Lifestyle and genetic diversity: A study on African populations

A major question in human population genetics is to understand the contribution of demographic history and selection to the patterns of genetic diversity that characterize human populations today. Identifying targets of selection in humans has been slow and difficult because is not easy to distinguish between the signatures left by selection from those due to demography. Gradually, however, studies of specific candidate loci together with genome-wide searches succeeded to ascertain a number of genes that show population differences due to adaptations especially to pathogens, climate and diet. Concerning diet, an important change in human prehistory occurred with the rise of agriculture, beginning 10-12 Kya ago in the Near East. The Neolithic transition to modes of subsistence not relying in hunting and gathering is not only associated with new food resources but also with reduced dietary diversity, explaining the belief that the Neolithic represents the start of an era propitiating dietary adaptations. In this study a candidate gene approach was applied to investigate whether differences in diets, roughly inferred from lifestyles of populations (hunter-gathering, agriculturalism and pastoralism), could have shaped diversity at genes that more or less directly play a role in the metabolism or in the taste perception of substances (including xenobiotics), that gain entry into the organism through food. The first genes examined were AGXT, PLRP2, MTRR, NAT2 and CYP3A5, since assumedly they might play a role in the metabolism of meat (AGXT), cereals (PLRP2), folates (MTRR and NAT2) and salt (CYP3A5) in food. In each of those genes, variants known to have potential phenotypic effects were selected. In order to enrich the data for African populations, which still remain understudied, six groups were screened for the selected variants: agriculturalists from Angola, Equatorial Guinea and Mozambique, pastoralists from Uganda, and the hunter-gatherers Baka Pygmies from Gabon and Khoisan from Namibia. In addition a sample from Portuguese was also studied. The analyses performed revealed a connection between patterns of genetic diversity at PLRP2 and NAT2 and lifestyles of populations, suggesting that both genes have evolved under a selective pressure related with diet. Contrarily, no signs were detected that AGXT, MTRR and CYP3A5 could represent dietary adaptations in humans. Still, CYP3A5 revealed the most unequivocal signature of selection, which in fact was found to be strongly correlated with latitude but not with differences in eating habits between populations. Concerning the taste genes, attention was focused on TAS1R1, TAS1R3, TAS2R16 and TAS238, which are involved in the perception of sweet, bitter and umami tastes. In each gene individual variations reported to influence different taste modalities were selected and screened in five African populations with different lifestyles and in the Portuguese. No signs emerged that diversity at those loci had been shaped by a dietary variable differing according to lifestyle of populations, except in TAS2R16, and restrictively in Africa, where the frequency of a variant decreasing sensibility to cyanogenic glycosides showed to be especially well represented in farmer groups from Western-Central Africa, raising the question on whether the detection of those bitter compounds was less critical in African farmers than in non-food producers. Some of the TAS genes analyzed presented unusual levels of differentiation across African, Asian and European populations, difficultly conciliated with the continental structure explainable by the dispersion history of human populations. This observation instigated the use of an alternative approach to address selection at the TAS genes, viewing which full sequences for different TAS regions were retrieved from the 1000 Genome database. Dissection of the patterns of molecular diversity led to identify several signatures of non-neutral evolution. Two genes from the TAS1R family (TAS1R1 and TAS1R3), exhibited signals of positive selection, whereas TAS2R38 presented the features expected for genes evolving under balancing selection. In TAS2R16 a complex evolutionary history was detected. In addition to the well-known role of TAS proteins as components of taste receptors in taste bud cells, it is being demonstrated that they are also involved in many other aspects related with human health. A better understanding of the functions of those proteins is still needed to understand the biological basis underlying what seems to be an adaptive evolution of these TAS genes in humans. In the future, new theoretical models and statistical methods better suited to address selection targeting phenotypic traits for which account many alleles each with small effects, together with the development of the functional approaches necessary to validate the genomic signatures of selection, will make it possible to obtain refreshed insights on phenotypic adaptations in humans, as well as to understand at which point they were prompted by the changes that accompanied the dispersion of humans out of Africa, or latter in the Neolithic, the transition to new subsistence economies.