Multiple rare variants as a cause of a common phenotype: several different lactase persistence associated alleles in a single ethnic group

J Mol Evol. 2009 Dec;69(6):579-88. doi: 10.1007/s00239-009-9301-y. Epub 2009 Nov 24.

Abstract

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 x 10(-9) and 1.0 x 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Animals
  • Black People / genetics*
  • Cohort Studies
  • Enhancer Elements, Genetic
  • Ethiopia / ethnology
  • Ethnicity / ethnology
  • Ethnicity / genetics
  • Evolution, Molecular
  • Gene Frequency
  • Genetic Variation*
  • Genetics, Population
  • Genotype
  • Humans
  • Lactase / genetics*
  • Lactase / metabolism
  • Lactose Intolerance / enzymology
  • Lactose Intolerance / ethnology*
  • Lactose Intolerance / genetics*
  • Milk / metabolism
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Selection, Genetic
  • Somalia

Substances

  • Lactase