Comparative Genomics of Peroxisomal Lipid Metabolism

描述(由申请人提供)：人类基因组和环境之间的相互作用塑造了复杂的人类表型的进化。自从人属出现以来，人类及其祖先与环境的相互作用发生了许多重大变化。其中一种互动涉及现代人迁出非洲之前肉类消费的急剧增加。我们假设人类和他们的祖先经历了脂肪代谢基因的选择，以响应饮食的变化。基于已知的这些通路的生理重要性，这些选择性改变可能强烈地影响涉及神经、心血管系统和肝脏的复杂的人类表型。 在这项建议中，我们将采用比较基因组学和功能基因组学方法来确定特定的脂代谢基因和在人类谱系中进行选择的途径。在这里，我们将比较和对比人类和密切相关的灵长类物种(主要是吃水果、吃树叶、吃草或杂食性)的过氧酶体脂肪代谢的数量差异。我们将使用成纤维细胞来检测这些代谢途径中的细胞差异，成纤维细胞是过氧酶体脂肪代谢的已建立的模型系统。在具体目标1中，我们将采用生化方法来量化这些代谢途径在每个物种中的活动。我们将重点关注肉类饮食中丰富的脂肪酸的分解代谢，我们预测这些脂肪酸将显示出依赖于饮食的特定物种的活动。在具体目标2中，我们将采用细胞生物学方法来评估每个物种中的过氧化物体组装和完整性，并与它们的脂质分解代谢率相关联。在具体目标3中，我们将采用基因组学方法来评估过氧物酶基因的表达和对饮食脂质治疗的转录反应。在具体目标4中，我们将采用统计遗传学的方法，对人类和其他灵长类动物的过氧体脂代谢基因的选择进行详细的测试。我们将筛选在人类迁出非洲之前发生的选择性扫描，这可能标志着人类优势等位基因的固定。总体而言，我们将使用各种新开发的功能和比较基因组学方法对人类过氧酶体脂肪代谢的选择性变化进行详细分析，这些方法可以应用于其他研究，检查与人类健康和疾病相关的代谢途径。

DESCRIPTION (provided by applicant): Interactions between the human genome and the environment have shaped the evolution of complex human phenotypes. Since the emergence of the genus Homo, there have been many significant changes in the interactions of humans and their ancestors with their environments. One such interaction involves dramatic increases in meat consumption prior to migrations of modern humans out of Africa. We hypothesize that humans and their ancestors have undergone selection in lipid metabolism genes in response to dietary shifts. Based on the known physiological importance of these pathways, these selective changes could strongly influence complex human phenotypes involving the nervous and cardiovascular systems and the liver. In this proposal, we will take comparative and functional genomics approaches to identify specific lipid metabolism genes and pathways undergoing selection in the human lineage. Here, we will compare and contrast quantitative differences in peroxisomal lipid metabolism in humans and closely related primate species that are primarily fruiteating, leaf-eating, grass-eating, or omnivorous. We will examine cellular differences in these metabolic pathways using fibroblasts, an established model system for peroxisomal lipid metabolism. In Specific Aim 1, we will take biochemical approaches to quantify the activities of these metabolic pathways in each species. We will focus on the catabolism of fatty acids abundant in meat-eating diets which we predict will show species-specific activities dependent upon diet. In Specific Aim 2, we will take cellular biology approaches to evaluate peroxisomal assembly and integrity in each species and correlate with their rates of lipid catabolism. In Specific Aim 3, we will take genomics approaches to evaluate the expression of peroxisomal genes and transcriptional responses to treatment with dietary lipids. In Specific Aim 4, we will take statistical genetics approaches to conduct detailed tests for selection in peroxisomal lipid metabolic genes in human and other primates. We will screen for selective sweeps that occurred prior to the migration of humans out of Africa that could mark the fixation of advantageous alleles in humans. Overall, we will conduct a detailed analysis of selective changes in human peroxisomal lipid metabolism using a variety of newly developed functional and comparative genomic approaches that could be applied towards other studies examining metabolic pathways relevant to human health and disease.