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  1. Dietary lactose is hydrolyzed by the enzyme lactase which is located in the brush border of small intestinal enterocytes. Lactase activity is high during infancy, when milk is the main nutrient. As in other mammals, lactase activity declines after the weaning phase in the majority of humans and remains low throughout life (phenotype: lactase nonpersistence, also known as restriction or adult-type hypolactasia; MIM 223100). In other healthy humans, lactase activity persists at a high level (phenotype: lactase persistence). Subjects with lactase nonpersistence have a low lactose digestion capacity (low LDC); those with lactase persistence can hydrolyze large amounts of lactose (high LDC). The adult lactase phenotypes can be diagnosed through small-intestinal biopsy or lactose-tolerance tests.

  2. Family studies, measurement of relative lactase activity, and a study of lactose digestion in twins show that the lactase phenotypes are genetically determined and can be explained by a Mendelian system of two autosomal alleles. The lactase persistence allele is dominant to the lactase nonpersistence (or restriction) allele: the individuals with low LDC are homozygous for the nonpersistence allele.

  3. The distribution of the lactase phenotypes in human populations is highly variable. In most tropical and subtropical countries and in all East Asian populations, lactase nonpersistence is predominant. In the Old World, lactase persistence predominates in only two human population groups: northwestern Europeans and milk-dependent nomads of the Afro-Arabian desert zone. Natural selection in favor of the lactase persistence gene due to improved utilization of animal milk in the nutrition of older children and adults with high LDC is a likely cause of the unusual lactase phenotype distribution in Europeans and Afro-Arabian nomads.

  4. The role of lactase nonpersistence in irritable bowel syndrome in adults and osteoporosis in postmenopausal women and the role of lactase persistence in promoting coronary heart disease and premature cataract are controversial. However, the genetically determined downregulation of lactase expression may contribute to malabsorption and abdominal complaints, particularly in young children.

  5. A number of nucleotide polymorphisms have been detected both in the coding and noncoding regions of the LCT gene. These polymorphisms are associated with one another to form very few haplotypes in Europeans and lactase persistence is associated with a particular haplotype (A). Studies on the expression of lactase mRNA transcripts that made use of these polymorphisms as markers have demonstrated that a genetic change in a cis-acting regulatory element is likely to be responsible for this polymorphism in lactase activity, at least in Europeans.

  6. A CT polymorphism at −13910 is strongly associated with persistence/nonpersistence in Finns and other Europeans and may be the causal change because the presence of the *T

    This chapter is derived and updated from Gebhard Flatz in the 7th edition of this work.

    allele causes enhancement of transcription in vitro and increases binding of a transcription factor Oct1. The −13910*T allele forms part of a very extended (more than 500 kb) A haplotype. This polymorphism however does not explain lactase persistence in all sub-Saharan Africans nor in Bedouins.

  7. In Africans, several additional mutations have been identified in the vicinity of −13910, two of which are statistically associated with lactose tolerance (at −14010*C and −13915*G). There is suggestive evidence that −14010*C also may enhance transcription, but −13915*G blocks, rather than enhances binding of Oct1.

  8. The new alleles occur on the background of different haplotypes suggesting quite independent origins and thus convergent evolution.

  9. The extended haplotype and reduced microsatellite diversity of the chromosome carrying −13910*T provided evidence of a recent mutation and strong directional selection. −14010* likewise occurs on a very extended haplotype.

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