Chromosome segregation is an essential process. The key chromosomal sites that ensure proper segregation of chromosomes are centromeres, which bind microtubules that pull chromosomes or chromatids apart during meiosis and mitosis. Centromere function is thus essential for chromosome segregation. Defective centromeres can lead to infertility, tumorigenesis and birth defects like Down's syndrome. Despite the conservation of the chromosome segregation process, centromeric DNA sequences evolve rapidly, both within and between closely related species. Moreover, essential centromeric proteins, which bind centromeric DNA to assemble microtubule-recruiting kinetochores, also evolve rapidly. This rapid evolution of both centromeric proteins and DNA is in sharp contrast to the expectation that they should be highly conserved to maintain essential function, whose basic mechanism has been conserved in all eukaryotes. We have proposed that this rapid evolution occurs due to 'centromere-drive', i.e., competition between chromosomes during female meiosis, in which only one of four meiotic products is chosen to be the egg pronucleus. Deleterious consequences of centromere-drive, especially in male meiosis, selects for the rapid evolution of centromeric and heterochromatin proteins, to quell drive or its deleterious effects. Using an approach that combines insights from evolutionary genetics and cell biology, we propose to test this model of genetic conflict in Drosophila species. We will further test the functional consequences of rapid evolution and genetic innovation in centromeric proteins, on the fundamental process of chromosome segregation.

Public Health Relevance

Centromere function is essential for high fidelity chromosome segregation. In contrast to the expectation that they should be highly conserved to maintain essential function In addition, essential centromeric proteins and DNA evolve rapidly. This unexpected rapid evolution can lead to incompatibilities between centromeric components that can interfere with chromosome segregation and lead to aneuploidy, resulting in cancer or birth defects (e.g., Down syndrome). My lab has adopted an interdisciplinary approach, combining insights from evolution, genetic and cell biology, to understand the biological causes of unexpected rapid evolution of centromeric DNA and proteins, and the consequences of this rapid evolution for centromere dysfunction, disease and evolution.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Genetic Variation and Evolution Study Section (GVE)
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Janes, Daniel E
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Fred Hutchinson Cancer Research Center
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United States
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Kursel, Lisa E; Malik, Harmit S (2018) The cellular mechanisms and consequences of centromere drive. Curr Opin Cell Biol 52:58-65
Schroeder, Courtney M; Malik, Harmit S (2018) Kindr Motors Drive in Meiosis. Cell 173:813-815
Molaro, Antoine; Young, Janet M; Malik, Harmit S (2018) Evolutionary origins and diversification of testis-specific short histone H2A variants in mammals. Genome Res 28:460-473
Ailion, Michael; Malik, Harmit S (2017) Genetics: Master Regulator or Master of Disguise? Curr Biol 27:R844-R847
Levin, Tera C; Malik, Harmit S (2017) Rapidly Evolving Toll-3/4 Genes Encode Male-Specific Toll-Like Receptors in Drosophila. Mol Biol Evol 34:2307-2323
Nuckolls, Nicole L; Bravo Núñez, María Angélica; Eickbush, Michael T et al. (2017) wtf genes are prolific dual poison-antidote meiotic drivers. Elife 6:
Bull, James J; Malik, Harmit S (2017) The gene drive bubble: New realities. PLoS Genet 13:e1006850
Kasinathan, Bhavatharini; Ahmad, Kami; Malik, Harmit S (2017) Waddington Redux: De Novo Mutations Underlie the Genetic Assimilation of Stress-Induced Phenocopies in Drosophila melanogaster. Genetics 207:49-51
McLaughlin Jr, Richard N; Malik, Harmit S (2017) Genetic conflicts: the usual suspects and beyond. J Exp Biol 220:6-17
Kursel, Lisa E; Malik, Harmit S (2017) Recurrent Gene Duplication Leads to Diverse Repertoires of Centromeric Histones in Drosophila Species. Mol Biol Evol 34:1445-1462

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