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Detecting recent positive selection in the human genome from haplotype structure


The ability to detect recent natural selection in the human population would have profound implications for the study of human history and for medicine. Here, we introduce a framework for detecting the genetic imprint of recent positive selection by analysing long-range haplotypes in human populations. We first identify haplotypes at a locus of interest (core haplotypes). We then assess the age of each core haplotype by the decay of its association to alleles at various distances from the locus, as measured by extended haplotype homozygosity (EHH). Core haplotypes that have unusually high EHH and a high population frequency indicate the presence of a mutation that rose to prominence in the human gene pool faster than expected under neutral evolution. We applied this approach to investigate selection at two genes carrying common variants implicated in resistance to malaria: G6PD1 and CD40 ligand2. At both loci, the core haplotypes carrying the proposed protective mutation stand out and show significant evidence of selection. More generally, the method could be used to scan the entire genome for evidence of recent positive selection.

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Figure 1: Experimental design of core and long-range SNPs for G6PD and TNFSF5.
Figure 2: Core haplotype frequency and relative EHH of G6PD and TNFSF5.
Figure 3: Control regions: core haplotype frequency against relative EHH.

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We thank B. Blumenstiel, M. DeFelice, A. Lochner, J. Moore, H. Nguyen and J. Roy for assistance in genotyping the 17 control regions. We also thank L. Gaffney, S. Radhakrishna, T. DiCesare and T. Lavery for graphics and technical support, B. Ferrell for the Beni samples, and A. Adeyemo and C. Rotimi for helping to collect the Yoruba and Shona samples. Finally, we thank M. Daly, E. Cosman, B. Gray, V. Koduri, T. Herrington and L. Peterson for comments on the manuscript. P.C.S. was supported by grants from the Rhodes Trust, the Harvard Office of Enrichment, and by a Soros Fellowship. This work was supported by grants from the National Institute of Health.

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Correspondence to Eric S. Lander.

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Sabeti, P., Reich, D., Higgins, J. et al. Detecting recent positive selection in the human genome from haplotype structure. Nature 419, 832–837 (2002).

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