Eukaryotic DNA is packaged into distinct chromatin compartments that mediate the expression, stability, and faithful inheritance of genetic information. These chromatin compartments support essential, highly conserved functions yet the chromatin proteins that define them are strikingly unconserved--domains and residues evolve rapidly even between closely related species. Although chromatin dysfunction is directly implicated in the initiation and progression of numerous cancers, the biological causes and functional consequences of this evolutionary innovation at chromatin proteins are virtually unknown. This proposal utilizes the classic evolutionary framework of a """"""""molecular arms race"""""""" between a host genome and its selfish genetic elements to gain new insights into essential chromatin-dependent cellular processes. Telomeric chromatin proteins prevent catastrophic chromosome fusions and support telomere length homeostasis yet they evolve rapidly.
The first aim posits that this evolution reflects recurrent innovation to suppress the fitness costs of selfih telomeres that """"""""cheat"""""""" female meiosis via non-Mendelian segregation. This hypothesis is tested by transgenically introducing into D. melanogaster """"""""mal-adapted"""""""" alleles of essential telomeric proteins that effectively reverse the amino acid evolution driven by genetic conflict over millions of years. The functional consequences of resurrecting the ancestral allele on genome instability phenotypes are quantified. In addition to rapid turnover of residues, wholesale turnover of chromatin protein repertoires between closely related species is common. The applicant's recent phylogenomic analysis of the Drosophila Heterochromatin Protein 1 (HP1) gene family discovered abundant gene birth and death across a 40 million year snapshot. Nevertheless, HP1 gene number per species is remarkably uniform, consistent with a """"""""revolving door"""""""" of gene replacement. Based on a combination of functional and phylogenetic data, the second aim tests the hypothesis that a Y chromosome-linked toxin-antitoxin system drives this revolving door of chromatin proteins that support a persistent male fertility function. Finally, the HP1 gene family in higher primates harbors over 25 currently unannotated retrogenes. The Drosophila HP1 family diversification suggests that many of these primate retrogenes encode functional proteins that support fertility and genome stability.
The final aim expands and characterizes primate HP1 retrogenes, elucidating their tissue-specific expression patterns, cytological localization and evolutionary signatures to delineate the biological processes driving a potential """"""""revolving door"""""""" in primate HP1s. By identifying the biological causes and consequences of chromatin protein innovation, these studies will provide novel insights into how rapid evolution renders our genome vulnerable to epigenetic disease and infertility.
The stability, expression, and inheritance of genetic information depends on the compartmentalization of our genome by specialized proteins. The disruption of this protein-DNA complex, called chromatin, results in the genome instability pervasive in virtually all types of cancer and in chromosomal birth defects like trisomy. My research combines evolutionary predictions with basic chromatin biology to generate unique insights into these disease and infertility states.
|Lee, Yuh Chwen G; Leek, Courtney; Levine, Mia T (2017) Recurrent Innovation at Genes Required for Telomere Integrity in Drosophila. Mol Biol Evol 34:467-482|
|Levine, Mia T; Vander Wende, Helen M; Hsieh, Emily et al. (2016) Recurrent Gene Duplication Diversifies Genome Defense Repertoire in Drosophila. Mol Biol Evol 33:1641-53|
|Levine, Mia T; Vander Wende, Helen M; Malik, Harmit S (2015) Mitotic fidelity requires transgenerational action of a testis-restricted HP1. Elife 4:e07378|