J Exp Zool B Mol Dev Evol 2026 Jan 12; doi: 10.1002/jezb.70012.

Escaping Constraints to Innovate: Maternal Neofunctionalization in a HoxB4 Duplicate.

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Transcription factors are typically thought to play a limited role in developmental evolution due to their high pleiotropic nature. However, such constraints may be relaxed following gene duplication or when proteins are organized into structural and functional modules, opening avenues for evolutionary innovation. Here, we integrate expression and genomic data to investigate the evolutionary dynamics of Hox gene duplicates in the allotetraploid frog Xenopus laevis. Despite overall conservation across the Hox clusters, we find that HoxB4L has acquired expression during maternally regulated stages and is evolving under positive selection. Protein-level changes include the number, length, and sequence of functionally important protein regions. Our results indicate that HoxB4L has escaped ancestral constraints and is undergoing maternal neofunctionalization as a result of cis-regulatory divergence and structural protein modifications. These findings illustrate how transcription factors can overcome developmental constraints and contribute to novel functions during early development.

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