Malaria is one of the deadliest infectious diseases in the world. Despite significant control and efforts, nearly half of the global population still lives in areas at risk of contracting malaria. According to the latest estimate by the World Health Organization, malaria causes nearly 250 million infections and over 600000 deaths annually. Little known is that in addition to having a huge impact on modern humans, malaria has also strongly influenced the evolutionary history of humanity. Megan Mitchell, a researcher at the Max Planck Harvard Research Center (MPI-EVA), stated that the "traces" of malaria have been written into the human genome, and the genetic variations that cause devastating blood diseases such as sickle cell disease persist in the human population because they "endow" partial resistance to malaria infection. Despite years of research on malaria, the origin and spread of the two deadliest malaria parasites, Plasmodium falciparum and Plasmodium vivax, have remained a mystery. Meanwhile, because malaria infection does not leave clear and visible traces in human skeletal remains, historical records are also difficult to interpret. Now, a recent development in the field of ancient DNA suggests that human teeth can preserve traces of pathogens present in the blood at the time of death, providing an opportunity to study diseases that are typically unseen in archaeological records. In order to explore the mysterious history of malaria and eradicate the disease, an international research team from 80 institutions and 21 countries reconstructed ancient malaria parasite genome data from 36 malaria infected individuals. These data span across 5500 years of human history. The recent research findings published in the journal Nature provide an unprecedented opportunity to study the spread of malaria worldwide and its historical impact at the global, regional, and even individual levels. Tracking the genetic footprint of Plasmodium falciparum in the Americas Malaria is an endemic disease in tropical regions of the Americas today. Scientists have long debated the transmission pathway of malaria parasites into the Americas. The research team analyzed the ancient DNA of an individual infected with malaria this time. This individual comes from Lake Momias, located in a remote cloud forest in the eastern Andes Mountains of Peru. Genomic analysis shows that the strain of Plasmodium vivax in Lake Momias bears striking similarities to ancient European strains of Plasmodium vivax. The research results indicate that European colonizers spread the species to the Americas within about a century after arriving there. Due to the impacts of war, slavery, and population displacement, infectious diseases including malaria devastated Native Americans during the colonial period, with mortality rates as high as 90% in some areas. It is worth noting that the team also discovered a genetic link between the Lake Momias strain and the modern Peruvian Plasmodium vivax population 400 to 500 years later. The data shows that pathogens have flourished here and established "endemic foci", producing parasites that still infect Peruvians today. Trade has led to high-altitude infections on the other side of the world, and the research team unexpectedly discovered the earliest known case of Plasmodium falciparum malaria at the Jokopani site in the Himalayan highlands (around 800 BC). The site is located along the Kaligandaki River Valley in Nepal, at an altitude of 2800 meters, which theoretically exceeds the habitat range of malaria parasites and mosquitoes. This region is cold and dry Christina Warina, associate professor of anthropology at Harvard University and leader of the MPI-EVA team, said, "Parasites and mosquitoes that spread malaria cannot survive at this altitude. This raises a key question: how did this Jokopani person contract malaria and ultimately die?" Genetic analysis shows that the infected person is a local male with genes adapted to living at high altitudes. At the same time, archaeological evidence suggests that local residents actively participated in long-distance trade. We think these areas are remote and difficult to reach today, but in fact, the Kaligandaki River Valley is a road that spans across the Himalayas Professor Mark Aldendorf from the University of California, Merced, said that his excavations in the area revealed long-distance trade. "People don't have to walk very far to reach the low-lying and poorly drained areas of Nepal and the Terai plain in India, where malaria flows." The study suggests that the man went to lower altitude malaria endemic areas for trade or other purposes, then returned or was brought back to Jokopani, where he was later buried. The detailed information revealed by ancient DNA provides clues for the countless ways in which infectious diseases such as malaria have spread in the past, which is also the basis for the formation of the current disease pattern. The reconstruction of ancient DNA into a new tool for disease resistance is now at a crossroads in the fight against malaria. Thanks to advances in mosquito control and coordinated public health campaigns, malaria deaths reached a historic low in the 2010s. However, the emergence of drug-resistant parasites and insecticide resistant vectors for malaria has the potential to reverse decades of progress, while climate change and environmental destruction will also make new regions vulnerable to attacks from malaria vector species. The research team hopes that the results of ancient DNA reconstruction can provide additional tools for combating or even eradicating this public health threat. This is the first time we have been able to explore the diversity of ancient parasites Johannes Kraus, Director of Archaeological Genetics at the Max Planck Institute for Evolutionary Anthropology, said, "We have seen how population movements in the past spread malaria, just as globalization has made malaria free countries and regions more susceptible to reintroducing malaria today. Studying ancient diseases such as malaria will provide a new window into understanding the microorganisms that still affect the world today