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1.
Direct detection of more than 50% of the Duchenne muscular dystrophy mutations by field inversion gels 总被引:5,自引:0,他引:5
Duchenne muscular dystrophy (DMD) is an X-linked disorder affecting about 1 in 3,500 males. It is allelic with the milder Becker muscular dystrophy. The biochemical basis for both diseases is unknown and no effective treatment is available. Long-range physical mapping has shown that the DMD gene, localized in Xp21, is extremely large, exceeding 2 million base pairs. Until now, carrier detection and prenatal diagnosis has involved the use of linked restriction fragment length polymorphism markers which detect muscular dystrophy-associated deletions in about 10% of the cases. Field inversion gel electrophoresis (FIGE) allows the detection of structural rearrangements in 21 out of 39 of the DMD patients studied (54%), of which 14 (65%) were not detected by conventional methods. Large deletions seem to make up a much higher fraction of the DMD mutations than so far indicated by other methods. A region prone to deletion was located in the distal half of the gene. FIGE analysis could provide a valuable extension of information for carrier detection and prenatal diagnosis. The technique should be generally applicable to the study of diseases involving structural chromosomal rearrangements. 相似文献
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Extremely low-coverage sequencing and imputation increases power for genome-wide association studies 总被引:1,自引:0,他引:1
Pasaniuc B Rohland N McLaren PJ Garimella K Zaitlen N Li H Gupta N Neale BM Daly MJ Sklar P Sullivan PF Bergen S Moran JL Hultman CM Lichtenstein P Magnusson P Purcell SM Haas DW Liang L Sunyaev S Patterson N de Bakker PI Reich D Price AL 《Nature genetics》2012,44(6):631-635
Genome-wide association studies (GWAS) have proven to be a powerful method to identify common genetic variants contributing to susceptibility to common diseases. Here, we show that extremely low-coverage sequencing (0.1-0.5×) captures almost as much of the common (>5%) and low-frequency (1-5%) variation across the genome as SNP arrays. As an empirical demonstration, we show that genome-wide SNP genotypes can be inferred at a mean r(2) of 0.71 using off-target data (0.24× average coverage) in a whole-exome study of 909 samples. Using both simulated and real exome-sequencing data sets, we show that association statistics obtained using extremely low-coverage sequencing data attain similar P values at known associated variants as data from genotyping arrays, without an excess of false positives. Within the context of reductions in sample preparation and sequencing costs, funds invested in extremely low-coverage sequencing can yield several times the effective sample size of GWAS based on SNP array data and a commensurate increase in statistical power. 相似文献
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The herbaceous understory stratum contains most of the plant diversity in ponderosa pine ( Pinus ponderosa P. & C. Lawson var. scopulorum Engelm.) forests of the American Southwest and provides critical food and habitat for many wildlife species. During the last century, this stratum has been affected by livestock grazing and by increased dominance of overstory trees. We sampled a unique grazing exclosure to examine the relative importance of long-term livestock grazing (grazed or ungrazed) and habitat (park or tree) on the understory community. We sampled 3 plots of 192 contiguous quadrats (each quadrat 0.5 m 2 ) in each of the 4 treatment combinations, for a total of 2304 quadrats. Species-area curves were generated by aggregating quadrats into nonoverlapping areas at grain sizes of 0.5 to 576 m 2 . The effects of habitat and grazing on species density were evident at very different scales. Species density was higher in park than tree plots at scales ≤32 m 2 but did not differ between habitats at larger scales. Species density differed minimally between grazed and ungrazed treatments at small grains, but grazed plots contained more species than ungrazed plots at larger grains. Grazing treatments differed at smaller grains (to 4–8 m 2 ) than did habitats (to 32 m 2 ), with respect to density of native species and graminoids. Grazed plots had more exotic species than ungrazed plots at all grain sizes, though few exotics were present. Twenty-two species were identified as indicator species associated with habitats and/or grazing treatments. Evaluations of plant community response to treatments would be improved by accounting for the grain at which data have been collected and analyzed and by identifying indicator species associated with various treatments. These data would enable more-informed conservation and management decisions. 相似文献
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Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease 总被引:1,自引:0,他引:1
