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 aneuploidy, infertility, and birth defects like Down?s syndrome. Despite the conservation of the chromosome segregation process, centromeric proteins like CenH3, which bind centromeric DNA to assemble microtubule-recruiting kinetochores, evolve rapidly between closely related species. Their rapid evolution is unexpected and could imperil the fidelity of the chromosome segregation process. We previously 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. Using an approach that combines insights from evolutionary genetics and cell biology, and state-of-the-art genome engineering tools, we propose to test this model of genetic conflict in Drosophila species. Furthermore, based on our finding of recurrent duplication of CenH3 in Drosophila species, we will test whether somatic versus germline centromeric functions have different functional constraints, which are easiest to resolve via gene duplication and specialization of CenH3 genes.
Belying the expectation that essential proteins must be highly conserved, centromeric proteins such as CenH3 evolve rapidly in plants and animals. Their unexpectedly rapid evolution can interfere with chromosome segregation and lead to aneuploidy and birth defects (e.g., Down syndrome). My lab has adopted an interdisciplinary approach to test two genetic conflict hypotheses, centromeric drive and antagonistic pleiotropy, to understand the biological causes and consequences of unexpected rapid evolution of centromeric proteins.
| 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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