model. We propose that these are young supernova remnants that have just begun interacting with their surrounding dense ISM.
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