# Cell biological mechanisms of centromere drive

> **NIH NIH R35** · UNIVERSITY OF PENNSYLVANIA · 2021 · $384,055

## Abstract

The centromere drive hypothesis invokes genetic conflict to explain the paradox that both centromere DNA
sequences and centromere-binding proteins have evolved rapidly, despite highly conserved centromere
function across eukaryotes. Genetic conflict at centromeres is grounded in the asymmetry inherent in female
meiosis I (MI). In this reductionist cell division, one chromosome from each homologous pair remains in the
egg and can be transmitted to the next generation, while the other is degraded in the polar body. Natural
selection strongly favors any allele that can increase its chance of remaining in the egg, in violation of Mendel's
First Law (Law of Segregation). Such biased chromosome segregation in meiosis does occur and is a form of
meiotic drive. The first part of the centromere drive hypothesis is that rapid evolution of centromere DNA is
driven by competition to orient towards the spindle pole that will remain in the egg. The model is that expansion
of repetitive sequences at a centromere leads to formation of a larger kinetochore and preferential retention in
the egg. The second part of the hypothesis explains the evolution of centromere proteins through conflict
between individual centromeres, which expand to gain a reproductive advantage, and the reproductive fitness
of the organism. If differences between centromeres of homologous chromosomes cause defects in male
meiosis, this fertility cost provides selective pressure favoring alleles of centromere-binding proteins that
equalize centromeres and suppress drive by binding independent of sequence. The centromere drive
hypothesis has had a major impact on the centromere field because it provides a conceptual framework for
understanding the evolution of centromere DNA and centromere proteins, but the underlying cell biological
mechanisms are unknown. This proposal addresses three major gaps in our understanding of centromere
drive. First, how does centromere DNA sequence influence centromere function? Centromeres are defined
epigenetically in most organisms, and the contribution of sequence has long been unclear. Second, how is
biased segregation in MI achieved? The mechanism by which one centromere preferentially remains in the egg
is unknown. Third, is there a fertility cost in male meiosis? Direct evidence for this crucial component of the
drive hypothesis is scant. If there is a cost, what is the mechanistic basis? To address these questions, we
have established an experimental system in which we observe drive, using a hybrid mouse model created by
crossing two strains with different centromeres. Genetic conflict has shaped many aspects of our genomes,
and centromeres are a particularly fascinating case because of the implications for non-Mendelian inheritance.
The outcomes of our experiments will provide the first mechanistic insight into the cell biology underlying
centromere drive. With broad consequences for reproductive biology and chromosome evolution, this project
represents ...

## Key facts

- **NIH application ID:** 10174942
- **Project number:** 5R35GM122475-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Michael Lampson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,055
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10174942

## Citation

> US National Institutes of Health, RePORTER application 10174942, Cell biological mechanisms of centromere drive (5R35GM122475-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10174942. Licensed CC0.

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