A prevailing view of molecular evolution of protein hormones was that they evolve at a constant rate and the functions are conserved among species. In this chapter, we describe cases where this view does not hold. When investigated in detail, many protein hormones reveal an episodic mode of evolution in some mammalian lineages, that is, while evolving at an approximately constant rate, most of the times the evolutionary rate was dramatically accelerated in some specific lineages.

One possible explanation for this phenomenon of episodic evolution is that positive evolution was driving the spread of some amino acid substitutions. This might have been caused by specific needs for adaptation. Currently, a test widely used to detect the presence of positive selection is the maximum likelihood analysis that compares the rates of nonsynonymous substitution and of synonymous substitution (the dN/dS ratio test) in each lineage to detect any perturbation of the background rates of evolution in the lineages studied. In this chapter, some of the cases where positive evolution was detected from the DNA sequences by this method are described.

A pattern that has repeatedly emerged in genes that showed the episodic mode of molecular evolution is the expansion of gene copies by gene duplication. This is shown for two examples in this chapter: the case of GH and the case of CG. In both cases, one copy maintains the original expression in the pituitary, while the other copies are expressed in a new organ, the placenta. The expression of CG in the placenta has given rise to a new mechanism of maintaining pregnancy. The expression of GH-like genes in the placenta is also likely to have evolved by natural selection (for a possible scenario, see Wallis, 1997); otherwise, they would have accumulated degenerative mutations or become lost (Force et al., 1999; Lynch et al., 2001). As mentioned earlier, an analysis of the GH and GH-related gene sequences suggested that these genes have evolved at a fast rate, possibly reflecting the influence of positive selection.

Considerable insight can be gained if one can study the functional and structural consequences of an observed amino acid substitution. With such information, it may be possible to infer the selective pressure associated with the specific amino acid substitution. In this respect the GH and GHR in primates provide an ideal model system. Some studies on the structural and functional consequences of amino acid changes have been described in an earlier section.

Lastly, when a protein hormone evolves a new function or undergoes positive selection, a new expression pattern may need to be established. In the case of the evolution of CG, it involved establishing the expression of the CGa subunit in a new tissue, the placenta. This was achieved through a series of novel molecular events. Whether the case of CG represents a general mechanism of achieving a new expression pattern is a topic to be pursued in the future.

In conclusion, the molecular evolution of protein hormones provides a paradigm to understand adaptive evolution at the nucleotide or amino acid level. They are often involved in the evolution of adaptive traits because protein hormones play an essential role in vertebrate physiology. The abundance of structural and functional data on protein hormones from primates, mainly due to their importance in medicine, is another advantage for pursuing research in the evolution of protein hormones. With the rapid development in molecular biology tools, the molecular evolution of protein hormones can be studied in detail. Thus, this topic holds a great potential for future research.

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