Phylogenomics and functional diversification of the Heterochromatin Protein 1 gen

描述（由申请人提供）：异染色质是我们基因组中基因贫乏、卫星丰富、转录沉默的区室，支持染色体分离和端粒完整性等基本细胞过程。这些过程在整个动物王国中是严格保守的，然而丰富的自私转座因子、卫星重复序列和分离扭曲基因座使得该基因组区室在进化时间上高度动态。异染色质蛋白1（HP 1）基因家族的三个创始成员支持这些保守的过程，通常在严格的限制下进化。然而，我们最近手工策划的计算方法在果蝇基因组中进行HP 1注释，将这个家族从3个基因扩展到14个基因，其中大多数基因进化迅速。这种动态的进化暗示了异染色质丰富的自私基因组寄生虫和这些异染色质相关的宿主蛋白之间的分子军备竞赛。例如，HP 1D/Rhino通过小RNA途径调节雌性生殖细胞对转座因子的防御。我建议完成我们详尽的搜索所有HP 1样基因在12个测序果蝇物种，然后确认转录跨组织面板和异染色质定位的荧光标记的蛋白质在细胞培养和体内。利用群体遗传学和分子进化分析，我将严格地确定序列进化的模式是否与自私的遗传因素正在进行的分子军备竞赛相一致。与此同时，我将测试特定的假设，即通过皮尔纳途径的转座因子防御驱动了HP 1D/rhino及其推定的雄性类似物HP 1 E的快速进化。最后，我将把我的综合方法应用于HP 1注释和验证高等灵长类动物，包括人类。目前在人类基因组中只有三个HP 1样基因被注释，十多年前通过与原始的三个果蝇HP 1样基因的同源性进行了描述。这三种人类HP 1基因在严格的限制下进化，这让人想起了果蝇。我对人类基因组中许多未表征的HP 1衍生基因复制事件的初步调查表明，类似的，但未经探索的，进化动力学与果蝇外参与遗传冲突的新型HP 1样基因一致。 公共卫生相关性：目前在人类基因组中注释的所有三种异染色质蛋白1（HP 1）基因与至少一种组织类型/细胞系（包括乳腺、脑、结肠和卵巢）以及白血病和甲状腺乳头状癌中的癌症进展相关。我的进化/比较基因组学方法有望确定HP 1基因的新生物学功能，从而促进我们对癌细胞中基因调控和染色体分离缺陷的理解。

DESCRIPTION (provided by applicant): 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.