Lactase haplotype diversity in the Old World

Lactase persistence, the genetic trait in which intestinal lactase activity persists at childhood levels into adulthood, varies in frequency in differ ent human populations, being most frequent in northern Europeans and certai n African and Arabian nomadic tribes, who have a history of drinking fresh milk. Selection is likely to have played an important role in establishing these different frequencies since the development of agricultural pastorali sm similar to9,000 years ago. We have previously shown that the element res ponsible for the lactase persistence/nonpersistence polymorphism in humans is cis-acting to the lactase gene and that lactase persistence is associate d, in Europeans, with the most common 70-kb lactase haplotype, A. We report here a study of the 11-site haplotype in 1,338 chromosomes from 11 populat ions that differ in lactase persistence frequency. Our data show that haplo type diversity was generated both by point mutations and recombinations. Th e four globally common haplotypes (A, B, C, and U) are not closely related and have different distributions; the A haplotype is at high frequencies on ly in northern Europeans, where lactase persistence is common; and the U ha plotype is virtually absent from Indo-European populations. Much more diver sity is seen in sub-Saharan Africans than in non-Africans, consistent with an "Out of Africa" model for peopling of the Old World. Analysis of recent recombinant haplotypes by allele-specific PCR, along with deduction of the root haplotype from chimpanzee sequence, allowed construction of a haplotyp e network that assisted in evaluation of the relative roles of drift and se lection in establishing the haplotype frequencies in the different populati ons. We suggest that genetic drift was important in shaping the general pat tern of non-African haplotype diversity with recent directional selection i n northern Europeans for the haplotype associated with lactase persistence.