Polymorphisms 'r us.

The completion of the working draft of the human genome demarcates a promising new era for scientists and clinicians. However, the first lesson of this triumph of cooperative science has been that of humility. The number of genes in each organism was awaited as anxiously as if it represented some sort of grade on the evolutionary final exam. Yeast finished the test early, scoring a 6,000, and, later, the flowering plant Arabidopsis thaliana, nearly a 26,000. Surely the score of Homo sapiens, "the beauty of the world, the paragon of animals," would dwarf the competition. When we got our grade back on the gene sequence we were reminded that, as Shakespeare wrote, we are merely a "quintessence of dust." It was a trifle disconcerting to find that our estimated score is only about 30,000--our exalted DNA contains a paltry 15% more genes than a flowering plant! After recovering from the shock of our low gene number, we can recognize that despite all those genes, the A. thaliana plant is not likely to create Hamlet or to launch a genome project anytime soon. The basis for the complexity of the organism must be reflected somewhere else than in the simple gene count. I would hazard the guess that the solution to this puzzle lies in the pattern of connectivity. A subtle change in gene number or protein structure could direct major alterations in the number and structure of the connections among components within the cell and among cells within the organism. Complex function arises not from the sum of individual proteins, but from the ensemble of their interactions. The development of a plethora of genome-profiling technologies raises the hope of understanding and addressing the genetic basis for the great variation among individuals in disease susceptibility and response to therapy. However, the fact that the genetic basis for the distinction between a human and a potato is not immediately obvious serves to emphasize the subtle changes that may underlie the genetic basis for variation among humans. In the appropriate context, apparently small genetic changes may have large phenotypic effects. Which brings us to the importance of the review of genetic polymorphisms of adrenergic receptors by Garland and Biaggioni in this issue. Genetic polymorphisms represent the common hereditary variations in the sequences of specific genes present in the population. Our uniqueness as individuals results predominantly from the aggregate effect of our particular set of polymorphisms. When polymorphisms influence the sequence and structure of crucial cellular targets, they can contribute to disease susceptibility. Garland and Biaggioni review the polymorphism literature for the adrenergic receptors, a family of at least nine heptahelical G-protein-coupled receptors that are important for autonomic function. More than a dozen adrenergic receptor polymorphisms have been identified and the phenotypic correlation for many of them has been explored. This is a burgeoning field, and Garland and Biaggioni provide a timely review. What is most striking about the literature, however, is how many of the studies are contradictory. For example, the Argl6Gly polymorphism of the [~2-adrenergic receptor has been positively linked to hypertension in African Caribbeans [1], but not linked to hypertension in Americans [2] or in black South Africans [3]. While some discrepancies may be attributed to problems in experimental design, much of the discordance has most likely arisen because the effects of a particular polymorphism depend on the genetic background. As underscored by the similar gene counts in people and plants, it is the pattern of interaction of gene products that mediates the major translation from genotype to phenotype.