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

随着时间的推移，生物体以两种方式对环境因素作出反应：(i)其一生中的短期变化（如表观遗传修饰和基因表达变化）和（ii）跨代的长期变化，即可遗传的进化反应，从而产生遗传上不同的种群-甚至可能产生新的物种。虽然涉及核表观遗传变异（以DNA甲基化的形式）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存在于一系列动物和植物中，但线粒体（细胞的动力）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重要性仍在很大程度上未被探索。考虑到线粒体在细胞存活和功能、衰老和人类疾病中的关键作用，这种重大的知识差距令人惊讶。本研究将通过结合表观基因组学、转录组学、生理学和细胞生物学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的理解中的这一基本知识缺口。这一建议建立在我之前关于双壳类动物线粒体双单亲遗传（DUI）和性别决定的分子机制的发现基金的基础上，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。该提案仍然关注具有DUI的双壳类，但也关注用于研究人类健康和疾病的两种模式生物（酵母和涡虫）。我提出了四个短期目标：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的流行程度；4)测试它们的功能。在目标1-2中，涡虫和双壳类动物将为研究不同环境下线粒体表观遗传和转录变化提供独特的机会，因为它们没有遗传变异（涡虫无性生殖），并且在相同的核背景（DUI）中存在两种不同的mtdna。在目标3-4中，双壳类动物的性别特异性mt编码蛋白除了产生能量外，还具有其他功能（尚不清楚），而酵母（酿酒酵母）具有重要的线粒体基因组大小，这将提供独特的机会来验证一个假设，即像核DNA一样，mtDNA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，是功能新颖的重要来源。在目前的建议中提出的问题是独特的和令人兴奋的，并有可能改变我们对线粒体在生物体中的作用的理解。

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.