Endocrine Abstracts

Hormones and hormone receptors in mammals, including humans, display bewildering complexity. The evolution of peptide hormone families with multiple members has been difficult to resolve because of their short sequences. Their G-protein-coupled receptor families are challenging because they display variable sequence rates along the proteins, between species, and over time. My laboratory has therefore combined analyses of sequences with investigation of conserved synteny, i.e. comparisons of the chromosomal locations of the genes between species. This facilitates identification of true species homologs. Using these approaches we have been able to disentangle the evolutionary histories of endocrine peptide and receptor families. Invariably, we find that the ancestor of vertebrates must have had more gene family members than humans have today. This ancestral complexity is due to two genome doublings in early vertebrate evolution, leading to quadruplication of the ancestral chromosome set, thereby generating additional gene copies for many peptides and receptors. The NPY-PYY-pancreatic polypeptide family once had seven receptors, only four of which still exist in humans. Today humans have three vasopressin receptors, whereas the ancestral vertebrate had six. An ancient duplicate of prolactin is present in birds and fish, but was lost in the mammalian lineage. The somatostatin receptor family previously had six members, one of which was lost before the origin of mammals. One of the most extreme cases is the receptor family for the somatostatin-related peptide urotensin II: mammals have only a single receptor, but our ancestors possessed no less then five, all of which still exist in some vertebrates such as a lizard and a turtle. Thus, although our neuroendocrine system is certainly quite complex, we have clearly degenerated by gene loss. Furthermore, many fishes have gained additional gene copies by another genome doubling as well as local gene duplications. An important question arises: which functions have we and other mammals lost that still exist in other vertebrates?