Causes and functional consequences of chromatin evolution
Causes and functional consequences of chromatin evolution
批准号:
10224857
负责人:
Mia Tauna Levine
金额:
$39.21万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-09-11 至 2022-12-31
关键词:
AgingAmino AcidsBiologicalBiologyBloodCRISPR/Cas technologyCell physiologyCellular biologyChromatinChromosome SegregationComplexConflict (Psychology)Congenital AbnormalityDNADNA PackagingDNA SequenceDevelopmental ProcessDiseaseDrosophila melanogasterElementsEngineeringEvolutionGenesGeneticGenomeGenomic InstabilityGenomicsHeterochromatinInfertilityLeftMalignant NeoplasmsMediatingMolecularMutationProteinsRaceRecurrenceResearchSelfish GenesSex ChromosomesShapesTestingTestisTimeTransgenic OrganismsTrisomyX ChromosomeY Chromosomearmcancer typechromatin proteingenetic approachgenetic informationgenome integrityinnovationinsightpressureprogramstelomeretransmission processtumorvirtual
中文摘要
项目总结
DNA包装到染色质中介导了染色体分离、端粒保护、基因组完整性和
其他基本的、保守的细胞过程。然而,许多染色质蛋白质惊人地不保守-
结构域和残基甚至在关系密切的物种之间进化得也很快。这种自相矛盾的保守,
快速进化的染色质蛋白支持的染色质依赖功能表明,维持
基本的细胞过程需要不断的创新。这一创新的生物学意义在于
几乎没有被开发过。除了少数几个例外,我们既不了解塑造
当代染色质蛋白也不是最近适应改变的染色质依赖功能。
然而,异常的染色质包装是许多血液和肿瘤、染色体癌症的标志。
先天缺陷和衰老。我的实验室集成了进化基因组学、转基因、细胞生物学和经典
遗传学以确定推动反复DNA包装创新的进化压力和
对基本的、依赖染色质的细胞和发育过程的影响。我们利用
宿主基因组与其自私基因之间“分子军备竞赛”的经典进化框架
元素,以获得对DNA包装进化的原因和功能后果的新见解。我们
特别关注适应性进化的染色质蛋白质,这些蛋白质包装了基因贫乏、富含重复和快速的
进化中的“异染色质”DNA序列富含在端粒和性染色体上。我们
假设在异染色质中茁壮成长的自私遗传元素对抗性染色体和
端粒包装蛋白。与这一假设一致,这些异染色质蛋白含有
基因组内部冲突留下的独特DNA特征--氨基酸变化的快速积累
进化过程中的突变(即正向选择)。从经验上检验反复出现的假设
一轮又一轮的自私分子逃避和异染色质蛋白抑制驱动着这些适应的信号,
我们设计了当代果蝇和黑腹果蝇自私成分之间的“进化错配”
快速进化的宿主蛋白的“复活”版本。具体地说,我们利用CRISPR/Cas9中介的编辑
删除或替换祖先重建的宿主基因。我们的初步结果显示,“男性--
适应的“端粒蛋白去抑制端粒嵌入的自私成分。同样,删除年轻的,睾丸-
限制性异染色质蛋白释放出破坏Y染色体的自私X染色体
变速箱。我们的“反向进化遗传学”方法为我们提供了独特的机会来(1)识别
自私因素及其目标;(2)阐明自私因素获得目标的机制。
传递优势以及染色质蛋白通过什么抑制它们。通过确定生物原因
和异染色质蛋白创新的后果,我们的研究计划为
快速进化使我们的基因组容易受到染色质介导的疾病和不孕不育的影响。
英文摘要
PROJECT SUMMARY
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.
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会议论文
Causes and functional consequences of chromatin evolution
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批准号:9750097
-
项目类别:
-
资助金额:$39.21万
-
财政年份:2017
-
负责人:Mia Tauna Levine
-
依托单位:
Causes and functional consequences of chromatin evolution
-
批准号:10551604
-
项目类别:
-
资助金额:$44.66万
-
财政年份:2017
-
负责人:Mia Tauna Levine
-
依托单位:
Causes and functional consequences of chromatin evolution
-
批准号:9380609
-
项目类别:
-
资助金额:$18.38万
-
财政年份:2017
-
负责人:Mia Tauna Levine
-
依托单位:
Causes and functional consequences of chromatin evolution
-
批准号:9976537
-
项目类别:
-
资助金额:$39.21万
-
财政年份:2017
-
负责人:Mia Tauna Levine
-
依托单位:
Evolutionary and functional diversification of chromatin proteins
-
批准号:8730205
-
项目类别:
-
资助金额:$9.0万
-
财政年份:2013
-
负责人:Mia Tauna Levine
-
依托单位:
Evolutionary and functional diversification of chromatin proteins
-
批准号:9308988
-
项目类别:
-
资助金额:$23.59万
-
财政年份:2013
-
负责人:Mia Tauna Levine
-
依托单位:
Evolutionary and functional diversification of chromatin proteins
-
批准号:8567656
-
项目类别:
-
资助金额:$9.0万
-
财政年份:2013
-
负责人:Mia Tauna Levine
-
依托单位:
Phylogenomics and functional diversification of the Heterochromatin Protein 1 gen
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批准号:8126109
-
项目类别:
-
资助金额:$5.13万
-
财政年份:2011
-
负责人:Mia Tauna Levine
-
依托单位:
Phylogenomics and functional diversification of the Heterochromatin Protein 1 gen
-
批准号:8264576
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项目类别:
-
资助金额:$5.39万
-
财政年份:2011
-
负责人:Mia Tauna Levine
-
依托单位:
海外基金