Harmit Malik (Fred Hutchinson Cancer Research Center)
MolBio Seminar Series
Harmit Malik is a member in the Division of Basic Sciences at the Fred Hutchinson Cancer Research Center in Seattle. He is also an Early Career Scientist of the Howard Hughes Medical Institute and Affiliate faculty at the University of Washington School of Medicine. He obtained his PhD in biology from the University of Rochester, USA in 1999. There, he worked with Thomas Eickbush on the evolutionary strategies of retrotransposable elements. In particular, he focused on R1 and R2 non-LTR retroposons that insert site-specifically into the ribosomal DNA of most arthropods, creating a fascinating paradigm of 'selfish DNA'. His graduate thesis also showed that in contrast to other mobile elements, non-LTR elements had been vertically inherited for hundreds of millions of years, and could be dated back to early eukaryotic evolution. As a postdoctoral fellow with Steve Henikoff, at the Fred Hutchinson Cancer Research Center he focused on the 'centromere paradox'- the extremely high rate of evolution of centromeric DNA (and as he discovered, proteins) in spite of extreme conservation of function. Together with Dr. Henikoff, he proposed the centromere-drive model in which centromeres in plants and animals compete with each other for transmission in female meiosis, since only one of the four meiotic products is transmitted to the next generation. Such asymmetry favors transmission of 'selfish' centromeres in female meiosis, even though it results in subsequent male sterility. This selects for essential centromeric and heterochromatin proteins to evolve rapidly to suppress centromere-drive. Dr. Malik started his own lab at the Fred Hutchinson Cancer Research Center in 2003 and has focused on these and other examples of genetic conflicts. His lab is testing the centromere-drive model as well as the possibility that such intrinsic conflicts for an essential process of chromosome segregation can result in rapid onset of postzygotic isolation between incipient species.
Dr. Malik, along with his collaborators Dr. Michael Emerman and Dr. Adam Geballe, has also dissected the evolutionary history of host-virus interactions between primate genomes and retroviruses or poxviruses. His lab's evolution-guided functional virology approach has revealed not just an ancient history of genetic conflicts facing primate antiviral genes, but also the means to identify the specificity domains by virtue of signatures of rapid evolution. These case studies of antiviral genes have revealed many common 'evolutionary rules' of genetic adaptation, using which it may be possible to even infer the action of past viral infections, even those that may not have left imprints in host genomes- a term he coins indirect 'paleovirology' (study of ancient viruses). More recently, his lab has discovered that one previously unappreciated form of viral adaptation is via 'gene-accordions' that facilitate acquisition of adaptive alleles.
Genetic Conflicts: The usual suspects and beyond
The eukaryotic cell has been traditionally viewed as an exquisitely designed symbiotic network of genes in co-evolutionary equilibrium. However, several fundamental features of our genes and genomes belie the expectation that they have reached an optimal functional state. Instead, a view is emerging that eukaryotic genomes harbor a conglomerate of different genetic entities, each with their own agenda and each locked in conflict with other genetic entities for evolutionary dominance. My lab is interested in understanding two forms of genetic conflict: intrinsic (within genome) conflicts that shape eukaryotic genome architecture, and extrinsic (between genomes) conflicts that shape genes involved in host-pathogen interactions. I will describe our studies of the antiviral protein PKR and its conflict with the poxviral antagonist K3L. I will also describe our studies on an ancient conflict between centromeric proteins and DNA, two essential components of the chromosome segregation apparatus in eukaryotes. Such conflicts could have direct consequences on post-zygotic reproductive isolation between incipient species.
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