Prather Lecture Series

Dr. Harmit S. Malik, Principal Investigator, Fred Hutchinson Cancer Research Center (FHCRC); Investigator, Howard Hughes Medical Institute; Professor, University of Washington; co-Associate Director, Basic Sciences, FHCRC, to give 2019 Prather Lectures,

November 12, 13, & 14, 2019

 

Harmit Malik

Harmit S. Malik studies 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. A deeper understanding of this phenomenon could have implications for human health, such as providing insights that lead to improved anti-viral drugs. Malik pioneered the study of “evolutionary echoes,” the traces of long-ago viral infections that left their mark on the host immune proteins that combat viruses. Using these echoes, Malik was able to infer the evolutionary influences of ancient, extinct viruses on the immune proteins of primates. This work has helped pioneer the field of paleovirology. A significant research area in the Malik lab is the study of rapid evolution in genes involved in essential cellular processes, such as chromosome segregation and mitochondrial biology. His lab has shown that rapid evolution of centromeric DNA and proteins that are recruited to centromeres can lead to reproductive isolation — the inability to successfully produce offspring — between emerging species and result in defective cell division.

In 2009, Malik was awarded the prestigious Howard Hughes Medical Institute (HHMI) Early Career Scientist award, and he was named an HHMI Investigator in 2013. In 2017, he received the Eli Lilly Prize in Microbiology, the most prestigious prize awarded by the American Society of Microbiology, and in 2019 he was elected to the US National Academy of Sciences. Malik received his BTech in Chemical Engineering from the Indian Institute of Technology, Mumbai, India, and his Ph.D in Biology, at the University of Rochester, NY.

 

Tuesday, November 12
4:00pm
Geological Museum Lecture Hall, 24 Oxford Street

Rules of Engagement: Molecular Arms Races Between Host and Viral Genomes

Prof. Malik studies the causes and consequences of genetic conflicts that take place between different genomes (e.g., host-virus interactions) 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. Antagonistic interactions drive host-virus evolutionary arms-races, which often manifest as recurrent amino acid changes (i.e., positive selection) at their protein-protein interaction interfaces. We investigated whether combinatorial mutagenesis of positions under positive selection in a host antiviral protein could enhance its restrictive properties. We tested ~700 variants of human MxA, generated by combinatorial mutagenesis, for their ability to restrict Thogoto orthomyxovirus (THOV), which is distantly related to the influenza A virus (IAV). We identified MxA super-restrictors with increased binding to THOV NP target protein and 10-fold higher anti-THOV restriction relative to wild-type human MxA, the most potent naturally-occurring anti-THOV restrictor identified. Our findings reveal a means to elicit super-restrictor antiviral proteins by leveraging signatures of positive selection. Although some MxA super-restrictors of THOV were impaired in their restriction of H5N1 influenza A virus (IAV), other super-restrictor variants increased THOV restriction without impairment of IAV restriction. Thus, antiviral proteins like MxA mitigate breadth-versus-specificity tradeoffs that could otherwise constrain their adaptive landscapes.

 

Wednesday, November 13
6:00pm
Geological Museum Lecture Hall, 24 Oxford Street
Free and open to the public
Presented in collaboration with the Harvard Museum of Natural History

Paleovirology: Ghosts and Gifts of Ancient Viruses

Human genomes are ancient battlegrounds of arms races waged between viruses and their hosts for millions of years. Just as historians reconstruct battlefields to better understand historical battles, evolutionary biologists and virologists can reconstruct how ancient viruses affected their hosts by analyzing their ‘fossil’ remains in our genomes. Paleovirology is the study of such extinct viruses. Malik will discuss what the study of these viruses can tell us about old and new viral infections, the role viruses have played in shaping human biology, and the insights they can provide for combating pathogenic viruses today.

This event will be livestreamed on the Harvard Museums of Science & Culture Facebook page. A recording of this program will be available on the HMSC Lecture Videos page approximately three weeks after the lecture.

Thursday, November 14
3:30-4:30pm
Biological Laboratories Lecture Hall 1080, 16 Divinity Avenue
Free and open to the public

Genetic Conflicts During Meiosis Shape Centromeres and Species

Prof. Malik studies the causes and consequences of genetic conflicts that take place between different genomes (e.g., host-virus interactions) 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. The Malik lab studies a variety of ‘arms-races’ which allows him to bring an explicitly broad evolutionary perspective onto the study of rapid evolution in genes involved in essential cellular processes such as chromosome segregation. Based on the unexpected discovery of rapid evolution of centromeric proteins in plants and animals, he and his collaborators first proposed the ‘centromere-drive’ model, in which centromeric DNA element act as selfish genetic elements to exploit asymmetries in female meiosis (in which only one of four meiotic products is chosen) for their own transmission, even at great cost to host fitness. Several aspects of the original ‘centromere-drive’ have now been elegantly demonstrated by other labs, but the question of what drives rapid evolution of centromeric proteins remains unsolved. Using a gene-swap strategy in Drosophila, in which centromeric histones are reverted to an ancestral state, his lab has pioneered a novel strategy to study the causes and consequences of this rapid evolution in vivo. His lab has also shown evidence for dramatic turnover in centromeric proteins, with evolutionarily young genes becoming essential for centromeric function whereas evolutionary old, essential genes can be rendered dispensable. Furthermore, his lab’s findings that centromeric histone duplications allow opportunities for gametic specialization further highlight the inherent differences in centromeric function in somatic versus germline cells in animals. Finally, his lab has shown how unusual genetic conflicts during meiosis may provide a basis of postzygotic reproductive isolation between recently diverged species.