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

Abstract

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.

Fig. 1

Haplotype network and geographic distribution of haplotypes in Africa, Europe, Middle East and Central Asia. Data from Supplementary Tables 5 and 6. a Maximum parsimony neighbour-joining network. The network is made by assuming single stepwise mutational changes, and shows in red the SNPs using their ‘positional’ names (see Supplementary Tables) at each of the mutational steps, and black numbers show the phased haplotypes while black letters show the LCT gene region haplotypes of Hollox et al. (2001). Circles are proportional to haplotype count and are coloured with reference to the LCT gene region haplotypes (Fig. 1b). Functional alleles are shown as LP. Ovals indicate inferred recombination events where there is more than one appearance of a nucleotide change. Note that branch lengths do not represent evolutionary time scales. b Shows the major regional distributions of the phased haplotypes and also shows this subdivided by language group. Derived alleles associated with lactase persistence (LP) are indicated in bold in the key. N represents the number of chromosomes examined per group. The same haplotype colours are used in the Pie segments in b as are used in a

Fig. 2

Extended haplotype homozygosity (EHH) in relation to recombination. a EHH of the known LP alleles (continuous lines) in comparison with the ancestral A, C, P, X, haplotypes on which they were derived (shown as dashed lines of corresponding colours) and also the B haplotype (using 958*T as core) in the 4 different continental groups. b EHH for the B haplotype (958*T—continuous lines) in comparison with all other haplotypes (958*C—dashed lines) in the four continental groups. Note that EHH for 958*T compares all other chromosomes, so that in Europeans the majority of these are −13910*T, and also note that the common ancestral A, C, P, U and X haplotypes fail to show this effect (a; Supplementary Fig. 4). c The EHH region of the common extended B haplotype (shaded in grey as in b is compared with the Linkage Disequilibrium Unit (LDU) maps from the Hapmap populations (black and grey lines; y-axis on the left), see http://www.internationalgenome.org/data for acronyms), and Linkage (cM) maps from the Icelandic families (red line; y-axis on the right). Black dashed lines are populations with LP alleles (> 10%) and grey lines groups in which they are almost absent. Shaded grey area shows the region of the common extended B haplotype. Relevant genes from this gene rich region are shown as horizontal lines