Trynka G Hunt KA Bockett NA Romanos J Mistry V Szperl A Bakker SF Bardella MT Bhaw-Rosun L Castillejo G de la Concha EG de Almeida RC Dias KR van Diemen CC Dubois PC Duerr RH Edkins S Franke L Fransen K Gutierrez J Heap GA Hrdlickova B Hunt S Izurieta LP Izzo V Joosten LA Langford C Mazzilli MC Mein CA Midah V Mitrovic M Mora B Morelli M Nutland S Núñez C Onengut-Gumuscu S Pearce K Platteel M Polanco I Potter S Ribes-Koninckx C Ricaño-Ponce I Rich SS Rybak A Santiago JL Senapati S Sood A 《Nature genetics》2011,43(12):1193-1201
Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease. 相似文献
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Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes 总被引:1,自引:0,他引:1
Zeggini E Scott LJ Saxena R Voight BF Marchini JL Hu T de Bakker PI Abecasis GR Almgren P Andersen G Ardlie K Boström KB Bergman RN Bonnycastle LL Borch-Johnsen K Burtt NP Chen H Chines PS Daly MJ Deodhar P Ding CJ Doney AS Duren WL Elliott KS Erdos MR Frayling TM Freathy RM Gianniny L Grallert H Grarup N Groves CJ Guiducci C Hansen T Herder C Hitman GA Hughes TE Isomaa B Jackson AU Jørgensen T Kong A Kubalanza K Kuruvilla FG Kuusisto J Langenberg C Lango H Lauritzen T Li Y Lindgren CM 《Nature genetics》2008,40(5):638-645
Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D. 相似文献
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Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor 总被引:2,自引:0,他引:2
Takahashi C Contreras B Iwanaga T Takegami Y Bakker A Bronson RT Noda M Loda M Hunt JL Ewen ME 《Nature genetics》2006,38(1):118-123
Mutations in the gene encoding the retinoblastoma tumor suppressor predispose humans and mice to tumor development. Here we have assessed the effect of Nras loss on tumor development in Rb1 heterozygous mice. Loss of one or two Nras alleles is shown to significantly reduce the severity of pituitary tumors arising in Rb1(+/-) animals by enhancing their differentiation. By contrast, C-cell thyroid adenomas occurring in Rb1(+/-) mice progress to metastatic medullary carcinomas after loss of Nras. In Rb1(+/-)Nras(+/-) animals, distant medullary thyroid carcinoma metastases are associated with loss of the remaining wild-type Nras allele. Loss of Nras in Rb1-deficient C cells results in elevated Ras homolog family A (RhoA) activity, and this is causally linked to the invasiveness and metastatic behavior of these cells. These findings suggest that the loss of the proto-oncogene Nras in certain cellular contexts can promote malignant tumor progression. 相似文献
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Monsuur AJ de Bakker PI Alizadeh BZ Zhernakova A Bevova MR Strengman E Franke L van't Slot R van Belzen MJ Lavrijsen IC Diosdado B Daly MJ Mulder CJ Mearin ML Meijer JW Meijer GA van Oort E Wapenaar MC Koeleman BP Wijmenga C 《Nature genetics》2005,37(12):1341-1344
Celiac disease is probably the best-understood immune-related disorder. The disease presents in the small intestine and results from the interplay between multiple genes and gluten, the triggering environmental factor. Although HLA class II genes explain 40% of the heritable risk, non-HLA genes accounting for most of the familial clustering have not yet been identified. Here we report significant and replicable association (P = 2.1 x 10(-6)) to a common variant located in intron 28 of the gene myosin IXB (MYO9B), which encodes an unconventional myosin molecule that has a role in actin remodeling of epithelial enterocytes. Individuals homozygous with respect to the at-risk allele have a 2.3-times higher risk of celiac disease (P = 1.55 x 10(-5)). This result is suggestive of a primary impairment of the intestinal barrier in the etiology of celiac disease, which may explain why immunogenic gluten peptides are able to pass through the epithelial barrier. 相似文献
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Germline mosaicism and Duchenne muscular dystrophy mutations 总被引:12,自引:0,他引:12
E Bakker C Van Broeckhoven E J Bonten M J van de Vooren H Veenema W Van Hul G J Van Ommen A Vandenberghe P L Pearson 《Nature》1987,329(6139):554-556
Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disease with an incidence of approximately 1 in 3,500 newborn boys. The DMD locus has a high mutation frequency: one third of the cases is thought to result from a new mutation. Linkage studies using probes to detect restriction fragment length polymorphisms and DNA deletion studies have greatly improved DMD carrier detection and prenatal diagnosis. Here we report on two families in which a pERT87 (DXS164) deletion was transmitted to more than one offspring by women who showed no evidence for the mutation in their own somatic (white blood) cells. We also show that the deletion in both siblings in one of the families is identical, indicating that the deletion must have occurred during mitosis in early germline proliferation, leading to a germline mosaicism. This phenomenon may turn out to be a major factor contributing to the induction of DMD mutations, and has important implications for the counselling of DMD families. 相似文献