# Cell Biological mechanisms of centromere drive

> **NIH NIH R35** · UNIVERSITY OF PENNSYLVANIA · 2024 · $426,563

## Abstract

The seemingly straightforward function of the centromere in directing chromosome segregation is difficult to
reconcile with multiple complexities of the underlying molecular machinery, particularly rapid evolution of both
centromere DNA and proteins and seemingly redundant pathways linking the DNA to spindle microtubules.
This project focuses on centromere drive as a key to unlocking centromere complexity. Selfish centromere
DNA sequences bias their transmission to the egg in female meiosis, while centromere proteins evolve to
suppress fitness costs of drive while maintaining essential centromere functions. Our recent work determined
how selfish centromeres interact with spindle microtubules to bias their segregation. We developed mouse
model systems exploiting natural variation in mouse centromere DNA, defined tubulin detyrosination as the key
post-translational modification creating meiotic spindle asymmetry, showed that microtubule-destabilizing
proteins act as drive effectors exploited by selfish centromeres, established an integrated model for both drive
and suppression, and sequenced Murinae genomes for molecular evolution analyses to identify rapidly
evolving centromere proteins. Our progress represents crucial steps towards understanding the centromere
drive conflict but leaves key gaps in our understanding of drive and suppression and centromere protein
evolution, which are addressed in this proposal. First, we will determine how selfish centromeres interact with
an asymmetric spindle to bias their segregation. Our previous findings suggest a hypothesis that we will test by
manipulating microtubule destabilizing activities at centromeres in live cells, using chemical optogenetic
approaches that we developed. Second, we will test whether genetically different centromeres differentially
recruit centromere proteins, a central but untested component of the centromere drive theory. Using hybrid
mouse zygotes with divergent maternal and paternal centromere satellite DNA sequences as a model system,
we will determine if rapidly evolving centromere protein interact differentially with different centromere DNA
sequences. Third, we will test for reproductive fitness costs associated with functional differences between
centromeres, taking advantage of our hybrid mouse model systems in which paired homologous chromosomes
in meiosis have divergent centromeres. Fourth, we will test the concept that centromere proteins have evolved
to suppress costs due to functional differences between centromeres, which has been the most challenging
part of the drive theory to address experimentally. With tractable experimental systems, a mechanistic model
for drive and suppression, and molecular evolution analyses of centromere proteins in place, we will address
this challenge by testing whether recurrent changes in rapidly evolving centromere proteins have functional
implications consistent with our model. Overall, by investigating centromeres in the context of gen...

## Key facts

- **NIH application ID:** 10839335
- **Project number:** 5R35GM122475-08
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Michael Lampson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $426,563
- **Award type:** 5
- **Project period:** 2017-09-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839335

## Citation

> US National Institutes of Health, RePORTER application 10839335, Cell Biological mechanisms of centromere drive (5R35GM122475-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10839335. Licensed CC0.

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