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471.
McCarroll SA Hadnott TN Perry GH Sabeti PC Zody MC Barrett JC Dallaire S Gabriel SB Lee C Daly MJ Altshuler DM;International HapMap Consortium 《Nature genetics》2006,38(1):86-92
The locations and properties of common deletion variants in the human genome are largely unknown. We describe a systematic method for using dense SNP genotype data to discover deletions and its application to data from the International HapMap Consortium to characterize and catalogue segregating deletion variants across the human genome. We identified 541 deletion variants (94% novel) ranging from 1 kb to 745 kb in size; 278 of these variants were observed in multiple, unrelated individuals, 120 in the homozygous state. The coding exons of ten expressed genes were found to be commonly deleted, including multiple genes with roles in sex steroid metabolism, olfaction and drug response. These common deletion polymorphisms typically represent ancestral mutations that are in linkage disequilibrium with nearby SNPs, meaning that their association to disease can often be evaluated in the course of SNP-based whole-genome association studies. 相似文献
472.
Valdar W Solberg LC Gauguier D Burnett S Klenerman P Cookson WO Taylor MS Rawlins JN Mott R Flint J 《Nature genetics》2006,38(8):879-887
Difficulties in fine-mapping quantitative trait loci (QTLs) are a major impediment to progress in the molecular dissection of complex traits in mice. Here we show that genome-wide high-resolution mapping of multiple phenotypes can be achieved using a stock of genetically heterogeneous mice. We developed a conservative and robust bootstrap analysis to map 843 QTLs with an average 95% confidence interval of 2.8 Mb. The QTLs contribute to variation in 97 traits, including models of human disease (asthma, type 2 diabetes mellitus, obesity and anxiety) as well as immunological, biochemical and hematological phenotypes. The genetic architecture of almost all phenotypes was complex, with many loci each contributing a small proportion to the total variance. Our data set, freely available at http://gscan.well.ox.ac.uk, provides an entry point to the functional characterization of genes involved in many complex traits. 相似文献
473.
The genetic basis of most conditions characterized by congenital contractures is largely unknown. Here we show that mutations in the embryonic myosin heavy chain (MYH3) gene cause Freeman-Sheldon syndrome (FSS), one of the most severe multiple congenital contracture (that is, arthrogryposis) syndromes, and nearly one-third of all cases of Sheldon-Hall syndrome (SHS), the most common distal arthrogryposis. FSS and SHS mutations affect different myosin residues, demonstrating that MYH3 genotype is predictive of phenotype. A structure-function analysis shows that nearly all of the MYH3 mutations are predicted to interfere with myosin's catalytic activity. These results add to the growing body of evidence showing that congenital contractures are a shared outcome of prenatal defects in myofiber force production. Elucidation of the genetic basis of these syndromes redefines congenital contractures as unique defects of the sarcomere and provides insights about what has heretofore been a poorly understood group of disorders. 相似文献
474.
475.
Snake envenomation is a socio-medical problem of considerable magnitude. About 2.5 million people are bitten by snakes annually,
more than 100,000 fatally. However, although bites can be deadly, snake venom is a natural biological resource that contains
several components of potential therapeutic value. Venom has been used in the treatment of a variety of pathophysiological
conditions in Ayurveda, homeopathy and folk medicine. With the advent of biotechnology, the efficacy of such treatments has
been substantiated by purifying components of venom and delineating their therapeutic properties. This review will focus on
certain snake venom components and their applications in health and disease.
Received 6 July 2006; received after revision 14 August 2006; accepted 28 September 2006 相似文献
476.
Based on the classification of bacterial lipolytic enzymes, family I.3 lipase is a member of the large group of Gram-negative
bacterial true lipases. This lipase family is distinguished from other families not only by the amino acid sequence, but also
by the secretion mechanism. Lipases of family I.3 are secreted via the well-known type I secretion system. Like most of proteins
secreted via this system, family I.3 lipases are composed of two domains with distinct yet related functions. Recent years
have seen an increasing amount of research on this lipase family, in terms of isolation, secretion mechanism, as well as biochemical
and biophysical studies. This review describes our current knowledge on the structure-function relationships of family I.3
lipase, with an emphasis on its secretion mechanism.
Received 18 April 2006; received after revision 3 July 2006; accepted 24 August 2006 相似文献
477.
Memories become stabilized through a time-dependent process that requires gene expression and is commonly known as consolidation. During this time, memories are labile and can be disrupted by a number of interfering events, including electroconvulsive shock, trauma and other learning or the transient effect of drugs such as protein synthesis inhibitors. Once consolidated, memories are insensitive to these disruptions. However, they can again become fragile if recalled or reactivated. Reactivation creates another time-dependent process, known as reconsolidation, during which the memory is restabilized. Here we discuss some of the questions currently debated in the field of memory consolidation and reconsolidation, the molecular and anatomical requirements for both processes and, finally, their functional relationship. 相似文献
478.
479.
Peutz-Jeghers syndrome (PJS, OMIM 175200) is an unusual inherited intestinal polyposis syndrome associated with distinct peri-oral
blue/black freckling [1–9]. Variable penetrance and clinical heterogeneity make it difficult to determine the exact frequency
of PJS [4]. PJS is a cancer predisposition syndrome. Affected individuals are at high risk for intestinal and extra-intestinal
cancers. In 1997, linkage studies mapped PJS to chromosome 19p [10, 11], and subsequently a serine/threonine kinase gene defect
(LKB1) was noted in a majority of PJS cases [12, 13]. A phenotypically similar syndrome has been produced in an LKB1 mouse
knockout model [14–18]. Several PJS kindred without LKB1 mutations have been described, suggesting other PJS loci [19–22].
The management of PJS is complex and evolving. New endoscopic technologies may improve management of intestinal polyposis.
Identification of specific genetic mutations and their targets will more accurately assess the clinical course, and help gage
the magnitude of cancer risk for affected individuals.
Received 20 February 2006; received after revision 5 May 2006; accepted 15 June 2006 相似文献
480.
Site- and state-specific lysine methylation of histones is catalyzed by a family of proteins that contain the evolutionarily
conserved SET domain and plays a fundamental role in epigenetic regulation of gene activation and silencing in all eukaryotes.
The recently determined three-dimensional structures of the SET domains from chromosomal proteins reveal that the core SET
domain structure contains a two-domain architecture, consisting of a conserved anti-parallel β-barrel and a structurally variable
insert that surround a unusual knot-like structure that comprises the enzyme active site. These structures of the SET domains,
either in the free state or when bound to cofactor S-adenosyl-L-homocysteine and/or histone peptide, mimicking an enzyme/cofactor/substrate complex, further yield the structural insights
into the molecular basis of the substrate specificity, methylation multiplicity and the catalytic mechanism of histone lysine
methylation.
Received 10 June 2006; accepted 22 August 2006 相似文献