Back in December, I posted an item on taste receptors expressed in the gut with mention of possible roles in sensing the microbiome. This week's Paper of the Week is entitled "Evolution of functionally diverse alleles associated with PTC bitter taste sensitivity in Africa" by the Tishkoff group and heightens those earlier, intriguing possibilities.
The publication dissects the long evolutionary history of the TAS2R38 gene encoding a bitter taste receptor. From RefSeq, we know that TAS2R38 encodes a seven-transmembrane G protein-coupled receptor that controls the ability to taste glucosinolates, a family of bitter-tasting compounds found in plants of the Brassica sp. Interestingly, TAS2R38 allows detection of bitter thiourea compounds, including 6-n-propylthiouracil (PROP) and phenylthiocarbamide (PTC). Humans who cannot taste these compounds tend to be poor at discriminating fat in foods, even though they prefer higher fat versions of these foods (Keller, KL 2012 J Food Science 77:S143). This would lead one to suppose, naturally, that the development of certain haplotypes of tasters and nontasters would arise as adaptation to the local diet. Tishkoff, et al show that is not likely to be the case.
First, the authors propose that the evolution of the three nonsynonymous mutations, which comprise the commonly observed haplotypes, likely represent an alternate path for building a diverse set of receptors in humans, which can then participate in various biological processes. They go on to suggest that a complex selection model, involving "ancient balancing and recent diversifying selection," has allowed both common and rare nonsynonymous variation, respectively, to persist in the coding exon of TAS2R38 in Africa. Importantly, different types of selection may have acted upon the noncoding regions compared to the TAS2R38 coding exon in all populations.
Second, diet is not the driver of haplotype frequencies. The authors propose that the three common haplotypes observed may appear at high frequencies due to selective pressures distinct from diet. Recent reports have demonstrated that bitter taste receptors are expressed in many cell types in the human gastrointestinal tract and lungs (second reference). Here this expression can affect glucose and insulin levels (Dotson et al. 2008), eliminate harmful inhaled substances, and promote relaxation of airways for better breathing. Thus, bitter taste loci, including TAS2R38, posses various functions and, as the authors write "raise[s] the possibility that common variants at TAS2R38 may be under selection due to their physiological roles in
human health beyond oral gustatory function." The authors were not able to distinguish which selective forces - taste, gut microbiome organisms or biochemical production, or inhalants - are acting upon the TAS2R38 haplotypes.
Third, the genetic analysis and evolutionary history of TAS2R38 suggest that, in contrast to a common variant-common disease hypothesis, sensitivity to PTC bitter taste indicates that both rare and common variants together are able to significantly affect normal variation of phenotypes. This, of course, has implications, as genome-wide association studies tackle a wider range of phenotypes in a more diverse set of populations, and as genome sequencing (whole and exome) seek to identify and associate rare variants with disease risk and occurrence.