This project focuses on the fundamental processes by which the genetic material is distributed to each new cell that is formed. As the DNA in a single human cell is approximately 6 feet long, it must be packaged into physical units termed chromosomes. Every time a cell divides, these chromosomes must be duplicated and faithfully distributed to each new cell. Over the course of a lifetime in humans, this must occur trillions of times. To facilitate this, mammalian cells form a molecular machine – called the “kinetochore” - that recognizes each chromosome and physically segregates these chromosomes to the newly formed cells. When this distribution machinery is defective, critical genetic material can be lost or disrupted, with serious consequences to the function and viability of those cells. Thus, it is critical to understand how kinetochores assemble and function. However, there are substantial open questions regarding the nature, function, and evolution of kinetochores. This project will explore the changes to the kinetochore machine across mammals and use evolutionary differences to create a new understanding of the way in which this machine functions and adapts to differing requirements. The Broader Impacts of the project will include the training of undergraduates, graduate students and post-doctoral researchers, along with a high-school teacher in research methodologies.

Eukaryotic chromosome segregation requires the kinetochore, the macromolecular structure that connects chromosomes to the microtubule polymers, which power their movement. Despite a conserved requirement in directing chromosome segregation, the kinetochore is remarkably flexible in its structure, composition, and organization across eukaryotes. This project will harness kinetochore evolutionary plasticity to probe the molecular logic by which kinetochores assemble and function. In particular, this project will test whether changes to kinetochore protein sequences, composition, and requirements across mammalian species represent evolutionary-driven mechanisms that optimize fundamentally similar kinetochore activities to meet diverse physiological constraints. By exploring this idea, this research seeks to generate a coherent molecular model for how kinetochore components act individually and in an integrated manner to achieve faithful chromosome segregation in a way that is robust and conserved, and yet tailored to the specific requirements of each species. Together, this project will define the logic of kinetochore wiring, reveal the composition of the critical kinetochore scaffold, the properties of the kinetochore-microtubule interface, and how these are modulated across evolution to achieve an optimal outcome.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

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Whitehead Institute for Biomedical Research
United States
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