Harmit Malik

Member, Division of Basic Sciences, Fred Hutchinson Cancer Research Center
Investigator, Howard Hughes Medical Institute
Affiliate Professor, Department of Genome Sciences

phone: (206) 667-5204
Fred Hutchinson Cancer Research Center, A1-162, Box 358080
hsmalik [ a t ] fhcrc.org
website

Research:

Genetic Conflict

Our genomes are a tenuous conglomerate of different genetic entities, each trying to maximize their own evolutionary success, often at great cost to their genomic neighbors. As expected, this conflict can create problems for the host organism. My lab is interested in evolutionary studies of genetic conflict to gain insight into their mechanisms and consequences. For this purpose, we study centromeres, mobile genetic elements and rapidly evolving proteins in Drosophila.

Centromeres are crucial for the faithful segregation of genetic information in eukaryotes, but they remain the most mysterious part of our genomes. In both animal and plant meiosis, in the process of forming an egg, of four meiotic products, only one becomes the egg, while the other three are evolutionary dead-ends. There is intense competition between various chromosomes, likely through their centromeres for success into the egg. Our hypothesis is that this results in the rapid gain of centromeric satellites often with deleterious consequences to the host. For instance, in humans, Robertsonian fusions (chromosomes fused at their centromeres) are transmitted more frequently in women, but male carriers of these fusions are partially to completely sterile. We study the rapid evolution of centromeric components to gain a better understanding of aneuploidy events (commonly observed in cancer cells) and to answer one of the long-standing questions in biology: how do two species evolve from one?

Mobile genetic elements are ubiquitous and constitute large fractions of eukaryotic genomes. They are the classical example of genomic mercenaries, interested in their own evolutionary success. We study the evolutionary origins of different classes of transposable elements and their consequences to host fitness and genome organization. We have been concentrating on the evolutionarily and medically important transition of a non-viral retrotransposon to an infectious retrovirus, using models in Drosophila and C. elegans. I have discovered a Drosophila host gene (Iris) homologous to the envelope genes of both insect baculoviruses and the gypsy and roo retroviral lineages. This gene has been present as a host gene in insect genomes for at least 250 million years (since the origin of Diptera) and may play a crucial role in membrane transport in female oogenesis.

Adaptively evolving proteins have been found as a consequence to genetic conflict, including host-parasite interactions (ex. Immunoglobulin, viral envelopes). Recent studies have found that a large number of ?speciation? genes encode either DNA-binding proteins or even components of the nuclear pore complex. My lab has initiated cytological and functional studies with the ultimate aim of understanding what selective pressures drive the adaptive evolution of these classical intra-cellular proteins (i.e. what genetic conflcit are they subject to). This will further our understanding of the role selection plays in the shaping of our genomes, and potentially expand the list of categories to which rapidly evolving proteins can belong.

Selected Publications:

Sawyer, S. L., Emerman, M. and Malik, H. S. (2004) Ancient adaptive evolution of the primate antiviral DNA editing enzyme, Apobec3G. PLoS Biology 2: e275.

Sawyer, S. L., Wu, L. I., Emerman, M. and Malik, H. S. (2005) Positive selection in primate TRIM5a identifies a critical species-specific retroviral restriction domain. Proc. Natl. Acad. Sci. USA 102: 2832-2837.

Malik, H. S. and Henikoff, S. (2005) Positive selection of Iris, a retroviral envelope-derived host gene in Drosophila melanogaster. PLoS Genetics. 1: 429-443.

Kaiser, S. M., Malik, H. S., and Emerman, M. (2007) Restriction of an Extinct Retrovirus by the Human TRIM5a Antiviral Protein. Science 316: 1756-1758.

Rodriguez, M. A., Vermaak, D., Bayes, J. J., and Malik, H. S. (2007) Species-specific positive selection of the male-specific lethal (MSL) complex that participates in dosage compensation in Drosophila melanogaster. Proc. Natl. Acad. Sci. 104: 15412–15417.

additional publication listings available via PubMed