Once determined, the neutral model can be subjected to various statistical tests. Unfortunately, the tests are so weak that rejection is possible only in extreme cases. Furthermore, minor modifications to the neutral theory frequently accommodate small deviations from naive expectation. Identifying rare adaptive amino acid replacements in an ocean of neutral change presents a formidable challenge. Another place for biologists to start is with phenotypes.
Phenotypes are the physical manifestations of genetic systems interacting with the environment.
It is perhaps for this reason that serious discussion of phenotypes rarely appears in studies of molecular evolution, which instead concentrate on the gene sequences. Yet phenotypes are crucial to understanding the process of natural selection because they show how organisms function in environments. If instead of merely analyzing gene sequences, evolutionists attempted to understand molecular phenotypes, the form and functions of proteins and enzymes in physiology and metabolism, they might gain deeper insights into the molecular basis of ancient adaptive events. The challenge, then, is to return molecular phenotypes to molecular phylogenies, and in so doing to recover the molecular basis of truly ancient adaptive events. Here, I shall combine four approaches to do this.