Multiple Rare Variants as a Cause of a Common Phenotype: Several Different Lactase Persistence Associated Alleles in a Single Ethnic Group
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Persistence of intestinal lactase into adulthood allows humans to use milk from other mammals as a source of food and water. This genetic trait has arisen by convergent evolution and the derived alleles of at least three different single nucleotide polymorphisms (–13910C>T, –13915T>G, –14010G>C) are associated with lactase persistence in different populations. Each allele occurs on an extended haplotype, consistent with positive directional selection. The SNPs are located in an ‘enhancer’ sequence in an intron of a neighboring gene (MCM6) and modulate lactase transcription in vitro. However, a number of lactase persistent individuals carry none of these alleles, but other low-frequency single nucleotide polymorphisms have been observed in the same region. Here we examine a cohort of 107 milk-drinking Somali camel-herders from Ethiopia. Eight polymorphic sites are identified in the enhancer. –13915*G and –13907*G (a previously reported candidate) are each significantly associated with lactase persistence. A new allele, –14009*G, has borderline association with lactase persistence, but loses significance after correction for multiple testing. Sequence diversity of the enhancer is significantly higher in the lactase persistent members of this and a second cohort compared with non-persistent members of the two groups (P = 7.7 × 10−9 and 1.0 × 10−3). By comparing other loci, we show that this difference is not due to population sub-structure, demonstrating that increased diversity can accompany selection. This contrasts with the well-documented observation that positive selection decreases diversity by driving up the frequency of a single advantageous allele, and has implications for association studies.
KeywordsLactase persistence Population genetics Evolutionary genetics Gene-culture co-evolution Selection Africa Milk Humans
We thank all the sample donors who participated in this study. We are grateful to H. Babiker, Elizabeth Caldwell, Matthew Forka, Dominic Gomis, M. Hawary, Steve Jones, Tudor Parfitt, Pat Smith and David Zeitlyn who all contributed to sample collection. We wish to thank Ranji Araseratnam for laboratory assistance, Bryony Jones for allowing us to quote unpublished data and Naser Ansari Pour, Sue Povey and Pascale Gerbault for helpful discussion of the manuscript. We also wish to thank two anonymous reviewers for their thoughtful comments. C.J.E. Ingram was funded by a BBSRC CASE studentship.
Conflicts of interest
N.B. is Chairman of The Centre for Genetic Anthropology (TCGA) and an Honorary Lecturer in the research department of Genetics, Evolution and Environment at University College London. He is also joint chairman of the London and City Group of Companies and has extensive business and financial interests including involvement in biotechnology ventures and educational material used by researchers in biomedicine and the life sciences. Nevertheless, he does not have any specific commercial interest in the subject matter of this study. The research has been funded in part by a charitable trust of which N.B. is a trustee. The charitable trust has no intellectual property or other rights whatsoever with respect to the research which forms the subject matter of the paper. All other authors have no conflict of interest.
- Blench R (1999) Why are there so many pastoral groups in eastern Africa? In: Azarya V, Breedveld A, De Bruijn M, Van Dijk H (eds) Pastoralists under pressure? Fulbe societies confronting change in west Africa. Brill Press, Boston, pp 29–49Google Scholar
- Enattah NS, Jensen TG, Nielsen M, Lewinski R, Kuokkanen M, Rasinpera H, El-Shanti H, Seo JK, Alifrangis M, Khalil IF, Natah A, Ali A, Natah S, Comas D, Mehdi SQ, Groop L, Vestergaard EM, Imtiaz F, Rashed MS, Meyer B, Troelsen J, Peltonen L (2008) Independent introduction of two lactase-persistence alleles into human populations reflects different history of adaptation to milk culture. Am J Hum Genet 82:57–72CrossRefPubMedGoogle Scholar
- Harvey CB, Hollox EJ, Poulter M, Wang Y, Rossi M, Auricchio S, Iqbal TH, Cooper BT, Barton R, Sarner M, Korpela R, Swallow DM (1998) Lactase haplotype frequencies in Caucasians: association with the lactase persistence/non-persistence polymorphism. Ann Hum Genet 62:215–223CrossRefPubMedGoogle Scholar
- Lettice LA, Horikoshi T, Heaney SJ, van Baren MJ, van der Linde HC, Breedveld GJ, Joosse M, Akarsu N, Oostra BA, Endo N, Shibata M, Suzuki M, Takahashi E, Shinka T, Nakahori Y, Ayusawa D, Nakabayashi K, Scherer SW, Heutink P, Hill RE, Noji S (2002) Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proc Natl Acad Sci USA 99:7548–7553CrossRefPubMedGoogle Scholar
- Mulcare CA, Weale ME, Jones AL, Connell B, Zeitlyn D, Tarekegn A, Swallow DM, Bradman N, Thomas MG (2004) 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 74:1102–1110CrossRefPubMedGoogle Scholar
- Nei M (1987) Molecular evolutionary genetics. Columbia University Press, New YorkGoogle Scholar
- Poulter M, Hollox E, Harvey CB, Mulcare C, Peuhkuri K, Kajander K, Sarner M, Korpela R, Swallow DM (2003) 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 67:298–311CrossRefPubMedGoogle Scholar
- Raymond M, Rousset F (1995b) GENEPOP (version 1.2): population genetics software for exact tests and ecumenicism. J Heredity 86:248–249Google Scholar
- Sokal RR, Rohlf FJ (1994) Biometry: the principles and practice of statistics in biological research, 3rd edn. WH Freeman and Company, New YorkGoogle Scholar
- Tag CG, Schifflers MC, Mohnen M, Gressner AM, Weiskirchen R (2007) A novel proximal -13914G>A base replacement in the vicinity of the common-13910T/C lactase gene variation results in an atypical LightCycler melting curve in testing with the MutaREAL lactase test. Clin Chem 53:146–148CrossRefPubMedGoogle Scholar
- Thomas MG, Weale ME, Jones AL, Richards M, Smith A, Redhead N, Torroni A, Scozzari R, Gratrix F, Tarekegn A, Wilson JF, Capelli C, Bradman N, Goldstein DB (2002) Founding mothers of Jewish communities: geographically separated Jewish groups were independently founded by very few female ancestors. Am J Hum Genet 70:1411–1420CrossRefPubMedGoogle Scholar
- Tishkoff SA, Reed FA, Ranciaro A, Voight BF, Babbitt CC, Silverman JS, Powell K, Mortensen HM, Hirbo JB, Osman M, Ibrahim M, Omar SA, Lema G, Nyambo TB, Ghori J, Bumpstead S, Pritchard JK, Wray GA, Deloukas P (2007) Convergent adaptation of human lactase persistence in Africa and Europe. Nat Genet 39:31–40CrossRefPubMedGoogle Scholar