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Am J Hum Genet. 2014 Apr 3;94(4):496-510. doi: 10.1016/j.ajhg.2014.02.009. Epub 2014 Mar 13.

Genetic origins of lactase persistence and the spread of pastoralism in Africa.

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Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:
Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA.
UMR 208, Musée de l'Homme, Muséum National d'Histoire Naturelle and Institut de Recherche pour le Développement, 75116 Paris, France.
Dipartimento di Biologia Ambientale, Università La Sapienza, 00185 Rome, Italy; Istituto Italiano di Antropologia, 00100 Rome, Italy.
Division of Anatomical Pathology, Department of Pathology, Faculty of Health Sciences, University of Stellenbosch, Tygerberg 7505, South Africa.
Department of Molecular Biology, Institute of Endemic Diseases, University of Khartoum, 15-13 Khartoum, Sudan.
Department of Biochemistry, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
Centre for Biotechnology Research and Development, Kenya Medical Research Institute, 54840-00200 Nairobi, Kenya.
Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:


In humans, the ability to digest lactose, the sugar in milk, declines after weaning because of decreasing levels of the enzyme lactase-phlorizin hydrolase, encoded by LCT. However, some individuals maintain high enzyme amounts and are able to digest lactose into adulthood (i.e., they have the lactase-persistence [LP] trait). It is thought that selection has played a major role in maintaining this genetically determined phenotypic trait in different human populations that practice pastoralism. To identify variants associated with the LP trait and to study its evolutionary history in Africa, we sequenced MCM6 introns 9 and 13 and ~2 kb of the LCT promoter region in 819 individuals from 63 African populations and in 154 non-Africans from nine populations. We also genotyped four microsatellites in an ~198 kb region in a subset of 252 individuals to reconstruct the origin and spread of LP-associated variants in Africa. Additionally, we examined the association between LP and genetic variability at candidate regulatory regions in 513 individuals from eastern Africa. Our analyses confirmed the association between the LP trait and three common variants in intron 13 (C-14010, G-13907, and G-13915). Furthermore, we identified two additional LP-associated SNPs in intron 13 and the promoter region (G-12962 and T-956, respectively). Using neutrality tests based on the allele frequency spectrum and long-range linkage disequilibrium, we detected strong signatures of recent positive selection in eastern African populations and the Fulani from central Africa. In addition, haplotype analysis supported an eastern African origin of the C-14010 LP-associated mutation in southern Africa.

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