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191.
A second generation human haplotype map of over 3.1 million SNPs 总被引:2,自引:0,他引:2
International HapMap Consortium Frazer KA Ballinger DG Cox DR Hinds DA Stuve LL Gibbs RA Belmont JW Boudreau A Hardenbol P Leal SM Pasternak S Wheeler DA Willis TD Yu F Yang H Zeng C Gao Y Hu H Hu W Li C Lin W Liu S Pan H Tang X Wang J Wang W Yu J Zhang B Zhang Q Zhao H Zhao H Zhou J Gabriel SB Barry R Blumenstiel B Camargo A Defelice M Faggart M Goyette M Gupta S Moore J Nguyen H Onofrio RC Parkin M Roy J Stahl E Winchester E Ziaugra L Altshuler D Shen Y Yao Z Huang W Chu X He Y Jin L Liu Y 《Nature》2007,449(7164):851-861
We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations. 相似文献
192.
Genome-wide detection and characterization of positive selection in human populations 总被引:3,自引:0,他引:3
Sabeti PC Varilly P Fry B Lohmueller J Hostetter E Cotsapas C Xie X Byrne EH McCarroll SA Gaudet R Schaffner SF Lander ES;International HapMap Consortium Frazer KA Ballinger DG Cox DR Hinds DA Stuve LL Gibbs RA Belmont JW Boudreau A Hardenbol P Leal SM Pasternak S Wheeler DA Willis TD Yu F Yang H Zeng C Gao Y Hu H Hu W Li C Lin W Liu S Pan H Tang X Wang J Wang W Yu J Zhang B Zhang Q Zhao H Zhao H Zhou J Gabriel SB Barry R Blumenstiel B Camargo A Defelice M Faggart M Goyette M Gupta S Moore J 《Nature》2007,449(7164):913-918
With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia. 相似文献
193.
194.
Mullighan CG Goorha S Radtke I Miller CB Coustan-Smith E Dalton JD Girtman K Mathew S Ma J Pounds SB Su X Pui CH Relling MV Evans WE Shurtleff SA Downing JR 《Nature》2007,446(7137):758-764
Chromosomal aberrations are a hallmark of acute lymphoblastic leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed a genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer. 相似文献
195.
Subducting slabs provide the main driving force for plate motion and flow in the Earth's mantle, and geodynamic, seismic and geochemical studies offer insight into slab dynamics and subduction-induced flow. Most previous geodynamic studies treat subduction zones as either infinite in trench-parallel extent (that is, two-dimensional) or finite in width but fixed in space. Subduction zones and their associated slabs are, however, limited in lateral extent (250-7,400 km) and their three-dimensional geometry evolves over time. Here we show that slab width controls two first-order features of plate tectonics-the curvature of subduction zones and their tendency to retreat backwards with time. Using three-dimensional numerical simulations of free subduction, we show that trench migration rate is inversely related to slab width and depends on proximity to a lateral slab edge. These results are consistent with retreat velocities observed globally, with maximum velocities (6-16 cm yr(-1)) only observed close to slab edges (<1,200 km), whereas far from edges (>2,000 km) retreat velocities are always slow (<2.0 cm yr(-1)). Models with narrow slabs (< or =1,500 km) retreat fast and develop a curved geometry, concave towards the mantle wedge side. Models with slabs intermediate in width ( approximately 2,000-3,000 km) are sublinear and retreat more slowly. Models with wide slabs (> or =4,000 km) are nearly stationary in the centre and develop a convex geometry, whereas trench retreat increases towards concave-shaped edges. Additionally, we identify periods (5-10 Myr) of slow trench advance at the centre of wide slabs. Such wide-slab behaviour may explain mountain building in the central Andes, as being a consequence of its tectonic setting, far from slab edges. 相似文献
196.
197.
Some of the most intriguing problems in solid-state physics arise when the motion of one electron dramatically affects the motion of surrounding electrons. Traditionally, such highly correlated electron systems have been studied mainly in materials with complex transition metal chemistry. Over the past decade, researchers have learned to confine one or a few electrons within a nanometre-scale semiconductor 'artificial atom', and to understand and control this simple system in detail(3). Here we combine artificial atoms to create a highly correlated electron system within a nano-engineered semiconductor structure. We tune the system in situ through a quantum phase transition between two distinct states, each a version of the Kondo state, in which a bound electron interacts with surrounding mobile electrons. The boundary between these competing Kondo states is a quantum critical point-namely, the exotic and previously elusive two-channel Kondo state, in which electrons in two reservoirs are entangled through their interaction with a single localized spin. 相似文献
198.
