DNA packaging into chromatin mediates chromosome segregation, telomere protection, genome integrity, and other essential, conserved cellular processes. However, many chromatin proteins are strikingly unconserved? domains and residues evolve rapidly between even closely related species. This paradox of conserved, chromatin-dependent functions supported by fast-evolving chromatin proteins suggests that maintaining essential cellular processes requires recurrent innovation. The biological significance of this innovation is virtually unexplored. With few exceptions, we understand neither the evolutionary forces that shape contemporary chromatin proteins nor the chromatin-dependent functions modified by recent adaptation. Nevertheless, aberrant chromatin packaging is the hallmark of many blood and tumor cancers, chromosomal birth defects, and aging. My lab integrates evolutionary genomics, transgenics, cell biology, and classical genetics to identify the evolutionary pressures that drive recurrent DNA packaging innovation and the consequences for fundamental, chromatin-dependent cellular and developmental processes. We utilize the classic evolutionary framework of a ?molecular arms race? between a host genome and its selfish genetic elements to gain new insights into the causes and functional consequences of DNA packaging evolution. We focus specifically on adaptively evolving chromatin proteins that package the gene-poor, repeat-rich, and fast- evolving ?heterochromatic? DNA sequence enriched at telomeres and along the sex chromosomes. We hypothesize that selfish genetic elements, which thrive in heterochromatin, antagonize sex chromosome and telomere packaging proteins. Consistent with this hypothesis, these heterochromatin proteins harbor the distinct DNA signature left behind by intra-genomic conflict?the rapid accumulation of amino acid-changing mutations over evolutionary time (i.e., positive selection). To empirically test the hypothesis that recurrent bouts of selfish element evasion and heterochromatin protein suppression drive these signatures of adaptation, we engineer ?evolutionary mismatches? between contemporary Drosophila melanogaster selfish elements and ?resurrected? versions of fast-evolving host proteins. Specifically, we leverage CRISPR/Cas9-mediated editing to delete or to swap in an ancestrally reconstructed host gene. Our preliminary results indicate that ?mal- adapted? telomere proteins de-repress telomere-embedded selfish elements. Similarly, deleting young, testis- restricted heterochromatin proteins unleashes a selfish X chromosome that sabotages Y chromosome transmission. Our ?reverse evolutionary genetics? approach offers us the unique opportunity to (1) identify selfish elements and their targets and (2) elucidate the mechanisms by which selfish elements gain a transmission advantage and by which chromatin proteins suppress them. By identifying the biological causes and consequences of heterochromatin protein innovation, our research program provides new insights into how rapid evolution renders our genome vulnerable to chromatin-mediated disease and infertility.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM124684-04
Application #
9976537
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Janes, Daniel E
Project Start
2017-09-11
Project End
2022-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Helleu, Quentin; Levine, Mia T (2018) Recurrent Amplification of the Heterochromatin Protein 1 (HP1) Gene Family across Diptera. Mol Biol Evol 35:2375-2389