Gene duplication is associated with the evolution of many novel biological functions at the molecular level. The dominant view, often referred to as "neofunctionalization", is that duplications precede many novel gene functions by creating functionally redundant copies which are less constrained than singletons. Numerous alternative models have been formulated, however, including several (such as "subfunctionalization" and "escape from adaptive constraints") in which novel functions emerge prior to duplication. Unfortunately, few studies have reconstructed the evolutionary history of a functionally diverse gene family sufficiently well to differentiate between these models. In order to understand how gene families evolve and to what extent they fit particular evolutionary models, here we examined the evolution of the g2 family of phospholipase A2 in 92 genomes from all major lineages of Vertebrata. This family is evolutionarily important and has been co-opted for a diverse range of functions, including innate immunity and venom. The genomic region in which this family is located is remarkably syntenic. This allowed us to reconstruct all duplication events over hundreds of millions of years of evolutionary history using a novel method to annotate gene clusters, which overcomes many limitations of automatic annotation. Surprisingly, we found that even at this level of resolution our data could not be unambiguously fit to existing models of gene family evolution. This suggests that each model may describe a part-truth that doesn't capture the full complexity of gene family evolution.

Family saga: reconstructing the evolutionary history of a functionally diverse gene family reveals complexity at the genetic origins of novelty