Suzuki K Okuno T Yamamoto M Pasterkamp RJ Takegahara N Takamatsu H Kitao T Takagi J Rennert PD Kolodkin AL Kumanogoh A Kikutani H 《Nature》2007,446(7136):680-684
Semaphorins are axon guidance factors that assist growing axons in finding appropriate targets and forming synapses. Emerging evidence suggests that semaphorins are involved not only in embryonic development but also in immune responses. Semaphorin 7A (Sema7A; also known as CD108), which is a glycosylphosphatidylinositol-anchored semaphorin, promotes axon outgrowth through beta1-integrin receptors and contributes to the formation of the lateral olfactory tract. Although Sema7A has been shown to stimulate human monocytes, its function as a negative regulator of T-cell responses has also been reported. Thus, the precise function of Sema7A in the immune system remains unclear. Here we show that Sema7A, which is expressed on activated T cells, stimulates cytokine production in monocytes and macrophages through alpha1beta1 integrin (also known as very late antigen-1) as a component of the immunological synapse, and is critical for the effector phase of the inflammatory immune response. Sema7A-deficient (Sema7a-/-) mice are defective in cell-mediated immune responses such as contact hypersensitivity and experimental autoimmune encephalomyelitis. Although antigen-specific and cytokine-producing effector T cells can develop and migrate into antigen-challenged sites in Sema7a-/- mice, Sema7a-/- T cells fail to induce contact hypersensitivity even when directly injected into the antigen-challenged sites. Thus, the interaction between Sema7A and alpha1beta1 integrin is crucial at the site of inflammation. These findings not only identify a function of Sema7A as an effector molecule in T-cell-mediated inflammation, but also reveal a mechanism of integrin-mediated immune regulation. 相似文献
199.
Lundqvist T Fisher SL Kern G Folmer RH Xue Y Newton DT Keating TA Alm RA de Jonge BL 《Nature》2007,447(7146):817-822
Glutamate racemase is an enzyme essential to the bacterial cell wall biosynthesis pathway, and has therefore been considered as a target for antibacterial drug discovery. We characterized the glutamate racemases of several pathogenic bacteria using structural and biochemical approaches. Here we describe three distinct mechanisms of regulation for the family of glutamate racemases: allosteric activation by metabolic precursors, kinetic regulation through substrate inhibition, and D-glutamate recycling using a d-amino acid transaminase. In a search for selective inhibitors, we identified a series of uncompetitive inhibitors specifically targeting Helicobacter pylori glutamate racemase that bind to a cryptic allosteric site, and used these inhibitors to probe the mechanistic and dynamic features of the enzyme. These structural, kinetic and mutational studies provide insight into the physiological regulation of these essential enzymes and provide a basis for designing narrow-spectrum antimicrobial agents. 相似文献
200.
Lee WS Vishik IM Tanaka K Lu DH Sasagawa T Nagaosa N Devereaux TP Hussain Z Shen ZX 《Nature》2007,450(7166):81-84
The superconducting gap--an energy scale tied to the superconducting phenomena--opens on the Fermi surface at the superconducting transition temperature (T(c)) in conventional BCS superconductors. In underdoped high-T(c) superconducting copper oxides, a pseudogap (whose relation to the superconducting gap remains a mystery) develops well above T(c) (refs 1, 2). Whether the pseudogap is a distinct phenomenon or the incoherent continuation of the superconducting gap above T(c) is one of the central questions in high-T(c) research. Although some experimental evidence suggests that the two gaps are distinct, this issue is still under intense debate. A crucial piece of evidence to firmly establish this two-gap picture is still missing: a direct and unambiguous observation of a single-particle gap tied to the superconducting transition as function of temperature. Here we report the discovery of such an energy gap in underdoped Bi2Sr2CaCu2O8+delta in the momentum space region overlooked in previous measurements. Near the diagonal of Cu-O bond direction (nodal direction), we found a gap that opens at T(c) and has a canonical (BCS-like) temperature dependence accompanied by the appearance of the so-called Bogoliubov quasi-particles, a classical signature of superconductivity. This is in sharp contrast to the pseudogap near the Cu-O bond direction (antinodal region) measured in earlier experiments. 相似文献