排序方式: 共有113条查询结果,搜索用时 15 毫秒
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Van Eerdewegh P Little RD Dupuis J Del Mastro RG Falls K Simon J Torrey D Pandit S McKenny J Braunschweiger K Walsh A Liu Z Hayward B Folz C Manning SP Bawa A Saracino L Thackston M Benchekroun Y Capparell N Wang M Adair R Feng Y Dubois J FitzGerald MG Huang H Gibson R Allen KM Pedan A Danzig MR Umland SP Egan RW Cuss FM Rorke S Clough JB Holloway JW Holgate ST Keith TP 《Nature》2002,418(6896):426-430
Asthma is a common respiratory disorder characterized by recurrent episodes of coughing, wheezing and breathlessness. Although environmental factors such as allergen exposure are risk factors in the development of asthma, both twin and family studies point to a strong genetic component. To date, linkage studies have identified more than a dozen genomic regions linked to asthma. In this study, we performed a genome-wide scan on 460 Caucasian families and identified a locus on chromosome 20p13 that was linked to asthma (log(10) of the likelihood ratio (LOD), 2.94) and bronchial hyperresponsiveness (LOD, 3.93). A survey of 135 polymorphisms in 23 genes identified the ADAM33 gene as being significantly associated with asthma using case-control, transmission disequilibrium and haplotype analyses (P = 0.04 0.000003). ADAM proteins are membrane-anchored metalloproteases with diverse functions, which include the shedding of cell-surface proteins such as cytokines and cytokine receptors. The identification and characterization of ADAM33, a putative asthma susceptibility gene identified by positional cloning in an outbred population, should provide insights into the pathogenesis and natural history of this common disease. 相似文献
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Genome stability requires one, and only one, DNA duplication at each S phase. The mechanisms preventing origin firing on newly replicated DNA are well documented, but much less is known about the mechanisms controlling the spacing of initiation events(2,3), namely the completion of DNA replication. Here we show that origin use in Chinese hamster cells depends on both the movement of the replication forks and the organization of chromatin loops. We found that slowing the replication speed triggers the recruitment of latent origins within minutes, allowing the completion of S phase in a timely fashion. When slowly replicating cells are shifted to conditions of fast fork progression, although the decrease in the overall number of active origins occurs within 2 h, the cells still have to go through a complete cell cycle before the efficiency specific to each origin is restored. We observed a strict correlation between replication speed during a given S phase and the size of chromatin loops in the next G1 phase. Furthermore, we found that origins located at or near sites of anchorage of chromatin loops in G1 are activated preferentially in the following S phase. These data suggest a mechanism of origin programming in which replication speed determines the spacing of anchorage regions of chromatin loops, that, in turn, controls the choice of initiation sites. 相似文献
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Gudbjartsson DF Arnar DO Helgadottir A Gretarsdottir S Holm H Sigurdsson A Jonasdottir A Baker A Thorleifsson G Kristjansson K Palsson A Blondal T Sulem P Backman VM Hardarson GA Palsdottir E Helgason A Sigurjonsdottir R Sverrisson JT Kostulas K Ng MC Baum L So WY Wong KS Chan JC Furie KL Greenberg SM Sale M Kelly P MacRae CA Smith EE Rosand J Hillert J Ma RC Ellinor PT Thorgeirsson G Gulcher JR Kong A Thorsteinsdottir U Stefansson K 《Nature》2007,448(7151):353-357
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality. Recent studies have provided evidence of a genetic contribution to AF. Mutations in potassium-channel genes have been associated with familial AF but account for only a small fraction of all cases of AF. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left-right asymmetry of the heart. 相似文献
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Mikkelsen TS Wakefield MJ Aken B Amemiya CT Chang JL Duke S Garber M Gentles AJ Goodstadt L Heger A Jurka J Kamal M Mauceli E Searle SM Sharpe T Baker ML Batzer MA Benos PV Belov K Clamp M Cook A Cuff J Das R Davidow L Deakin JE Fazzari MJ Glass JL Grabherr M Greally JM Gu W Hore TA Huttley GA Kleber M Jirtle RL Koina E Lee JT Mahony S Marra MA Miller RD Nicholls RD Oda M Papenfuss AT Parra ZE Pollock DD Ray DA Schein JE Speed TP Thompson K VandeBerg JL Wade CM Walker JA Waters PD Webber C 《Nature》2007,447(7141):167-177
We report a high-quality draft of the genome sequence of the grey, short-tailed opossum (Monodelphis domestica). As the first metatherian ('marsupial') species to be sequenced, the opossum provides a unique perspective on the organization and evolution of mammalian genomes. Distinctive features of the opossum chromosomes provide support for recent theories about genome evolution and function, including a strong influence of biased gene conversion on nucleotide sequence composition, and a relationship between chromosomal characteristics and X chromosome inactivation. Comparison of opossum and eutherian genomes also reveals a sharp difference in evolutionary innovation between protein-coding and non-coding functional elements. True innovation in protein-coding genes seems to be relatively rare, with lineage-specific differences being largely due to diversification and rapid turnover in gene families involved in environmental interactions. In contrast, about 20% of eutherian conserved non-coding elements (CNEs) are recent inventions that postdate the divergence of Eutheria and Metatheria. A substantial proportion of these eutherian-specific CNEs arose from sequence inserted by transposable elements, pointing to transposons as a major creative force in the evolution of mammalian gene regulation. 相似文献
