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

Anke Liebert,Bryony Leigh Jones,Pascale Gerbault,Neil Bradman,Mark G Thomas,Saioa López,Nikolas Maniatis,Dallas M Swallow,Winston Lau,Nicolas Montalva

doi:10.1007/s00439-017-1847-y

Anke Liebert, Bryony Leigh Jones + Show 8 more

Open Access

https://doi.org/10.1007/s00439-017-1847-y

Copy DOI

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.

Highlights

There is good functional evidence that the genetic trait of persistence of intestinal lactase activity into adult life can be caused by five or more independent single nucleotide variants in a regulatory region upstream of the lactase gene LCT (Fang et al 2012; Ingram et al 2007; Jensen et al 2011; Liebert et al 2016; Olds and Sibley 2003; Troelsen et al 2003)
Present-day frequencies of these alleles have been attributed to positive selection for lactase persistence, which allows the dietary consumption of animal milk by adult humans without risk of symptoms of lactose intolerance
This work provides a comprehensive view of the Old World distribution of known lactase persistence (LP)-associated alleles; an updated database can be found in Supplementary Table 3

Summary

Introduction

There is good functional evidence that the genetic trait of persistence of intestinal lactase activity into adult life can be caused by five or more independent single nucleotide variants in a regulatory region (a transcriptional enhancer) upstream of the lactase gene LCT (Fang et al 2012; Ingram et al 2007; Jensen et al 2011; Liebert et al 2016; Olds and Sibley 2003; Troelsen et al 2003). Estimation of the age of expansion of the European allele using population genetic and modelling approaches places it during the Neolithic period and suggests selection coefficients ranging from 0.8 to 19% (Bersaglieri et al 2004; Gerbault et al 2009; Itan et al 2009) Such coefficients are extraordinarily high in view of the fact that the cultural adaptation of fermentation of milk products, which reduces the lactose concentration, allows milk to be used as a source of calories in the diet of lactase non-persistent people, circumventing its adverse effects (Segurel and Bon 2017)

Methods

Results

Conclusion