背景:基因复制是基因组扩展的重要过程,有时允许新的基因功能发展。重复的基因可以通过多个过程保留,无论是通过剂量平衡等过程的中间时间段,或通过亚功能化和新功能化等过程在延长的时间内。
结果:这里,我们通过结合剂量平衡来描述亚功能化和剂量平衡之间的相互作用,以探索重复副本的选择压力,从而建立了现有的亚功能化马尔可夫模型。我们的模型使用生物物理框架结合了剂量平衡,该框架惩罚了具有化学计量不平衡蛋白质的遗传状态的适应性。这些不平衡状态导致暴露的疏水表面区域的浓度增加,导致有害的误操作。我们比较了我们的亚功能化+剂量-平衡模型(Sub+Dos)和以前的仅亚功能化(Sub-Only)模型。此比较包括保留概率如何随时间变化,取决于有效人群规模和与剂量不平衡伴侣之间的虚假相互作用相关的选择性成本。我们显示了全基因组复制和小规模复制事件的Sub-Only和SubDos模型之间的比较。
结论:这些比较表明,在全基因组复制之后,剂量平衡作为亚官能化过程的时间依赖性选择性障碍,通过引起整体延迟,但最终导致通过亚功能化保留的基因组的更大部分。最终保留的基因组百分比较高是由替代竞争过程引起的,非功能化,在更大程度上被选择性地阻止。在小规模重复中,看到了相反的模式,在剂量平衡驱动更快的亚官能化速率的情况下,但最终导致一小部分基因组保留为重复。这种更快的亚官能化速率是因为相互作用的基因产物的剂量平衡在复制后立即受到负面影响,并且重复的丢失恢复了化学计量平衡。我们的发现支持了对剂量平衡效应敏感的基因的亚功能化,例如参与复合物的蛋白质,不是一个纯粹的中性过程。通过对化学计量不平衡的基因伴侣的更强选择,亚官能化和非官能化的速率较慢;然而,这最终导致了更大比例的亚功能化基因对。
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.
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.
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.