Harmit Malik, PhD (Fred Hutch, HHMI) - Webinar

Harmit Malik, PhD (Fred Hutch, HHMI) - Webinar

Butler Seminar Series

Event Date/Location

September 29, 2021 - 12:00 pm to 1:00 pm

Speaker

  • Harmit Malik

    Harmit Malik

    Professor and Associate Director Basic Sciences Division, Fred Hutch
    HHMI Investigator
    HHMI

    Harmit Malik got his BTech, Chemical Engineering, Indian Institute of Technology, Mumbai, India. He then moved to the US to get his PhD in Biology, at the University of Rochester, NY, studying the evolution of retrotransposable elements with Dr. Thomas Eickbush. In 1999, he moved to Seattle to the Fred Hutchinson Cancer Research Center (the “Hutch"), to do his postdoc with Dr. Steve Henikoff. In 2003, he started his own lab at the Hutch, where he is currently a Full Professor & co-Associate Director of the Division of Basic Sciences. In 2009, he was awarded an Early Career Scientist of the Howard Hughes Medical Institute and a Full Investigator in 2013. Harmit Malik studies the causes and consequences of genetic conflicts that take place between different genomes (e.g., host-virus interactions, mitochondrial conflicts with nuclear genomes) or between components of the same genome (e.g., chromosomal competition at centromeric regions). He is interested in understanding these "molecular arms races" and how they drive recurrent genetic innovation, from the perspective of both evolutionary biology and human disease. For example, Malik and his colleagues have used an evolutionary lens to dissect and discover both primate antiviral as well as viral adaptation strategies. By taking advantage of viral ‘fossils’ in animal genomes and intense episodes of ancient host gene adaptation, his work has helped found the field of Paleovirology. His lab has been able to describe functional outcomes of ancient host-virus arms races by resurrecting both host and viral proteins from the evolutionary record. His work has received significant accolades for him and his lab members. Most recently, he was awarded the 2017 Eli Lilly Prize in Microbiology, the most prestigious prize awarded by the American Society of Microbiology and elected to the US National Academy of Sciences in 2019.

Topic

Rules of engagement: molecular arms races between host and viral genomes

The evolutionary battle between viruses and the immune system is essentially a high-stakes arms race. The immune system makes antiviral proteins, called restriction factors, which can stop the virus from replicating. In response, viruses evolve to evade the effects of restriction factors. To counter this, restriction factors evolve too, and the cycle continues, in which both sides rapidly evolve at interaction interfaces to gain or evade immune defense. For example, primate TRIM5α uses its rapidly evolving ‘v1’ loop to bind retroviral capsids whereas the MxA antiviral protein uses its rapidly evolving Loop L4 domain to recognize viruses such as influenza; single mutations in these loops can dramatically improve retroviral restriction. The challenge for the immune system is that mammals do not evolve as fast as viruses. How then, in the face of this disadvantage, can the immune system hope to keep pace with viral evolution? Using deep mutational scanning, we comprehensively measured how single mutations in the TRIM5α v1 loop affect restriction of divergent retroviruses. Unexpectedly, we found that most mutations increase weak antiviral function. Moreover, most random mutations do not disrupt potent viral restriction, even when it is newly acquired via a single adaptive substitution. Our results indicate that TRIM5α’s adaptive landscape is remarkably broad and mutationally resilient, maximizing its chances of success in evolutionary arms races with retroviruses. We also exploit combinatorial mutagenesis at rapidly evolving positions to dissect and enhance the antiviral properties of MxA antiviral proteins, revealing unprecedented capacity for antiviral adaptation and a 'breath versus specificity' tradeoff that constrains their natural evolution.

 

Audience

Restricted to faculty, staff and students at Princeton University

Host

Ricardo Mallarino, Molecular Biology Dept.