Role of parasitic selection in the evolution of human hemoglobin mutations

疟疾是人类进化的一股重要力量。这种疾病的压力推动了人类几种抗疟疾特征的进化，其中最著名的是镰状血红蛋白。尽管几十年来血红蛋白多态性一直与抗疟疾特性有关，但这些突变如何防止感染仍然是一个谜。我的实验室出现了一条令人兴奋的新研究路线，指向一种涉及疟疾寄生虫如何消化血红蛋白的分子细节的新机制。最近，我们发现赋予寄生虫耐药性的突变显著降低了寄生虫的适应性，因为它们干扰了血红蛋白的消化。有趣的是，这些与健康相关的代谢变化对源自ß血红蛋白氨基末端的肽的加工有显著影响，这与人类镰状性状的位点相同。随后，我们发现寄生虫优先消化野生型而不是镰状血红蛋白，这表明该分子的保护特性可能与其内在的消化率有关。本研究的目的是利用新一代高分辨率质谱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。我们的方法是构建寄生虫血红蛋白代谢的详细消化图，并利用基因工程寄生虫确定个体酶对这一途径的贡献。这种酶/肽关联图将使我们能够解开这种复杂的半有序途径，并将代谢扰动与特定酶联系起来。一旦建立了这些地图，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度成本。如果成功，这个项目将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疾病的基本代谢途径；3)阐明塑造我们物种进化的最重要的力量之一。我正在申请资金支持三名研究生和两名本科生加入我这个令人兴奋的新研究领域。

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 ß 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.