Letters to Nature

Nature 419, 832-837 (24 October 2002) | doi:10.1038/nature01140; Received 7 June 2002; Accepted 19 September 2002; Published online 9 October 2002

Detecting recent positive selection in the human genome from haplotype structure

Pardis C. Sabeti1,2,7, David E. Reich1, John M. Higgins1, Haninah Z. P. Levine1, Daniel J. Richter1, Stephen F. Schaffner1, Stacey B. Gabriel1, Jill V. Platko1, Nick J. Patterson1, Gavin J. McDonald1, Hans C. Ackerman3, Sarah J. Campbell3, David Altshuler1,4, Richard Cooper5, Dominic Kwiatkowski3, Ryk Ward2 & Eric S. Lander1,6

  1. Whitehead Institute/MIT Center for Genome Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA
  2. Institute of Biological Anthropology, University of Oxford, Oxford, OX2 6QS, UK
  3. Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK
  4. Departments of Genetics and Medicine, Harvard Medical School, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
  5. Department of Preventive Medicine and Epidemiology, Loyola University Medical School, Maywood, Illinois 60143, USA
  6. Department of Biology, MIT, Cambridge, Massachusetts 02139, USA
  7. Harvard Medical School, Boston, Massachusetts 02115, USA

Correspondence to: Eric S. Lander1,6 Correspondence and requests for materials should be addressed to E.S.L. (e-mail: Email: lander@genome.wi.mit.edu).

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: G6PD 1 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.