Overlapping complementary DNA clones were isolated from epithelial cell libraries with a genomic DNA segment containing a portion of the putative cystic fibrosis (CF) locus, which is on chromosome 7. Transcripts, approximately 6500 nucleotides in size, were detectable in the tissues affected in patients with CF. The predicted protein consists of two similar motifs, each with (i) a domain having properties consistent with membrane association and (ii) a domain believed to be involved in ATP (adenosine triphosphate) binding. A deletion of three base pairs that results in the omission of a phenylalanine residue at the center of the first predicted nucleotide-binding domain was detected in CF patients.

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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