Haplotype tagging for the identification of common disease genes

Genome-wide linkage disequilibrium (LD) mapping of common disease genes could be more powerful than linkage analysis if the appropriate density of polymorphic markers were known and if the genotyping effort and cost of producing such an LD map could be reduced. Although different metrics that measure the extent of LD have been evaluated, even the most recent studies have not placed significant emphasis on the most informative and cost-effective method of LD mapping-that based on haplotypes. We have scanned 135 kb of DNA from nine genes, genotyped 122 single-nucleotide polymorphisms (SNPs; approximately 184,000 genotypes) and determined the common haplotypes in a minimum of 384 European individuals for each gene. Here we show how knowledge of the common haplotypes and the SNPs that tag them can be used to (i) explain the often complex patterns of LD between adjacent markers, (ii) reduce genotyping significantly (in this case from 122 to 34 SNPs), (iii) scan the common variation of a gene sensitively and comprehensively and (iv) provide key fine-mapping data within regions of strong LD. Our results also indicate that, at least for the genes studied here, the current version of dbSNP would have been of limited utility for LD mapping because many common haplotypes could not be defined. A directed re-sequencing effort of the approximately 10% of the genome in or near genes in the major ethnic groups would aid the systematic evaluation of the common variant model of common disease.     

The trend and fluctuation of historical floods in the middle reaches of the Yangtze River

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Pathogenic bacteria attach to human fibronectin through a tandem beta-zipper

Staphylococcus aureus and Streptococcus pyogenes, two important human pathogens, target host fibronectin (Fn) in their adhesion to and invasion of host cells. Fibronectin-binding proteins (FnBPs), anchored in the bacterial cell wall, have multiple Fn-binding repeats in an unfolded region of the protein. The bacterium-binding site in the amino-terminal domain (1-5F1) of Fn contains five sequential Fn type 1 (F1) modules. Here we show the structure of a streptococcal (S. dysgalactiae) FnBP peptide (B3) in complex with the module pair 1F12F1. This identifies 1F1- and 2F1-binding motifs in B3 that form additional antiparallel beta-strands on sequential F1 modules-the first example of a tandem beta-zipper. Sequence analyses of larger regions of FnBPs from S. pyogenes and S. aureus reveal a repeating pattern of F1-binding motifs that match the pattern of F1 modules in 1-5F1 of Fn. In the process of Fn-mediated invasion of host cells, therefore, the bacterial proteins seem to exploit the modular structure of Fn by forming extended tandem beta-zippers. This work is a vital step forward in explaining the full mechanism of the integrin-dependent FnBP-mediated invasion of host cells.     

High resolution structure of the RNA duplex [U(U-A)6A]2

RNA is involved in many biological functions, ranging from information storage and transfer to the catalysis of reactions involving both nucleic acids and proteins. Previous crystallographic studies on RNA oligomeric chains provide only averaged structures or information limited in resolution. The oligomer [U(U-A)6A]2 was chosen for the study of protein-RNA interactions in viruses. Its size and base composition mimic portions of the genomic RNA in alfalfa mosaic virus that bind to the amino terminus of the viral subunit. The actual sequence was designed to guarantee the formation of a single species of duplex and to facilitate the production of the pure oligomer in large quantities. The molecular structure, derived from the 2.25 A resolution X-ray diffraction data, allows the most detailed analysis of an A-RNA helix reported to date. Two kinks are observed that divide the duplex into three blocks, each close to a canonical A-helical conformation. A few intermolecular hydrogen bonds involving 2'-hydroxyl groups stabilize this peculiar conformation of the RNA, which may be related to the temperature used for the crystallization (35 degrees C). The structure demonstrates both the plasticity of the RNA molecule and the role of the 2'-hydroxyl groups in intermolecular interactions.     

Microsoft C 与 MASM 混合编程的研究

讨论了Microsoft C语言中调用MASM 5．0汇编语言程序的方法，并针对一些易出现的问题，如程序接口部分的要求，C语言与汇编程序间参数的传递，寄存器的使用等，提出了解决办法．     

FCGR3B copy number variation is associated with susceptibility to systemic, but not organ-specific, autoimmunity

Naturally occurring variation in gene copy number is increasingly recognized as a heritable source of susceptibility to genetically complex diseases. Here we report strong association between FCGR3B copy number and risk of systemic lupus erythematosus (P = 2.7 x 10(-8)), microscopic polyangiitis (P = 2.9 x 10(-4)) and Wegener's granulomatosis in two independent cohorts from the UK (P = 3 x 10(-3)) and France (P = 1.1 x 10(-4)). We did not observe this association in the organ-specific Graves' disease or Addison's disease. Our findings suggest that low FCGR3B copy number, and in particular complete FCGR3B deficiency, has a key role in the development of systemic autoimmunity.     

Parameters for reliable results in genetic association studies in common disease.

It is increasingly apparent that the identification of true genetic associations in common multifactorial disease will require studies comprising thousands rather than the hundreds of individuals employed to date. Using 2,873 families, we were unable to confirm a recently published association of the interleukin 12B gene in 422 type I diabetic families. These results emphasize the need for large datasets, small P values and independent replication if results are to be reliable.