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71.
Golubchik T Brueggemann AB Street T Gertz RE Spencer CC Ho T Giannoulatou E Link-Gelles R Harding RM Beall B Peto TE Moore MR Donnelly P Crook DW Bowden R 《Nature genetics》2012,44(3):352-355
Streptococcus pneumoniae ('pneumococcus') causes an estimated 14.5 million cases of serious disease and 826,000 deaths annually in children under 5 years of age(1). The highly effective introduction of the PCV7 pneumococcal vaccine in 2000 in the United States(2,3) provided an unprecedented opportunity to investigate the response of an important pathogen to widespread, vaccine-induced selective pressure. Here, we use array-based sequencing of 62 isolates from a US national monitoring program to study five independent instances of vaccine escape recombination(4), showing the simultaneous transfer of multiple and often large (up to at least 44 kb) DNA fragments. We show that one such new strain quickly became established, spreading from east to west across the United States. These observations clarify the roles of recombination and selection in the population genomics of pneumococcus and provide proof of principle of the considerable value of combining genomic and epidemiological information in the surveillance and enhanced understanding of infectious diseases. 相似文献
72.
Maize HapMap2 identifies extant variation from a genome in flux 总被引:3,自引:0,他引:3
Chia JM Song C Bradbury PJ Costich D de Leon N Doebley J Elshire RJ Gaut B Geller L Glaubitz JC Gore M Guill KE Holland J Hufford MB Lai J Li M Liu X Lu Y McCombie R Nelson R Poland J Prasanna BM Pyhäjärvi T Rong T Sekhon RS Sun Q Tenaillon MI Tian F Wang J Xu X Zhang Z Kaeppler SM Ross-Ibarra J McMullen MD Buckler ES Zhang G Xu Y Ware D 《Nature genetics》2012,44(7):803-807
Whereas breeders have exploited diversity in maize for yield improvements, there has been limited progress in using beneficial alleles in undomesticated varieties. Characterizing standing variation in this complex genome has been challenging, with only a small fraction of it described to date. Using a population genetics scoring model, we identified 55 million SNPs in 103 lines across pre-domestication and domesticated Zea mays varieties, including a representative from the sister genus Tripsacum. We find that structural variations are pervasive in the Z. mays genome and are enriched at loci associated with important traits. By investigating the drivers of genome size variation, we find that the larger Tripsacum genome can be explained by transposable element abundance rather than an allopolyploid origin. In contrast, intraspecies genome size variation seems to be controlled by chromosomal knob content. There is tremendous overlap in key gene content in maize and Tripsacum, suggesting that adaptations from Tripsacum (for example, perennialism and frost and drought tolerance) can likely be integrated into maize. 相似文献
73.
Yang J Ferreira T Morris AP Medland SE;Genetic Investigation of ANthropometric Traits 《Nature genetics》2012,44(4):369-75, S1-3
We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium. 相似文献
74.
Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs 总被引:1,自引:0,他引:1
Lee SH DeCandia TR Ripke S Yang J;Schizophrenia Psychiatric Genome-Wide Association Study Consortium 《Nature genetics》2012,44(3):247-250
Schizophrenia is a complex disorder caused by both genetic and environmental factors. Using 9,087 affected individuals, 12,171 controls and 915,354 imputed SNPs from the Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (PGC-SCZ), we estimate that 23% (s.e. = 1%) of variation in liability to schizophrenia is captured by SNPs. We show that a substantial proportion of this variation must be the result of common causal variants, that the variance explained by each chromosome is linearly related to its length (r = 0.89, P = 2.6 × 10(-8)), that the genetic basis of schizophrenia is the same in males and females, and that a disproportionate proportion of variation is attributable to a set of 2,725 genes expressed in the central nervous system (CNS; P = 7.6 × 10(-8)). These results are consistent with a polygenic genetic architecture and imply more individual SNP associations will be detected for this disease as sample size increases. 相似文献
75.
A new study reports comparative genomic analysis of 52 geographically diverse strains of Chlamydia trachomatis. The authors reconstruct a genome-wide phylogeny of the species and report extensive genome-wide recombination across multiple lineages of this intracellular bacterial pathogen. 相似文献
76.
