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.

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)1. We used 'longrange haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection2, 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 virus3, in West Africa; SLC24A5 and SLC45A2, both involved in skin pigmentation4,5, in Europe; and EDAR and EDA2R, both involved in development of hair follicles6, in Asia. ©2007 Nature Publishing GroupCorrespondence and requests for materials should be addressed to P.C.S. (pardis@broad.mit.edu).. * These authors contributed equally to this work. † Lists of participants and affiliations appear at the end of the paper. Author Contributions P.C.S., P.V., B.F. and E.S.L. initiated the project. P.V., B.F. and P.C.S. developed key software. P.C.S., P.V., B.F., S.F.S., J.L., E.H., C.C., X.X., E.B., S.A.McC. and R.G. performed analysis. P.C.S., E.B. and E.H. performed experiments. P.C.S., E.S.L., P.V. and S.F.S. wrote the manuscript.Full Methods and any associated references are available in the online version of the paper at www.nature.com/nature.Supplementary Information is linked to the online version of the paper at www.nature.com/nature.Reprints and permissions information is available at www.nature.com/reprints. An increasing amount of information about genetic variation, together with new analytical methods, is making it possible to explore the recent evolutionary history of the human population. The first phase of the International Haplotype Map, including ~1 million single nucleotide polymorphisms (SNPs)7, allowed preliminary examination of natural selection in humans. Now, with the publication of the Phase 2 map (HapMap2)1 in a companion paper, over 3 million SNPs have been genotyped in 420 chromosomes from three continents (120 European (CEU), 120 African (YRI) and 180 Asian from Japan and China (JPT + CHB)). Europe PMC Funders GroupIn our analysis of HapMap2, we first implemented two widely used tests that detect recent positive selection by finding common alleles carried on unusually long haplotypes2. The two, the Long-Range Haplotype (LRH)8 and the integrated Haplotype Score (iHS)9 tests...

The JUNO experiment locates in Jinji town, Kaiping city, Jiangmen city, Guangdong province. The geographic location is east longitude 112 • 31'05' and North latitude 22 • 07'05'. The experimental site is 43 km to the southwest of the Kaiping city, a county-level city in the prefecture-level city Jiangmen in Guangdong province. There are five big cities, Guangzhou, Hong Kong, Macau, Shenzhen, and Zhuhai, all in ∼200 km drive distance, as shown in figure 3.

Plants counteract fluctuations in water supply by regulating all aquaporins in the cell plasma membrane. Channel closure results either from the dephosphorylation of two conserved serine residues under conditions of drought stress, or from the protonation of a conserved histidine residue following a drop in cytoplasmic pH due to anoxia during flooding. Here we report the X-ray structure of the spinach plasma membrane aquaporin SoPIP2;1 in its closed conformation at 2.1 A resolution and in its open conformation at 3.9 A resolution, and molecular dynamics simulations of the initial events governing gating. In the closed conformation loop D caps the channel from the cytoplasm and thereby occludes the pore. In the open conformation loop D is displaced up to 16 A and this movement opens a hydrophobic gate blocking the channel entrance from the cytoplasm. These results reveal a molecular gating mechanism which appears conserved throughout all plant plasma membrane aquaporins.

The diagnosis of many neurologic diseases benefits from the ability to quantitatively assess iron in the brain. Paramagnetic iron modifies the magnetic susceptibility causing magnetic field inhomogeneity in MRI. The local field can be mapped using the MR signal phase, which is discarded in a typical image reconstruction. The calculation of the susceptibility from the measured magnetic field is an ill-posed inverse problem. In this work, a bayesian regularization approach that adds spatial priors from the MR magnitude image is formulated for susceptibility imaging. Priors include background regions of known zero susceptibility and edge information from the magnitude image. There is a growing scientific and clinical interest in quantitatively mapping magnetic biomaterials by measuring their susceptibilities using MRI. Quantifying endogenous paramagnetic iron would be useful for assessing blood oxygenation (1-3) and iron overloading in organs such as the liver (4) and the heart (5). The diagnosis and monitoring of vascular and neurodegenerative diseases in the brain would benefit directly from iron quantification (6). Susceptibility quantification may allow exploiting the strong diamagnetism of calciumbased structures to characterize osteoporosis (7,8) or calcifications in the breast and brain. Furthermore, quantitative susceptibility mapping (QSM) would allow robust quantification of paramagnetic and superparamagnetic contrast agents essential to molecular and cellular imaging (9-11) and also be valuable to the characterization of cardiovascular function (12)(13)(14). Recently, an MR reporter gene enabling iron accumulation within the cell was demonstrated (15), and quantifying the induced iron would be very important for investigating in vivo molecular biology.Quantifying the susceptibility from the magnetic field is an inverse problem similar to magnetoencephalography, in which magnetic sources inside the brain must be located and quantified from limited measurements of the field outside the head (16). While quantification based on geometrical models has long been used for specific applications (1,2,4,8,14,(17)(18)(19)(20), the reconstruction of susceptibility maps in which each voxel has an unknown susceptibility is a much more complex problem. While some approaches have been theoretically proposed (6,21,22), the ill-posedness due to limited measurements was dealt with recently by using regularization approaches (8,23) or acquisition strategies (24). Here, a bayesian regularized approach is presented that introduces priors derived from the MR magnitude image. It is shown that imposing values at given locations together with seeking a solution that shares edges with the MR magnitude image is more robust that the previously proposed methods (23). The technique is validated using simulations and phantom experiments. Additionally, in vivo brain susceptibility maps are obtained, introducing a new quantitative contrast that is directly linked to the amount of iron in the brain. MATERIALS AND METHODS Susceptibility an...