World-wide distributions of lactase persistence alleles and the complex effects of recombination and selection.

The genetic trait of lactase persistence (LP) is associated with at least five independent functional single nucleotide variants in a regulatory region about 14 kb upstream of the lactase gene [-13910*T (rs4988235), -13907*G (rs41525747), -13915*G (rs41380347), -14009*G (rs869051967) and -14010*C (rs145946881)]. These alleles have been inferred to have spread recently and present-day frequencies have been attributed to positive selection for the ability of adult humans to digest lactose without risk of symptoms of lactose intolerance. One of the inferential approaches used to estimate the level of past selection has been to determine the extent of haplotype homozygosity (EHH) of the sequence surrounding the SNP of interest. We report here new data on the frequencies of the known LP alleles in the 'Old World' and their haplotype lineages. We examine and confirm EHH of each of the LP alleles in relation to their distinct lineages, but also show marked EHH for one of the older haplotypes that does not carry any of the five LP alleles. The region of EHH of this (B) haplotype exactly coincides with a region of suppressed recombination that is detectable in families as well as in population data, and the results show how such suppression may have exaggerated haplotype-based measures of past selection.

Diversity of lactase persistence in African milk drinkers.

The genetic trait of lactase persistence is attributable to allelic variants in an enhancer region upstream of the lactase gene, LCT. To date, five different functional alleles, -13910*T, -13907*G, -13915*G, -14009*G and -14010*C, have been identified. The co-occurrence of several of these alleles in Ethiopian lactose digesters leads to a pattern of sequence diversity characteristic of a 'soft selective sweep'. Here we hypothesise that throughout Africa, where multiple functional alleles co-exist, the enhancer diversity will be greater in groups who are traditional milk drinkers than in non-milk drinkers, as the result of this sort of parallel selection. Samples from 23 distinct groups from 10 different countries were examined. Each group was classified 'Yes 'or 'No' for milk-drinking, and ethnicity, language spoken and geographic location were recorded. Predicted lactase persistence frequency and enhancer diversity were, as hypothesised, higher in the milk drinkers than the non-milk-drinkers, but this was almost entirely accounted for by the Afro-Asiatic language speaking peoples of east Africa. The other groups, including the 'Nilo-Saharan language speaking' milk-drinkers, show lower frequencies of LP and lower diversity, and there was a north-east to south-west decline in overall diversity. Amongst the Afro-Asiatic (Cushitic) language speaking Oromo, however, the geographic cline was not evident and the southern pastoralist Borana showed much higher LP frequency and enhancer diversity than the other groups. Together these results reflect the effects of parallel selection, the stochastic processes of the occurrence and spread of the mutations, and time depth of milk drinking tradition.