Heterochromatin is the gene-poor, satellite-rich, transcriptionally silent compartment of our genome that supports such basic cellular processes as chromosome segregation and telomere integrity. These processes are strictly conserved across the animal kingdom, yet abundant selfish transposable elements, satellite repeats, and segregation- distorting loci render this genome compartment highly dynamic over evolutionary time. The three founding members of the Heterochromatin Protein 1(HP1) gene family support these conserved processes and generally evolve under strict constraint. Our recent hand-curated computational approach to HP1 annotation across Drosophila genomes, however, expanded this family from three to 14 genes, most of which evolve rapidly. This dynamic evolution implicates a molecular arms race between heterochromatin's abundant selfish genomic parasites and these heterochromatin-associated host proteins. HP1D/Rhino, for example, regulates female germline defense against transposable elements via a small RNA pathway. I propose to complete our exhaustive search for all HP1-like genes in the 12 sequenced Drosophila species followed by confirmation of both transcription across a tissue panel and heterochromatin localization of fluorescently tagged proteins in cell culture and in vivo. Using population genetic and molecular evolution analyses, I will rigorously determine if patterns of sequence evolution are consistent with an ongoing molecular arms race with selfish genetic elements. In parallel, I will test the specific hypothesis that transposable element defense via the piRNA pathway drives the rapid evolution of HP1D/rhino and its putative male analog, HP1E. Finally, I will apply my comprehensive approach to HP1 annotation and verification to higher primates, including humans. Only three HP1-like genes are currently annotated in the human genome, described over a decade ago by homology to the original three Drosophila HP1-like genes. Reminiscent of Drosophila, these three human HP1s are evolving under strict constraint. My preliminary survey of the many uncharacterized HP1-derived gene duplication events across the human genome implicates similar, though unexplored, evolutionary dynamics consistent with novel HP1- like genes engaged in genetic conflict outside of Drosophila.

Public Health Relevance

All three Heterochromatin Protein 1 (HP1) genes currently annotated in the human genome are linked to cancer progression in at least one tissue type/cell line, including breast, brain, colon, and ovary, and in leukemia and papillary thyroid carcinoma. My evolutionary/comparative genomic approach promises to identify new biological functions for HP1 genes that advance our understanding of the gene regulation and chromosome segregation defects in cancer cells.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F08-E (20))
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Reddy, Michael K
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Fred Hutchinson Cancer Research Center
United States
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Levine, Mia T; Malik, Harmit S (2011) Learning to protect your genome on the fly. Cell 147:1440-1