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Abstract

A SNP in the gene encoding lactase (LCT) (C/T-13910) is associated with the ability to digest milk as adults (lactase persistence) in Europeans, but the genetic basis of lactase persistence in Africans was previously unknown. We conducted a genotype-phenotype association study in 470 Tanzanians, Kenyans and Sudanese and identified three SNPs (G/C-14010, T/G-13915 and C/G-13907) that are associated with lactase persistence and that have derived alleles that significantly enhance transcription from the LCT promoter in vitro. These SNPs originated on different haplotype backgrounds from the European C/T-13910 SNP and from each other. Genotyping across a 3-Mb region demonstrated haplotype homozygosity extending >2.0 Mb on chromosomes carrying C-14010, consistent with a selective sweep over the past 7,000 years. These data provide a marked example of convergent evolution due to strong selective pressure resulting from shared cultural traits—animal domestication and adult milk consumption.

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Acknowledgements

We thank K. Panchapakesan, E. King, S. Morrow and T. Severson for technical assistance. We thank E. Sibley and L.C. Olds for sharing advice and materials and T. Bersaglieri and J. Hirschhorn for sharing data. We thank S.J. Deo, P. Lufungulo, W. Ntandu, A. Mabulla, J.L. Mountain, J. Hanby, D. Bygott, A. Tibwitta, D. Kariuki, L. Alando, E. Aluvala, F. Mohammed, A. Teia and A.A. Mohamed for their assistance with sample collection. We thank A. Clark for critical review of the manuscript and for helpful suggestions and we thank L. Peltonen, N. Enattah and C. Ehret for discussion. We thank the African participants who generously donated DNA and phenotype information so that we might learn more about their population history and the genetic basis of lactase persistence in Africa. This study was funded by L.S.B. Leakey and Wenner Gren Foundation grants, US National Science Foundation (NSF) grants BSC-0196183 and BSC-0552486, US National Institutes of Health (NIH) grant R01GM076637 and David and Lucile Packard and Burroughs Wellcome Foundation Career Awards to S.A.T. K.P. and H.M.M. were funded by NSF grant IGERT-9987590 to S.A.T. F.A.R. was supported by US National Institutes of Health (NIH) grant F32HG03801. B.F.V. and J.K.P. were supported by NIH grant HG002772-1. The Institute for Genome Sciences and Policy of Duke University supported the work of C.C.B., J.S.S. and G.A.W. The Wellcome Trust supported the work of J.G., S.B. and P.D.

Author information

Author notes

    • Sarah A Tishkoff
    •  & Floyd A Reed

    These authors contributed equally to this work.

Affiliations

  1. Department of Biology, University of Maryland, College Park, Maryland 20742, USA.

    • Sarah A Tishkoff
    • , Floyd A Reed
    • , Alessia Ranciaro
    • , Kweli Powell
    • , Holly M Mortensen
    •  & Jibril B Hirbo
  2. Department of Biology, University of Ferrara, 44100 Ferrara, Italy.

    • Alessia Ranciaro
  3. Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA.

    • Benjamin F Voight
    •  & Jonathan K Pritchard
  4. Institute for Genome Sciences & Policy and Department of Biology, Duke University, Durham, North Carolina 27708, USA.

    • Courtney C Babbitt
    • , Jesse S Silverman
    •  & Gregory A Wray
  5. Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum, 15-13 Khartoum, Sudan.

    • Maha Osman
    •  & Muntaser Ibrahim
  6. Kenya Medical Research Institute, Centre for Biotechnology Research and Development, 54840-00200 Nairobi, Kenya.

    • Sabah A Omar
  7. Department of Biochemistry, Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania.

    • Godfrey Lema
    •  & Thomas B Nyambo
  8. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

    • Jilur Ghori
    • , Suzannah Bumpstead
    •  & Panos Deloukas

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Contributions

S.A.T. conceived and supervised the study. S.A.T., K.P., H.M.M., A.R., J.B.H., M.O., M.I., S.A.O., G.L. and T.B.N. were involved in DNA collection and phenotype testing. A.R. performed the resequencing and initial identification of association of candidate SNPs with the phenotype. S.A.T. and F.A.R. selected the SNPs to be genotyped and samples to test for gene expression. P.D., J.G. and S.B. performed the SNP design and genotyping. F.A.R. processed and phased the raw data and performed the genotype-phenotype association analyses, plots of haplotype homozygosity from unphased data, dominance estimates and pairwise plot of LD. B.F.V. performed, and J.K.P. co-supervised, the iHS test to detect positive selection and plots of haplotype homozygosity from phased data as well as rejection-sampling analyses to estimate age of alleles and selection parameters. H.M.M. constructed the haplotype networks. C.C.B., J.S.S. and G.A.W. built the expression constructs, carried out transcription assays and analyzed the results of expression assays. The paper was written primarily by S.A.T., with contributions from F.A.R., B.F.V., J.K.P., C.C.B., G.A.W. and P.D. The supplementary information was written by S.A.T. and F.A.R. with contributions from B.F.V., J.K.P., C.C.B., G.A.W. and P.D.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sarah A Tishkoff.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Distribution of phenotype values for the pooled African data set.

  2. 2.

    Supplementary Fig. 2

    Plots of the extent and decay of haplotype homozygosity in the region surrounding the G-rs2322813, G-13907 and G-13915 alleles.

  3. 3.

    Supplementary Fig. 3

    Plot of the degree of LD between each pair of genotyped SNPs.

  4. 4.

    Supplementary Table 1

    Language, subsistence and lactase persistence classifications of sampled populations and LP-associated allele frequencies.

  5. 5.

    Supplementary Table 2

    Genotyped SNP identifications and locations.

  6. 6.

    Supplementary Table 3

    Significance of iHS under assorted demographic models

  7. 7.

    Supplementary Methods

  8. 8.

    Supplementary Discussion

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DOI

https://doi.org/10.1038/ng1946

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