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Evolutionary and functional diversification of chromatin proteins

染色质蛋白的进化和功能多样化

基本信息

批准号：
9308988
负责人：
Mia Tauna Levine
金额：
$ 23.59万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-09 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9308988
关键词：
Alleles Amino Acids Antitoxins Automobile Driving Biological Biological Process Biology Birth Blood Cell physiology Cellular biology Centromere Cessation of life Chromatin Chromosome Segregation Chromosomes Complement Complex Conflict (Psychology)Congenital Abnormality Cytology DNA DNA biosynthesis Data Disease Drosophila genome Drosophila genus Elements Epigenetic Process Event Evolution Family Female Fertility Functional disorder Gene Family Genes Genetic Genome Genome Stability Genomic Instability Heterochromatin Homeostasis Infertility Length Link Liquid substance Malignant Neoplasms Mediating Meiosis Modeling Molecular Mutation Pattern Phenotype Phylogenetic Analysis Phylogeny Primates Process Proteins Pseudogenes Race Recurrence Research Shapes Structure System Testing Tissues Toxin Transgenic Organisms Trisomy Y Chromosome arm base cancer type chromatin protein chromosome fusion cost fitness gene replacement genetic element genetic information heterochromatin-specific nonhistone chromosomal protein HP-1 innovation insight like heterochromatin protein 1 male novel prevent public health relevance segregation sperm cell telomere tumor virtual

项目摘要

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：真核DNA被包装成不同的染色质隔间，调节遗传信息的表达、稳定性和忠实遗传。这些染色质隔间支持基本的、高度保守的功能，但定义它们的染色质蛋白却惊人地不保守--结构域和残基即使在密切相关的物种之间也会迅速进化。尽管染色质功能障碍直接与许多癌症的发生和发展有关，但染色质蛋白的这种进化创新的生物学原因和功能后果几乎是未知的。这一建议利用宿主基因组与其自私遗传元素之间的“分子军备竞赛”的经典进化框架，以获得对基本染色质依赖的细胞过程的新见解。端粒染色质蛋白阻止灾难性的染色体融合，并支持端粒长度的动态平衡，但它们进化迅速。第一个目标是，这种进化反映了反复的创新，以抑制自拍端粒的适应成本，这些端粒通过非孟德尔式的分离“欺骗”了雌性减数分裂。这一假说的检验是通过转基因将基本端粒蛋白的“不良适应”等位基因引入到黑腹木霉中，这种等位基因有效地逆转了由数百万遗传冲突驱动的氨基酸进化。很多年了。复活祖先等位基因对基因组不稳定表型的功能后果进行了量化。除了残基的快速周转外，染色质蛋白质谱在密切相关物种之间的批发周转也很常见。申请人最近对果蝇异染色质蛋白1(HP1)基因家族的系统基因组分析发现，在4000万年的快照中，有丰富的基因出生和死亡。尽管如此，每个物种的HP1基因数量是非常一致的，这与基因替换的“旋转门”一致。基于功能和系统发育数据的组合，第二个目的是测试这样一个假设，即Y染色体连锁的毒素-抗毒素系统驱动着染色质蛋白质的旋转门，这些蛋白质支持持久的男性生育功能。最后，高等灵长类动物的HP1基因家族包含超过25个目前未被注释的逆转录基因。果蝇HP1家族的多样性表明，这些灵长类逆转录基因中的许多都编码支持生育和基因组稳定的功能蛋白。最终目的是扩展和表征灵长类HP1逆转录基因，阐明它们的组织特异性表达模式、细胞学定位和进化特征，以描绘驱动灵长类HP1潜在“旋转门”的生物学过程。通过确定染色质蛋白质创新的生物学原因和后果，这些研究将为快速进化如何使我们的基因组容易受到表观遗传疾病和不孕不育的影响提供新的见解。