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Convergent adaptation of human lactase persistence in Africa and Europe

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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Figure 1: Map of the LCT and MCM6 gene region and location of genotyped SNPs.
Figure 2: Map of phenotype and genotype proportions for each population group considered in this study.
Figure 3: Genotype-phenotype association for G/C-14010, T/G-13915 and C/G-13907.
Figure 4: Haplotype networks consisting of 55 SNPs spanning a 98-kb region encompassing LCT and MCM6.
Figure 5: Dual-luciferase reporter assay of LCT promoter and MCM6 introns.
Figure 6: Comparison of tracts of homozygous genotypes flanking the lactase persistence–associated SNPs.
Figure 7: Plots of the extent and decay of haplotype homozygosity in the region surrounding the C-14010 allele.

References

  1. Swallow, D.M. Genetics of lactase persistence and lactose intolerance. Annu. Rev. Genet. 37, 197–219 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Hollox, E. & Swallow, D.M. in The Genetic Basis of Common Diseases (eds. King, R. A., Rotter, J.I. & Motulsky, A.G.) 250–265 (Oxford Univ. Press, Oxford, 2002).

    Google Scholar 

  3. Durham, W.H. Coevolution: Genes, Culture, and Human Diversity (Stanford University Press, Stanford, California, 1992).

    Google Scholar 

  4. Enattah, N.S. et al. Identification of a variant associated with adult-type hypolactasia. Nat. Genet. 30, 233–237 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Wang, Y. et al. The lactase persistence/non-persistence polymorphism is controlled by a cis-acting element. Hum. Mol. Genet. 4, 657–662 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Poulter, M. et al. The causal element for the lactase persistence/non-persistence polymorphism is located in a 1 Mb region of linkage disequilibrium in Europeans. Ann. Hum. Genet. 67, 298–311 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Hogenauer, C. et al. Evaluation of a new DNA test compared with the lactose hydrogen breath test for the diagnosis of lactase non-persistence. Eur. J. Gastroenterol. Hepatol. 17, 371–376 (2005).

    Article  PubMed  Google Scholar 

  8. Ridefelt, P. & Hakansson, L.D. Lactose intolerance: lactose tolerance test versus genotyping. Scand. J. Gastroenterol. 40, 822–826 (2005).

    Article  PubMed  Google Scholar 

  9. Kuokkanen, M. et al. Transcriptional regulation of the lactase-phlorizin hydrolase gene by polymorphisms associated with adult-type hypolactasia. Gut 52, 647–652 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Olds, L.C. & Sibley, E. Lactase persistence DNA variant enhances lactase promoter activity in vitro: functional role as a cis regulatory element. Hum. Mol. Genet. 12, 2333–2340 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Troelsen, J.T., Olsen, J., Moller, J. & Sjostrom, H. An upstream polymorphism associated with lactase persistence has increased enhancer activity. Gastroenterology 125, 1686–1694 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Lewinsky, R.H. et al. T-13910 DNA variant associated with lactase persistence interacts with Oct-1 and stimulates lactase promoter activity in vitro. Hum. Mol. Genet. 14, 3945–3953 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Hollox, E.J. et al. Lactase haplotype diversity in the Old World. Am. J. Hum. Genet. 68, 160–172 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Bersaglieri, T. et al. Genetic signatures of strong recent positive selection at the lactase gene. Am. J. Hum. Genet. 74, 1111–1120 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Myles, S. et al. Genetic evidence in support of a shared Eurasian-North African dairying origin. Hum. Genet. 117, 34–42 (2005).

    Article  PubMed  Google Scholar 

  16. The International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  17. Voight, B.F., Kudaravalli, S., Wen, X. & Pritchard, J.K. A map of recent positive selection in the human genome. PLoS Biol. 4, e72 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Nielsen, R. et al. A scan for positively selected genes in the genomes of humans and chimpanzees. PLoS Biol. 3, e170 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Mulcare, C.A. et al. The T allele of a single-nucleotide polymorphism 13.9 kb upstream of the lactase gene (LCT) (C-13.9kbT) does not predict or cause the lactase-persistence phenotype in Africans. Am. J. Hum. Genet. 74, 1102–1110 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Coelho, M. et al. Microsatellite variation and evolution of human lactase persistence. Hum. Genet. 117, 329–339 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Arola, H. Diagnosis of hypolactasia and lactose malabsorption. Scand. J. Gastroenterol. Suppl. 202, 26–35 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. Pritchard, J.K., Stephens, M., Rosenberg, N.A. & Donnelly, P. Association mapping in structured populations. Am. J. Hum. Genet. 67, 170–181 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Reed, F.A., Reeves, R.G. & Aquadro, C.F. Evidence of susceptibility and resistance to cryptic X-linked meiotic drive in natural populations of Drosophila melanogaster. Evolution Int. J. Org. Evolution 59, 1280–1291 (2005).

