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.

The structural genes for Shiga toxin, designated stx A and stx B, were cloned from Shigella dysenteriae type 1 3818T, and a nucleotide sequence analysis was performed. Both stx A and stx B were present on a single transcriptional unit, with stx A preceding stx B. The molecular weight calculated for the processed A subunit was 32,225, while the molecular weight of the processed B subunit was 7,691. Comparison of the nucleotide sequences for Shiga toxin and Shiga-like toxin I (SLT-I) from Escherichia coli revealed that the genes for Shiga toxin and SLT-I were greater than 99% homologous; three nucleotide changes were detected in three separate codons of the A subunits. Only one of these codon differences resulted in a change in the amino acid sequence: a threonine in Shiga toxin at position 45 of the A subunit compared with a serine in the corresponding position in SLT-I. Furthermore, Shiga toxin and SLT-I had identical signal peptides for the A and B subunits, as well as identical ribosome-binding sites, a putative promoter, and iron-regulated operator sequences. These findings indicate that Shiga and SLT-I are essentially the same toxin. Southern hybridization studies with total cellular DNA from several Shigella strains and internal toxin probes for SLT-I and its antigenic variant SLT-II showed that a single fragment in S. dysenteriae type 1 hybridized strongly with the internal SLT-I probe. Fragments with weaker homology to the SLT-I probe were detected in S. flexneri type 2a but no other shigellae. No homology between the Shiga-like toxin II (SLT-II) probe and any of the Shigella DNAs was detected. Whereas SLT-I and SLT-II are phage encoded, no phage could be induced from S. dysenteriae type 1 or other Shigella spp. tested. These results suggest that the Shiga (SLT-I) toxin genes responsible for high toxin production are present in a single copy in S. dysenteriae type 1 but not in other shigellae. The findings further suggest that SLT-II genes are absent in shigellae, as are toxin-converting phages.Shiga toxin is a cell-associated protein toxin composed of one copy of an A subunit (molecular weight estimated as 32,000) and five copies of a B subunit (molecular weight estimated as 7,700) (8, 38). The toxin inhibits protein synthesis in eucaryotic cells by cleaving the N-glycosidic bond at adenine 4324 in 28S rRNA (Y. Endo, K. Tsurugi, T. Yutsudo, Y. Takeda, T. Ogasawara, and K. Igarashi, Eur. J. Biochem., in press). The mode of action of Shiga toxin is therefore identical to that of the plant toxin ricin (10). The biological and biochemical properties of Shiga toxin have recently been reviewed by O'Brien and Holmes (27).Shigella species other than Shigella dysenteriae type 1 and certain strains of Escherichia coli, Salmonella typhimurium, Vibrio cholerae, and Campylobacter jejuni produce low levels of a cytotoxin(s) that is neutralizable by antibodies against purified Shiga toxin from S. dysenteriae type 1 (30, 32; A. D. O'Brien, M. E. Chen, R. K. Holmes, J. Kaper, and M. Levine, Letter, Lancet, i:77-78, 1984;...