Mitochondrial epigenetics and ORFan genes: exploiting the mitochondrial genetic system to fuel phenotypic variation and functional novelties

线粒体表观遗传学和 ORFan 基因：利用线粒体遗传系统促进表型变异和功能新颖性

• 批准号: RGPIN-2019-04076
• 负责人: Breton, Sophie
• 金额: $ 3.06万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=765193
• 关键词: Mitochondrial; epigenetics; ORFan; genes; exploiting

Organisms respond to environmental factors over time in two ways: (i) short-term changes during their lifetime (e.g. epigenetic modifications and gene expression changes) and (ii) long-term changes across generations, i.e. heritable evolutionary responses, resulting in genetically distinct populations - potentially even new species. While empirical examples of rapid responses and evolutionary adaptations involving nuclear epigenetic variation (in the form of DNA methylation) and genetic variation (through the evolution of lineage-specific or adaptive genes or ORFan genes) exist from a range of animals and plants, the importance of mitochondria (the powerhouse of cells) and their genomes (mtDNA) in promoting adaptation to both short- and long-term environmental changes using the same mechanisms is still largely unexplored. This major knowledge gap is surprising given the pivotal role of mitochondria in cell survival and functions, aging and human diseases. The proposed research will address this fundamental knowledge gap in our understanding of adaptation and speciation processes through the use an integrative approach combining epigenomics, transcriptomics, physiology and cell biology to investigate the capacity of mitochondria and their genomes to adapt to changing environments. This proposal builds on results from my previous Discovery Grant on the molecular mechanisms underlying doubly uniparental inheritance (DUI) of mitochondria and sex determination in bivalves, which suggested that bivalves likely exploit the mitochondrial genetic system to fuel phenotypic variation and evolutionary innovations. The proposal still focus on bivalves with DUI but also on two model organisms used to study human health and diseases (yeast and planarians). I propose four short-term objectives: 1) measure the mitochondrial epigenetic response to environmental changes; 2) measure the functional consequences of mitochondrial epigenetic variation; 3) estimate the prevalence of mtORFans; and 4) and test their function(s). In objectives 1-2, planarians and bivalves will offer unique opportunities to study mitochondrial epigenetic and transcriptional changes under diverse environmental regimes respectively because of their absence of genetic variation (asexual reproduction in planarians) and the presence of two different mtDNAs in the same nuclear background (DUI). In objectives 3-4, bivalves, with their sex-specific mt-encoded proteins with (still unknown) functions other than energy production, and yeast (S. cerevisiae), with their important mitochondrial genome size, will offer unique opportunities to test the hypothesis that like the nuclear DNA, the mtDNA possesses several overlooked small protein-coding genes that have key functions and are important sources of functional novelty. The questions posited in the current proposal are unique and exciting, and have the potential for transforming our understanding of the role of mitochondria in living organisms.

随着时间的推移，生物体以两种方式对环境因素做出反应：(i) 其一生中的短期变化（例如表观遗传修饰和基因表达变化）和 (ii) 几代人之间的长期变化，即可遗传的进化反应，导致遗传上不同种群——甚至可能是新物种。虽然一系列动物和植物中存在涉及核表观遗传变异（以 DNA 甲基化形式）和遗传变异（通过谱系特异性或适应性基因或 ORFan 基因的进化）的快速反应和进化适应的经验例子，但重要性线粒体（细胞的动力室）及其基因组（mtDNA）在使用相同机制促进对短期和长期环境变化的适应方面的作用在很大程度上仍未被探索。鉴于线粒体在细胞生存和功能、衰老和人类疾病中的关键作用，这一重大知识差距令人惊讶。拟议的研究将通过使用表观基因组学、转录组学、生理学和细胞生物学相结合的综合方法来研究线粒体及其基因组适应不断变化的环境的能力，从而解决我们对适应和物种形成过程理解中的这一基本知识差距。该提案建立在我之前的发现基金研究成果的基础上，该研究成果涉及双壳类线粒体双单亲遗传（DUI）和性别决定的分子机制，这表明双壳类动物可能利用线粒体遗传系统来促进表型变异和进化创新。该提案仍然关注酒后驾车的双壳类动物，但也关注两种用于研究人类健康和疾病的模式生物（酵母和涡虫）。我提出四个短期目标：1）测量线粒体表观遗传对环境变化的反应； 2）测量线粒体表观遗传变异的功能后果； 3) 估计mtORFans的流行率； 4) 并测试其功能。在目标 1-2 中，涡虫和双壳类动物将提供独特的机会，分别在不同的环境条件下研究线粒体表观遗传和转录变化，因为它们不存在遗传变异（涡虫的无性繁殖）并且在相同的核背景中存在两种不同的 mtDNA （酒后驾车）。在目标 3-4 中，双壳类动物及其性别特异性 mt 编码蛋白具有（仍未知）除能量产生以外的功能，而酵母（酿酒酵母）则具有重要的线粒体基因组大小，将提供独特的机会来测试假设与核 DNA 一样，线粒体 DNA 拥有几个被忽视的小蛋白质编码基因，这些基因具有关键功能，并且是功能新颖性的重要来源。当前提案中提出的问题是独特且令人兴奋的，并且有可能改变我们对线粒体在生物体中的作用的理解。