Mitochondrial-nuclear gene co-evolution and adaptation

该申请是R24财团资助（PA-00-099），以支持四个学术机构的五个独立小组之间的合作研究。这项研究的长期目标是更全面地了解进行呼吸的蛋白质复合物的合作功能，并推断这些功能在人类进化过程中是如何变化的。目前正在验证的主要假设是，在灵长类动物进化过程中，许多由核基因组和线粒体基因组编码的呼吸链蛋白已经适应地共同进化。先前的研究表明，电子传递系统（ETS）的某些亚单位在祖先谱系上经历了积极的达尔文选择和共同进化，最终形成了类人猿灵长类动物（猴子、猿和人类）。该联盟将通过从密集和多样化的灵长类动物系统发育样本中对ETS基因进行测序，并采用严格的最大似然（ML）分析方法来完善这些研究。这些方法将应用于所有的ETS配合物，重点是那些已经确定晶体结构的配合物。这些目标将通过以下具体目标来实现：具体目标1：将从系统发育多样化的灵长类动物中测序线粒体DNA （mtDNA）基因组。编码一些ETS亚基的蛋白质编码基因将被单独分析，以寻找积极的达尔文选择证据。整个基因组将进行系统发育分析。特异性目标2：选择编码与mtdna编码亚基相互作用的蛋白质的核基因，将从同一物种中测序。这些基因将被分析作为积极选择的证据。具体目标3：通过结合三级结构信息的基于系统发育的ML方法，将分析相互作用的蛋白质和编码它们的基因，以寻找适应性共同进化的证据。这些数据和分析将用于更全面地验证这样一种假设，即某些ETS蛋白质在灵长类祖先的进化过程中经历了达尔文选择的积极过程，最终进化为人类。这一信息对理解人类的能量代谢具有重要意义，特别是在人类进化过程中与大脑扩张有关的能量代谢。此外，关于哪些蛋白质或蛋白质部分最近经历了正选择的信息可能有助于确定干预某些人类线粒体疾病的目标。

This application is for an R24 Consortium Grant (PA-00-099) to support collaborative research between five independent groups at four academic institutions. The long-term goals of this research are to more fully understand the cooperative functioning of the protein complexes that carry out respiration, and to infer how these functions may have changed during human evolution. The major hypothesis being tested is that many of the respiratory chain proteins, which are encoded both by the nuclear and mitochondrial genomes, have adaptively co-evolved during primate evolution. Previous studies have suggested that certain subunits of the electron transport system (ETS) underwent episodes of positive Darwinian selection and co-evolution on ancestral lineages leading to the anthropoid primates (monkeys, apes, and humans). The consortium will refine these studies, both by sequencing ETS genes from a dense and diverse phylogenetic sample of primates and by applying rigorous maximum likelihood (ML) methods of analysis. These approaches will be applied to all of the ETS complexes, with most emphasis on those for which crystal structures have been determined. These goals will be accomplished through the following Specific Aims: Specific Aim 1: Mitochondrial DNA (mtDNA) genomes will be sequenced from phylogenetically-diverse primates. The protein-coding genes, which code for some of the ETS subunits, will be individually analyzed for evidence of positive Darwinian selection. The whole genomes will be analyzed phylogenetically. Specific Aim 2: Selected nuclear genes that code for proteins that interact with the mtDNA-encoded subunits will be sequenced from the same species. These genes will be analyzed for evidence of positive selection. Specific Aim 3: The interacting proteins, and the genes that encode them, will be analyzed for evidence for adaptive co-evolution by phylogeny-based ML methods that incorporate tertiary structural information. These data and analyses will be used to more fully test the hypothesis that certain ETS proteins underwent episodes of positive Darwinian selection on ancestral primate lineages leading to humans. This information has important implications for understanding energy metabolism in humans, particularly as related to brain expansion during human evolution. Furthermore, information about which proteins, or parts of proteins, have undergone recent positive selection may help define targets for intervention in certain human mitochondrial diseases.