Liebert, A; (2014) Evolutionary and molecular genetics of regulatory alleles responsible for lactase persistence. Doctoral thesis , UCL (University College London).

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Abstract

Persistence of lactase into adulthood varies in frequency worldwide and is attributable to several different single nucleotide changes in an enhancer of the LCT gene. One of these is at particularly high frequencies in Europeans and several others have been found elsewhere. However, information about their worldwide distribution is patchy. 2056 DNA samples from populations of Europe, Asia and the Middle East were sequenced to examine the distribution of allelic variants of the LCT enhancer region. It was confirmed that -13910*T is also the predominant allele around the periphery of Europe, and that this allele extends as far as the South and East of the Arabian Peninsula. Other alleles appear to have spread out of Africa or Arabia and most variation was found in the Middle East. No new common alleles were found that were likely to be causal. In previous studies four lactase persistence associated nucleotide substitutions (-13910*T, -14010*C, -13915*G and -13907*G) have been studied functionally. In this thesis four additional enhancer alleles were examined using enhancer/promoter construct transfections and electrophoretic mobility shift assays. Three enhancer variants alter transcription factor binding in vitro and/or reporter-gene expression. Bioinformatic tools and specific antibodies were used to assist in identifying the transcription factors involved. The results show that different mechanisms lead to a disruption of the normal down-regulation of lactase in adult life. Known haplotypic markers were assessed on an overlapping set of samples and a greater number of flanking markers was typed in an extended region of 1.8 Mb around LCT, in order to chart the evolutionary relationships and extent of historic recombination of the chromosomes carrying the derived alleles, as well as those th at do not. All of the functional alleles tested have longer extended haplotypes than their ancestral counterparts, but so also does the derived variant at position -958, a haplotype marker for the B haplotype. The finding of an extended region of high linkage disequilibrium in all populations, and an extended B haplotype, is discussed in relation to the methods to study selection. Because phenotypic studies suggest missing functional variants, the immediate promoter and a part of intron 2 of LCT were also selected for sequencing. No serious candidates were found in intron 2. Two alleles in the immediate promoter were studied by transfections but there was little evidence for any in vitro effect of these variants.

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