69.1 Sunday, Jan. 6 Adaptive hyper-mutability of Hoxa-13a in cypriniforms CROW, Karen; AMEMIYA, Chris; WAGNER, GŁnter P. *; San Francisco State University; Benaroya Research Institute; Yale University email@example.com
Asymmetric divergence is a frequently observed phenomenon among duplicated genes. Faster divergence of a paralog is usually driven either by directional selection or relaxed selection affecting non-synonymous substitutions differentially. Here we compare the molecular evolution of a teleost specific paralog pair Hoxa-13a/b in cypriniforms and show that the Hoxa-13a diverges much faster than Hoxa-13b and that this higher rate affects both synonymous and non-synonymous substitutions, as well as the rate of insertions. The rate increase coincides with the origin of ostariophysans, i.e. is not an immediate consequence of gene duplication, which occurred before the origin of teleosts. There are several lines of evidence that Hoxa-13a, the faster evolving gene, is not a pseudogene: 1. RT-PCR shows that Hoxa-13a is expressed more than Hoxa-13b in later stages of zebrafish larval development (i.e. after 24 hours post fertilization), 2) both proteins have transcriptional repressor activity in an artifical recruitment assay, 3) morpholino induced knockdown of Hoxa-13a leads to specific defects in a derived feature, the yolk sack extension. Hence we conclude that Hoxa-13a has a biological role in zebrafish development. Nevertheless, the synonymous substitution rate of Hoxa-13a is approximately three times higher yet there is no difference in sequence composition that could explain a difference in mutation rate. The faster evolving Hoxa-13a paralog seems to be experiencing a locus specific hyper-mutability, as has been found for other fast evolving proteins, like the toxins in Conus snails (Espiritu et al., 2001 Toxicon 39:1899-1916). These results suggests that mutation rate may be locally modified in evolution with the effect of enhancing evolvability.