Superoxide dismutase reduces injury in many disease processes, implicating superoxide anion radical (02 ) as a toxic species in vivo. A critical target of superoxide may be nitric oxide (NO-) produced by endothelium, macrophages, neutrophils, and brain synaptosomes. Superoxide and NO-are known to rapidly react to form the stable peroxynitrite anion (ONOO-). We have shown that peroxynitrite has a pKa of 7.49 ± 0.06 at 3TC and rapidly decomposes once protonated with a half-life of 1.9 sec at pH 7.4. Peroxynitrite decomposition generates a strong oxidant with reactivity similar to hydroxyl radical, as assessed by the oxidation of deoxyribose or dimethyl sulfoxide. Product yields indicative of hydroxyl radical were 5.1 ± 0.1% and 24.3 + 1.0%, respectively, of added peroxynitrite. Product formation was not affected by the metal chelator diethyltriaminepentaacetic acid, suggesting that iron was not required to catalyze oxidation. In contrast, desferrioxamine was a potent, competitive inhibitor of peroxynitriteinitiated oxidation because of a direct reaction between desferrioxamine and peroxynitrite rather than by iron chelation. We propose that superoxide dismutase may protect vascular tissue stimulated to produce superoxide and NON under pathological conditions by preventing the formation of peroxynitrite.Vascular injury secondary to ischemia/reperfusion, inflammation, xenobiotic metabolism, hyperoxic exposure, and other diseases results in loss of endothelial barrier function, adhesion of platelets, and abnormal vasoregulation. The ability of superoxide dismutase (SOD) to often reduce endothelial injury indirectly implicates the participation of superoxide anion radical (Oj-) with many pathological processes (1). While O-' can be directly toxic (2), it has a limited reactivity with most biological molecules, raising questions about its toxicity per se (3). To account for the apparent toxicity of O-j in vivo, the secondary production of the far-more-reactive hydroxyl radical (HO-) is frequently proposed to occur by the iron-catalyzed Haber Recently, endothelium, macrophages, and brain synaptosome preparations have been shown to produce NOR by oxidizing arginine by a calcium-activated NADPH-dependent enzyme (6-9). NOR appears to be a major form of the endothelium-derived relaxing factor (EDRF) (10). Vasodilatory agents such as acetylcholine, ATP, and bradykinin initiate a receptor-mediated influx of Ca2 , triggering the production and extracellular release of NO-, which then activates soluble heme-containing guanylate cyclases to produce cGMP in vascular smooth muscle and platelets. Increased cGMP promotes relaxation in vascular smooth muscle and inhibits platelet aggregation as well as adhesion of platelets to endothelium (11). Macrophages produce NOR as part of their cytotoxic armamentarium (6).The half-life of EDRF and NON ranges from 4 to 50 sec (12), which is approximately doubled by SOD (13,14). NOR does not bind directly to the copper of SOD (15), suggesting that stabilization involves the scavenging of...

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...

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A haplotype map of the human genomeThe International HapMap Consortium* Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.