Title:

Structural constraints and drivers of molecular evolution in a macromolecular complex; the kinetochore

Evolutionary theory suggests that cellular structures of critical importance should be subject to strong purifying selection as protein changes would result in inviability. However, how this evolutionary principle relates to multi-subunit molecular complexes remains incompletely explored. For example, the macromolecular kinetochore complex, which mediates the faithful segregation of DNA during cell division, violates the expectation of purifying selection as subsets of kinetochore proteins exhibit rapid evolution despite its critical role. Here, we developed a multi-level approach to investigate the evolutionary dynamics of the kinetochore as a model for understanding how an essential multi-protein structure can experience high rates of diversifying selection while maintaining function. Our comprehensive approach analyzed 57 kinetochore genes for signatures of purifying and diversifying selection across 70 mammalian species. Intraspecies comparisons of kinetochore gene evolution showed that members of the order Afrotheria experience higher rates of episodic diversifying selection than other mammalian orders. Among individual loci, genes that serve regulatory functions, such as the mitotic checkpoint genes, are conserved under strong purifying selection. In contrast, the proteins that serve as the structural base of the kinetochore, including the inner kinetochore and the outer kinetochore, evolve rapidly across species. We also demonstrated that diversifying selection is targeted to regions of these proteins that lack clear structural predictions. Finally, we identified sites that exhibit corresponding trends in evolution across different genes, potentially providing evidence of compensatory evolution in this complex. Together, our evolutionary study of the kinetochore reveals a potential avenue by which selection can alter the genes that comprise an essential cellular complex without compromising its function.

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