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Scally A Dutheil JY Hillier LW Jordan GE Goodhead I Herrero J Hobolth A Lappalainen T Mailund T Marques-Bonet T McCarthy S Montgomery SH Schwalie PC Tang YA Ward MC Xue Y Yngvadottir B Alkan C Andersen LN Ayub Q Ball EV Beal K Bradley BJ Chen Y Clee CM Fitzgerald S Graves TA Gu Y Heath P Heger A Karakoc E Kolb-Kokocinski A Laird GK Lunter G Meader S Mort M Mullikin JC Munch K O'Connor TD Phillips AD Prado-Martinez J Rogers AS Sajjadian S Schmidt D Shaw K Simpson JT Stenson PD Turner DJ 《Nature》2012,483(7388):169-175
Gorillas are humans' closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera. We propose a synthesis of genetic and fossil evidence consistent with placing the human-chimpanzee and human-chimpanzee-gorilla speciation events at approximately 6 and 10 million years ago. In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing. We also compare the western and eastern gorilla species, estimating an average sequence divergence time 1.75 million years ago, but with evidence for more recent genetic exchange and a population bottleneck in the eastern species. The use of the genome sequence in these and future analyses will promote a deeper understanding of great ape biology and evolution. 相似文献
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DNA methylation is highly dynamic during mammalian embryogenesis. It is broadly accepted that the paternal genome is actively depleted of 5-methylcytosine at fertilization, followed by passive loss that reaches a minimum at the blastocyst stage. However, this model is based on limited data, and so far no base-resolution maps exist to support and refine it. Here we generate genome-scale DNA methylation maps in mouse gametes and from the zygote through post-implantation. We find that the oocyte already exhibits global hypomethylation, particularly at specific families of long interspersed element 1 and long terminal repeat retroelements, which are disparately methylated between gametes and have lower methylation values in the zygote than in sperm. Surprisingly, the oocyte contributes a unique set of differentially methylated regions (DMRs)--including many CpG island promoters--that are maintained in the early embryo but are lost upon specification and absent from somatic cells. In contrast, sperm-contributed DMRs are largely intergenic and become hypermethylated after the blastocyst stage. Our data provide a genome-scale, base-resolution timeline of DNA methylation in the pre-specified embryo, when this epigenetic modification is most dynamic, before returning to the canonical somatic pattern. 相似文献
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Michelle Gilles-Baillien Myriam Verbert 《Cellular and molecular life sciences : CMLS》1978,34(9):1174-1175
Summary During hibernation of tortoises, a marked decrease in the short-circuit current together with an increase in the electrical resistance are observed across the small intestine, colon and bladder mucosa and D-aldosterone (which is decreased in the plasma) has no effect on these parameters.Acknowledgments. This work has been aided by grant No. 2.4544.76 from the Fonds de la Recherche Fondamentale Collective attributed to Prof. E. Schoffeniels. 相似文献
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Wang PY Caspi L Lam CK Chari M Li X Light PE Gutierrez-Juarez R Ang M Schwartz GJ Lam TK 《Nature》2008,452(7190):1012-1016
Energy and glucose homeostasis are regulated by food intake and liver glucose production, respectively. The upper intestine has a critical role in nutrient digestion and absorption. However, studies indicate that upper intestinal lipids inhibit food intake as well in rodents and humans by the activation of an intestine-brain axis. In parallel, a brain-liver axis has recently been proposed to detect blood lipids to inhibit glucose production in rodents. Thus, we tested the hypothesis that upper intestinal lipids activate an intestine-brain-liver neural axis to regulate glucose homeostasis. Here we demonstrate that direct administration of lipids into the upper intestine increased upper intestinal long-chain fatty acyl-coenzyme A (LCFA-CoA) levels and suppressed glucose production. Co-infusion of the acyl-CoA synthase inhibitor triacsin C or the anaesthetic tetracaine with duodenal lipids abolished the inhibition of glucose production, indicating that upper intestinal LCFA-CoAs regulate glucose production in the preabsorptive state. Subdiaphragmatic vagotomy or gut vagal deafferentation interrupts the neural connection between the gut and the brain, and blocks the ability of upper intestinal lipids to inhibit glucose production. Direct administration of the N-methyl-d-aspartate ion channel blocker MK-801 into the fourth ventricle or the nucleus of the solitary tract where gut sensory fibres terminate abolished the upper-intestinal-lipid-induced inhibition of glucose production. Finally, hepatic vagotomy negated the inhibitory effects of upper intestinal lipids on glucose production. These findings indicate that upper intestinal lipids activate an intestine-brain-liver neural axis to inhibit glucose production, and thereby reveal a previously unappreciated pathway that regulates glucose homeostasis. 相似文献