Dosage balance acts as a time-dependent selective barrier to subfunctionalization.

Background: Gene duplication is an important process for genome expansion, sometimes allowing for new gene functions to develop. Duplicate genes can be retained through multiple processes, either for intermediate periods of time through processes such as dosage balance, or over extended periods of time through processes such as subfunctionalization and neofunctionalization.

Results: Here, we built upon an existing subfunctionalization Markov model by incorporating dosage balance to describe the interplay between subfunctionalization and dosage balance to explore selective pressures on duplicate copies. Our model incorporates dosage balance using a biophysical framework that penalizes the fitness of genetic states with stoichiometrically imbalanced proteins. These imbalanced states cause increased concentrations of exposed hydrophobic surface areas, which cause deleterious mis-interactions. We draw comparison between our Subfunctionalization + Dosage-Balance Model (Sub + Dos) and the previous Subfunctionalization-Only (Sub-Only) Model. This comparison includes how the retention probabilities change over time, dependent upon the effective population size and the selective cost associated with spurious interaction of dosage-imbalanced partners. We show comparison between Sub-Only and Sub + Dos models for both whole-genome duplication and small-scale duplication events.

Conclusion: These comparisons show that following whole-genome duplication, dosage balance serves as a time-dependent selective barrier to the subfunctionalization process, by causing an overall delay but ultimately leading to a larger portion of the genome retained through subfunctionalization. This higher percentage of the genome that is ultimately retained is caused by the alternative competing process, nonfunctionalization, being selectively blocked to a greater extent. In small-scale duplication, the reverse pattern is seen, where dosage balance drives faster rates of subfunctionalization, but ultimately leads to a smaller portion of the genome retained as duplicates. This faster rate of subfunctionalization is because the dosage balance of interacting gene products is negatively affected immediately after duplication and the loss of a duplicate restores the stoichiometric balance. Our findings provide support that the subfunctionalization of genes that are susceptible to dosage balance effects, such as proteins involved in complexes, is not a purely neutral process. With stronger selection against stoichiometrically imbalanced gene partners, the rates of subfunctionalization and nonfunctionalization slow; however, this ultimately leads to a greater proportion of subfunctionalized gene pairs.