Caldwell, E.F.; (2005) Molecular evidence for dietary adaption in humans. Doctoral thesis , University of London.

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Abstract

Starch digestion begins in the mouth where it is hydrolysed into smaller polysaccharides by the enzyme salivary amylase. Three salivary amylase genes (AMY1A, B & C) and a pseudogene (AMYP1) have been described and are located in tandem on chromosome 1. Polymorphic variation has been demonstrated in Caucasians in the form of the number of repeats of the AMY1 genes, as follows: (lA-lB-Pl)n-lC. This variation has been reported to result in differing levels salivary amylase enzyme production and, as a result, differences in the efficiency of starch digestion in the mouth. It is proposed in this thesis that an increase in salivary gene copy number may be an adaptation to high starch diets as a result of the adoption of agriculture. Reliable high-throughput multiplex PCR based methods have been designed to quantify AMY1 gene copy number and to also to type 6 microsatellite markers closely linked to the AMY gene cluster. Data have been collected for 14 human populations, with different histories of cereal agriculture and ancestral levels of starch in the diet. Data have also been collected on AMY1 gene copy number in 5 chimpanzees (Pan troglodytes). The AMY1 allele frequency difference (measured using FST) between the two most extreme populations, the Mongolians and Saami, was not an outlier on a distribution of FST based on presumed neutral 11,024 SNPs from the human genome. The chimpanzee data suggest that the most frequent allele (AMY1*H1) in humans may not be the ancestral allele, as all chimpanzee chromosomes tested carried the AMY1*H0 allele (containing only one copy of the AMY1 gene). A more sensitive selection test, the analysis of the intra-allelic variability of the AMY1 repeat alleles using closely linked microsatellites, showed no compelling evidence for recent positive selection at the AMY1 locus in humans. As a result, genetic drift could not be ruled out as an explanation for the observed AMY1 allele frequency differences among populations. Alanine:glyoxylate aminotransferase (AGT) is an intermediary metabolic enzyme that is targeted to different organelles in different species. Previous studies have shown that there is a clear relationship between the organellar distribution of AGT and diet. Non-human primates show the herbivorous peroxisomal distribution of AGT. In humans a point mutation and insertion deletion polymorphism have been associated with peroxisome-to-mitochondria AGT mis-targeting. Data have been collected using a PCR/RFLP based method, in 11 human populations. In a comparison with FST values from 11.024 SNP loci, 94.5% of SNPs had a lower FST than a comparison of AGT allele frequencies for Saami and Chinese. This unusually high allele frequency difference between Chinese and Saami is consistent with the signature of recent positive selection driven by the unusually high meat content in the Saami diet.

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