Mitochondrial-nuclear gene co-evolution and adaptation

该申请是为了获得R24财团资助（PA-00-099），以支持四个学术机构的五个独立团体之间的合作研究。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可能发生了怎样的变化。正在测试的主要假设是，许多呼吸链蛋白，这是由核和线粒体基因组编码，在灵长类动物进化过程中适应性地共同进化。以前的研究表明，电子传递系统（ETS）的某些亚基经历了积极的达尔文选择和共同进化的祖先谱系，导致灵长类动物（猴子，猿和人类）。该联盟将通过对来自灵长类动物的密集和多样的系统发育样本的ETS基因进行测序以及应用严格的最大似然（ML）分析方法来完善这些研究。这些方法将被应用到所有的ETS配合物，最强调的是那些晶体结构已被确定。这些目标将通过以下具体目标实现：具体目标1：线粒体DNA（mtDNA）基因组将从遗传多样性的灵长类动物测序。编码ETS亚基的蛋白质编码基因将被单独分析，以寻找正达尔文选择的证据。整个基因组将进行遗传学分析。特定目标2：从同一物种中选择编码与mtDNA编码亚基相互作用的蛋白质的核基因进行测序。这些基因将被分析以寻找正选择的证据。具体目标3：相互作用的蛋白质和编码它们的基因将通过基于遗传学的ML方法进行分析，以获得适应性共同进化的证据，该方法包含三级结构信息。这些数据和分析将被用来更全面地检验这一假设，即某些ETS蛋白质经历了对灵长类祖先谱系的积极达尔文选择，从而导致人类。这些信息对于理解人类的能量代谢具有重要意义，特别是与人类进化过程中的大脑扩张有关。此外，关于哪些蛋白质或蛋白质的部分经历了最近的正选择的信息可能有助于确定某些人类线粒体疾病的干预目标。

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.