The Genom of Homo sapiens.pdf

370 DRAYNA ET AL.Figure 5. Predicted protein sequence of the PTC gene in one individual from human (taster allele), chimpanzee, and lowland gorilla.Amino acid residues in the human sequence that differ between the human taster and non-taster alleles are highlighted in green. Chimpand gorilla amino acid residues that differ from the human sequence are highlighted in orange.Evolutionary ConsiderationsThe sense of bitter taste is believed to serve as a protectionagainst the ingestion of toxic compounds in plantmaterial, most of which are perceived as bitter. AlthoughPTC has not been observed in nature, it is structurally relatedto a group of compounds that occur in cruciferousvegetables and are toxic in large quantities, with the thyroidas the primary organ affected. For example, cabbagecontains the thyrotoxic compound goitrin, which, likemany members of this chemical family, is not stronglyperceived as bitter by PTC non-tasters. A question thatarises is how the non-taster allele rose to such high frequenciesin some populations given the apparent selectivedisadvantage this imposes. One possibility is suggestedby the fact that the alterations present in thenon-taster allele are not obviously disabling mutations,such as stop codons or deletions. This gives rise to thepossibility that the PTC non-taster allele encodes a receptorthat is fully functional for a different but as yet unknownbitter toxic substance. Subsequent investigation ofDNA sequence variation may provide evidence for selectionof the non-taster allele, as opposed to drift, that canaccount for its current high frequency. Additional studieswould be required to test hypotheses about the nature ofsuch positive selective forces.Lessons for Identifying GenesUnderlying Complex TraitsAlthough a large fraction of the variance in PTC tasteability is attributable to this single locus on chromosome7, the long-standing uncertainties regarding the geneticsof PTC non-tasting suggest that this trait can serve as amodel for common complex traits in humans, includingsome diseases. What lessons for complex disease genediscovery can we draw from the PTC example? First, animportant advantage in our linkage studies was providedby the large nuclear families present in the Utah CEPHpopulation, which produced strong statistical support forlinkage and clarified the uncertainties from previous linkagestudies. In addition, the worldwide distribution ofPTC gene haplotypes is consistent with the view that thenon-taster allele is of ancient origin, having arisen before