Evolution of the relaxin/insulin-like gene family in placental mammals: implications for its early evolution

The relaxin (RLN) and insulin-like (INSL) gene family is a group of genes involved in a variety of physiological roles that includes bone formation, testicular descent, trophoblast development, and cell differentiation. This family appears to have expanded in vertebrates relative to non-vertebrate chordates, but the relative contribution of whole genome duplications (WGDs) and tandem duplications to the observed diversity of genes is still an open question. Results from our comparative analyses favor a model of divergence post vertebrate WGDs in which a single-copy progenitor found in the last common ancestor of vertebrates experienced two rounds of WGDs before the functional differentiation that gave rise to the RLN and INSL genes. One of the resulting paralogs was subsequently lost, resulting in three proto-RLN/INSL genes on three separate chromosomes. Subsequent rounds of tandem gene duplication and divergence originated the set of paralogs found on a given cluster in extant vertebrates. Our study supports the hypothesis that differentiation of the RLN and INSL genes took place independently in each RLN/INSL cluster after the two WGDs during the evolutionary history of vertebrates. In addition, we show that INSL4 represents a relatively old gene that has been apparently lost independently in all Euarchontoglires other than apes and Old World monkeys, and that RLN2 derives from an ape-specific duplication.