Event

Our genomic DNA is packaged into distinct compartments that support essential, highly conserved cellular processes. Paradoxically, the 'chromatin' proteins that establish and maintain these compartments are strikingly unconserved. Sequence divergence and whole-gene turnover is common even between closely related species. Although chromatin dysfunction is a hallmark of cancer, these plastic but essential components of chromatin biology have received minimal attention. I combine comparative genomics, evolutionary genetics, and cell biology to gain insight into the causes and functional consequences of this evolution. I first set out to increase our compendium of these plastic genes. I computationally searched 12 sequenced fruit fly (Drosophila) genomes spanning 40 million years of evolution for new members of the Heterochromatin Protein 1 (HP1) gene family. I discovered 22 additional HP1 genes that encode unprecedented structural diversity, species-specificity, and sex-biased expression. I observed prolific gene gains and losses across the phylogeny yet a remarkably constant HP1 gene number per species, consistent with a 'revolving door' of recurrent gene death and replacement. To elucidate the biological forces driving this intriguing pattern, I have functionally dissected an exemplary HP1 member that has recurrently degenerated over the Drosophila phylogeny but is retained in the model system D. melanogaster. Males depleted of this HP1 protein are sterile but make abundant motile sperm that deposit paternal DNA into the egg. This paternal DNA fails to complete the first embryonic mitosis, leading to developmental arrest. My data suggest that during wildtype sperm development, this HP1 gene primes the paternal DNA for embryonic mitosis. Curiously, this essential gene has degenerated along Drosophila lineages that harbor recent karyotype evolution involving sex chromosomes.  This phylogenetic signature suggests that chromosome fusions might recurrently render this gene dispensable. Under this model, sex chromosome rearrangements ameliorate vulnerability to mitotic defects. I have shown that the sex chromosomes, and not the autosomes, are indeed uniquely vulnerable to mitotic errors in these defective embryos. I propose that HP1 depletion results in incomplete replication of late-replicating genome compartments, which are specifically enriched on the D. melanogaster sex chromosomes. Replication timing offers both a molecular mechanism of HP1 action and an explanation for the striking correlation of karyotype evolution and HP1 gene death. My ongoing work directly tests the hypothesis that these chromosome rearrangements alter replication timing and, more broadly, drive the HP1 gene family revolving door.  A link between replication timing and chromosomal rearrangements has broad implications for the causes and consequences of both primate and cancer genome evolution where karyotype diversity abounds.