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 We wish to thank Ranji Araseratnam for laboratory assistance, Bryony Jones for allowing us to quote unpublished data and Naser Ansari Pour, Sue Povey and Pascale Gerbault for helpful discussion of the manuscript.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.
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