77.
Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm 总被引:2,自引:0,他引:2
ME Lindsay D Schepers NA Bolar JJ Doyle E Gallo J Fert-Bober MJ Kempers EK Fishman Y Chen L Myers D Bjeda G Oswald AF Elias HP Levy BM Anderlid MH Yang EM Bongers J Timmermans AC Braverman N Canham GR Mortier HG Brunner PH Byers J Van Eyk L Van Laer HC Dietz BL Loeys 《Nature genetics》2012,44(8):922-927
Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies. 相似文献
78.
Gutiérrez-López MD Gilsanz A Yáñez-Mó M Ovalle S Lafuente EM Domínguez C Monk PN González-Alvaro I Sánchez-Madrid F Cabañas C 《Cellular and molecular life sciences : CMLS》2011,68(19):3275-3292
ADAM17/TACE is a metalloproteinase responsible for the shedding of the proinflammatory cytokine TNF-α and many other cell
surface proteins involved in development, cell adhesion, migration, differentiation, and proliferation. Despite the important
biological function of ADAM17, the mechanisms of regulation of its metalloproteinase activity remain largely unknown. We report
here that the tetraspanin CD9 and ADAM17 partially co-localize on the surface of endothelial and monocytic cells. In situ
proximity ligation, co-immunoprecipitation, crosslinking, and pull-down experiments collectively demonstrate a direct association
between these molecules. Functional studies reveal that treatment with CD9-specific antibodies or neoexpression of CD9 exert
negative regulatory effects on ADAM17 sheddase activity. Conversely, CD9 silencing increased the activity of ADAM17 against
its substrates TNF-α and ICAM-1. Taken together, our results show that CD9 associates with ADAM17 and, through this interaction,
negatively regulates the sheddase activity of ADAM17. 相似文献
79.
Yvonne G. J. van Helden Roger W. L. Godschalk Hans J. M. Swarts Peter C. H. Hollman Frederik J. van Schooten Jaap Keijer 《Cellular and molecular life sciences : CMLS》2011,68(3):489-504
Molecular mechanisms triggered by high dietary beta-carotene (BC) intake in lung are largely unknown. We performed microarray
gene expression analysis on lung tissue of BC supplemented beta-carotene 15,15′-monooxygenase 1 knockout (Bcmo1
−/−) mice, which are—like humans—able to accumulate BC. Our main observation was that the genes were regulated in an opposite direction in male and female Bcmo1
−/− mice by BC. The steroid biosynthetic pathway was overrepresented in BC-supplemented male Bcmo1
−/− mice. Testosterone levels were higher after BC supplementation only in Bcmo1
−/− mice, which had, unlike wild-type (Bcmo1
+/+) mice, large variations. We hypothesize that BC possibly affects hormone synthesis or metabolism. Since sex hormones influence
lung cancer risk, these data might contribute to an explanation for the previously found increased lung cancer risk after
BC supplementation (ATBC and CARET studies). Moreover, effects of BC may depend on the presence of frequent human BCMO1 polymorphisms, since these effects were not found in wild-type mice. 相似文献
80.
Freinbichler W Colivicchi MA Stefanini C Bianchi L Ballini C Misini B Weinberger P Linert W Varešlija D Tipton KF Della Corte L 《Cellular and molecular life sciences : CMLS》2011,68(12):2067-2079
The so-called reactive oxygen species (ROS) are defined as oxygen-containing species that are more reactive than O(2) itself, which include hydrogen peroxide and superoxide. Although these are quite stable, they may be converted in the presence of transition metal ions, such as Fe(II), to the highly reactive oxygen species (hROS). hROS may exist as free hydroxyl radicals (HO·), as bound ("crypto") radicals or as Fe(IV)-oxo (ferryl) species and the somewhat less reactive, non-radical species, singlet oxygen. This review outlines the processes by which hROS may be formed, their damaging potential, and the evidence that they might have signaling functions. Since our understanding of the formation and actions of hROS depends on reliable procedures for their detection, particular attention is given to procedures for hROS detection and quantitation and their applicability to in vivo studies. 相似文献