The origin, evolution, and dynamics of micropeptides in the immune system

Our immune systems — and those of all animals — are among the most rapidly evolving parts of our bodies, due in part to the evolutionary “arms race” we face against fast-evolving viruses and other pathogens. But how new immune-related genes arise in evolution remains poorly understood. Li Zhao, Ph.D., and Mandë Holford, Ph.D., are leading a project to better understand how immune genes that code for tiny proteins known as micropeptides arise in evolution. The team will characterize immune-related micropeptides in humans and in fruit flies, focusing specifically on micropeptides that play a role in the innate immune system, our first line of defense against pathogens. Humans have both an innate and an adaptive immune system, while insects have only innate immunity. They will also focus on an evolutionarily new micropeptide in the fruit fly to better understand its function in the immune system and how it evolved.  

Affiliated Investigators

Li Zhao, Ph.D.

The Rockefeller University

Li Zhao is an Assistant Professor and Head of Laboratory of Evolutionary Genetics and Genomics at The Rockefeller University. Her lab focuses on understanding the origin and evolution of novel genes and phenotypes. One of the major directions is to use de novo genes, which are originated from non-genic sequences of genomes, as a unique paradigm to decipher the complex relationship between genetic and functional innovation. Since many protein-coding de novo genes produce small proteins or micropeptides, they provide a unique opportunity to investigate the origin, expression regulation, structure, and functions of these novel products. One of the lab’s special interests is to understand how these genes contribute to evolution, health, reproduction, and immune systems. Her lab thus develops and employs a broad spectrum of computational and empirical approaches to generate and analyze large-scale data and uses experimental tools to study these questions in various systems. 

Dr. Zhao received her Ph.D. from Chinese Academy of Sciences, where she studied the evolution of novel genes and genome architecture. During her postdoctoral training with David Begun at University of California Davis, she used computational and population genetic approaches to study the evolution of de novo originated genes within species, revealing patterns of the earliest stages of gene origination. Dr. Zhao is a recipient of the Sloan Research Fellowship (2018) and the Irma T. Hirschl/Monique Weill-Caulier Trust Research Award (2018). She is a Rita Allen Foundation Scholar (2019) and a Vallee Foundation Scholar (2020).

Mandë Holford, Ph.D.

Hunter College

Dr. Mandë Holford is a tenured Associate Professor in Chemistry at Hunter College and CUNY-Graduate Center, with scientific appointments at The American Museum of Natural History and Weill Cornell Medicine. Her research combines biological and chemical techniques to examine venoms and venomous animals. She is particularly interested in using venoms to study rapidly evolving genes and to examine the cellular physiology of malfunctioning signals in pain and cancer. Dr. Holford’s lab applied an evolutionary venomics approach, integrating phylogenetic, transcriptomics, and proteomics, to investigate the evolution of venom in terebrid snails and to characterize their venom peptides. She was first to reconstruct the molecular phylogeny of the group and demonstrate the analgesic and antitumor activity of terebrid peptides. More recently, Dr. Holford has focused on developing invertebrate venom gland model systems that can be genetically manipulated to study the molecular innovation of venom. She is active in science education, advancing the public understanding of science, and science diplomacy. She co-founded Killer Snails, LLC, an award winning EdTech company that uses tabletop, digital, and XR games about nature as a conduit to advance scientific learning in K-12 classrooms. Her honors include being named: a Sustainability Pioneer and Champion Scientist by the World Economic Forum, Breakthrough Women in Science by the Howard Hughes Medical Institute and NPR’s Science Friday, a Wings WorldQuest Women of Discovery Fellow, a Camille Dreyfus Teacher-Scholar, an NSF CAREER awardee, a AAAS Science & Technology Policy Fellow, and Fellow of the California Academy of Sciences. She received her PhD from The Rockefeller University with Tom Muir.