Role of parasitic selection in the evolution of human hemoglobin mutations

* 疟疾是人类进化的主要力量。来自这种疾病的压力推动了人类几种抗疟特性的进化，其中最著名的是镰状血红蛋白。尽管血红蛋白多态性与抗疟疾特性有关已有数十年，但这些突变如何防止感染仍然是一个谜。我的实验室里出现了一个令人兴奋的新研究方向，它指出了一种新的机制，涉及疟疾寄生虫如何消化血红蛋白的分子细节。最近，我们发现，赋予寄生虫抗药性的突变会显著降低寄生虫的适应性，因为它们会干扰血红蛋白的消化。有趣的是，这些与适应性相关的代谢变化对源自β血红蛋白氨基末端的肽的加工有显著的影响，β血红蛋白氨基末端与人类镰刀性状相同。随后，我们发现寄生虫优先消化野生型镰状血红蛋白，这表明这种分子的保护特性可能与其内在的消化率有关。本研究的目标是使用新一代高分辨率质谱方法系统地评估血红蛋白突变，蛋白质消化和寄生虫适应性之间的关系。我们的方法是构建一个详细的消化地图的寄生虫的血红蛋白代谢，并确定个人酶的贡献，这一途径使用基因工程寄生虫。这种酶/肽关联图将使我们能够解开这个复杂的半有序途径，并将代谢扰动与特定的酶相关联。一旦这些图谱构建完成，我们将系统地评估镰状血红蛋白和其他人类突变对寄生虫营养的影响。我们还将使用一种令人兴奋的基于同位素的新方法来测量血红蛋白突变的适应性成本。如果成功，该项目将1）建立新一代的分析工具，使研究人员能够研究完整细胞中的蛋白质代谢，2）阐明世界上最致命的寄生虫病的基本代谢途径，3）阐明塑造我们物种进化的最重要力量之一。我要求资金支持三名研究生和两名本科生加入我在这个令人兴奋的新的研究线。

*Malaria is a major force in human evolution. Pressure from this disease has driven the evolution of several antimalarial traits in people, the best known of which is sickle hemoglobin. Although hemoglobin polymorphisms have been linked to antimalarial properties for decades, how these mutations protect against infections remains a mystery. An exciting new line of research emerging from my laboratory points to a novel mechanism involving the molecular details of how malaria parasites digest hemoglobin. Recently, we showed that mutations conferring drug resistance to parasites significantly reduce parasite fitness because they interfere with hemoglobin digestion. Intriguingly, these fitness-linked metabolic changes have a pronounced effect on the processing of peptides originating from the amino terminus of β hemoglobin—the same locus as the human sickle trait. Subsequently, we have found that parasites preferentially digest wildtype over sickle hemoglobin, which suggests that the protective properties of this molecule may relate to its intrinsic digestibility. The goal of this research is to systematically evaluate the relationship between hemoglobin mutations, protein digestion, and parasite fitness using a new generation of high-resolution mass spectrometry methods. Our approach is to construct a detailed digestion map of the parasite's hemoglobin metabolism and identify the contributions of individual enzymes to this pathway using genetically engineered parasites. This enzyme/peptide association map will allow us to unravel this complex semi-ordered pathway and associate metabolic perturbations with specific enzymes. Once these maps have been constructed, we will systematically evaluate the impact sickle hemoglobin, and other human mutations, have on the parasite's nutrition. We will also use an exciting new isotope-based approach for measuring the fitness cost of hemoglobin mutations. If successful, this project will 1) establish a new generation of analytical tools that will allow researchers to investigate protein metabolism in intact cells, 2) elucidate an essential metabolic pathway in the world's most deadly parasitic disease, and 3) shed light on one of the most significant forces that have shaped the evolution of our species. I am requesting funds to support three graduate students and two undergraduate students to join me in this exciting new line of research.**