    Article  Google Scholar 

  24. Cheung, V.G. et al. Mapping determinants of human gene expression by regional and genome-wide association. Nature 437, 1365–1369 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Maynard-Smith, J. & Haigh, J. The hitch-hiking effect of a favourable gene. Genet. Res. 23, 23–35 (1974).

    Article  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  27. Spencer, C.C. & Coop, G. SelSim: a program to simulate population genetic data with natural selection and recombination. Bioinformatics 20, 3673–3675 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Gifford-Gonzalez, D. in African Archeology (ed. Stahl, A.B.) 187–224 (Blackwell, London, 2005).

    Google Scholar 

  29. Ambrose, S. Chronology of the Later Stone Age and food production in East Africa. J. Arch. Sci. 25, 377–391 (1998).

    Article  Google Scholar 

  30. Simoons, F.J. The geographic hypothesis and lactose malabsorption. A weighing of the evidence. Am. J. Dig. Dis. 23, 963–980 (1978).

    Article  CAS  PubMed  Google Scholar 

  31. Cook, G.C. Did persistence of intestinal lactase into adult life originate in the Arabian peninsula? Man 13, 418–427 (1978).

    Article  Google Scholar 

  32. Reed, F.A. & Aquadro, C.F. Mutation, selection and the future of human evolution. Trends Genet. 22, 479–484 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Newman, J. The Peopling of Africa (Yale Univ. Press, New Haven and London, 1995).

    Google Scholar 

  34. Ehret, C. Memoire 8: Nairobi. in Culture History in the Southern Sudan (eds. Mack, J. & Robertshaw, P.) 19–48 (British Institute in Eastern Africa, Nairobi, Kenya, 1983).

    Google Scholar 

  35. Cavalli-Sforza, L.L., Piazza, A. & Menozzi, P. History and Geography of Human Genes (Princeton Univ. Press, Princeton, New Jersey, 1994).

    Google Scholar 

  36. Tishkoff, S.A. & Verrelli, B.C. Patterns of human genetic diversity: implications for human evolutionary history and disease. Annu. Rev. Genomics Hum. Genet. 4, 293–340 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Di Rienzo, A. & Hudson, R.R. An evolutionary framework for common diseases: the ancestral-susceptibility model. Trends Genet. 21, 596–601 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Tishkoff, S.A. et al. Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance. Science 293, 455–462 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Wray, G.A. et al. The evolution of transcriptional regulation in eukaryotes. Mol. Biol. Evol. 20, 1377–1419 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Miller, S.A., Dykes, D.D. & Polesky, H.F. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 16, 1215 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Whittaker, P., Bumpstead, S., Downes, K., Ghori, J. & Deloukas, P. in Cell Biology: a Laboratory Handbook (ed. Celis, J.) (Elsevier, Amsterdam, 2006).

    Google Scholar 

  42. Cochran, W.G. Some methods for strengthening the common chi-square test. Biometrics 10, 417–451 (1954).

    Article  Google Scholar 

  43. Stouffer, S.A., Suchman, E.A., DeVinney, L.C., Star, S.A. & Williams, R.M. The American Soldier: Adjustment During Army Life Vol. 1 (Princeton Univ. Press, Princeton, New Jersey, 1949).

    Google Scholar 

  44. Scheet, P. & Stephens, M. A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase. Am. J. Hum. Genet. 78, 629–644 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pritchard, J.K., Seielstad, M.T., Perez-Lezaun, A. & Feldman, M.W. Population growth of human Y chromosomes: a study of Y chromosome microsatellites. Mol. Biol. Evol. 16, 1791–1798 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Wiuf, C. Recombination in human mitochondrial DNA? Genetics 159, 749–756 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Li, N. & Stephens, M. Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data. Genetics 165, 2213–2233 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Kong, A. et al. A high-resolution recombination map of the human genome. Nat. Genet. 31, 241–247 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Bandelt, H., Forster, P. & Rohl, A. Median-joining networks for inferring intraspecific phylogenies. Mol. Biol. Evol. 16, 37–48 (1999).

    Article  CAS  PubMed  Google Scholar 

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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

Authors and Affiliations

Authors

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.

Corresponding author

Correspondence to Sarah A Tishkoff.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Distribution of phenotype values for the pooled African data set. (PDF 611 kb)

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. (PDF 400 kb)

Supplementary Fig. 3

Plot of the degree of LD between each pair of genotyped SNPs. (PDF 2978 kb)

Supplementary Table 1

Language, subsistence and lactase persistence classifications of sampled populations and LP-associated allele frequencies. (PDF 15 kb)

Supplementary Table 2

Genotyped SNP identifications and locations. (PDF 27 kb)

Supplementary Table 3

Significance of iHS under assorted demographic models (PDF 22 kb)

Supplementary Methods (PDF 161 kb)

Supplementary Discussion (PDF 115 kb)

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Tishkoff, S., Reed, F., Ranciaro, A. et al. Convergent adaptation of human lactase persistence in Africa and Europe. Nat Genet 39, 31–40 (2007). https://doi.org/10.1038/ng1946

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