Harmit Malik studies the battlefield of evolutionary conflict. Within each organism, genes compete for evolutionary dominance in the genome and the opportunity to be passed on to the next generation. Genes also fend off the assaults of outside invaders such as bacteria and viruses. By comparing the genomes of different organisms and reconstructing their evolutionary histories, Malik describes the biological forces that shape essential DNA elements as well as the ongoing struggle between pathogens and their hosts.
Biology was a shift for Malik. He arrived at the University of Rochester in 1993 with an undergraduate degree in chemical engineering from the Indian Institute of Technology Bombay and was soon assigned to teach an introductory genetics course. Although Malik had started taking biology courses in India after reading The Selfish Gene by Richard Dawkins, he had never formally studied genetics.
Malik, described by a colleague as someone who can absorb and integrate everything he has ever read or heard, accepted the challenge. He stayed a chapter ahead of his students in the textbook, explained everything as simply as he could, and won awards for his teaching.
At the same time, Malik began studying the prototypical example of so-called selfish genes, which exploit their host organism for self-perpetuation: They are the pieces of DNA known as retrotransposons that lurk in the genomes of plants and animals and try to insert copies of themselves elsewhere in their host's genome. Most geneticists had assumed that retrotransposons spread from one organism to another by transferring to new hosts like viruses over the course of evolution. Malik proved otherwise. He analyzed the DNA sequences of retrotransposons in different species of Drosophila and showed that they must have been present in the evolutionary progenitor of fruit flies. Then, he compared retrotransposons in different organisms, tracing their lineage to the first eukaryotes—the single-celled ancestors of plants and animals. "We were basically able to extend their history over more than a billion years of evolution," he says. This surprising result, from his graduate studies, has since become the standard textbook account of retrotransposon history. He was later able to show that retroviruses likely arose by virtue of a different lineage of retrotransposons hijacking the infection-causing envelope genes from other types of viruses.
Malik traveled to Seattle for a postdoctoral position with HHMI investigator Steven Henikoff at the Fred Hutchinson Cancer Research Center. Both were intrigued by parts of our chromosomes, such as the centromeres that bind pairs of chromosomes together after they reproduce. If they are so central to cellular function, wouldn't changing them be fatal? Surprisingly, data indicated that instead of resisting evolutionary change, these regions were evolving with unexpected rapidity.
To estimate rates of evolutionary change in the DNA of centromeres, which are repetitive sequences that do not code for proteins, Malik looked at the proteins that attached to these regions as they function. These proteins have evolved at a high rate, indicating that they change quickly to keep up with changes in the centromeres. Malik and Henikoff have proposed that centromeres compete with each other during the cell divisions that are the precursor to forming eggs. This process drives rapid evolutionary change. Centromeres "try to get a step ahead of their cousins in this evolutionary game of persistence," says Malik. "There is all this wonderful biology that we can explain based on this selection." For example, Malik and Henikoff have suggested that the rapid evolution of centromeres may contribute to the formation of new species, because rapid changes in the centromeres may cause reproductive incompatibilities between closely related subspecies, making it difficult for them to interbreed.
Now running his own lab at the Fred Hutchinson Cancer Research Center, Malik has broadened his research to look at the "arms races" that occur between pathogens and their human hosts. When a virus or bacterium causes a potentially lethal disease in humans, genes that encode pathogen-fighting proteins evolve to fight the invader. The result is a sort of genetic scar—alterations of a gene that memorialize its battle with a pathogen. Malik and his colleagues have identified several such genes in humans and primates that bear these evolutionary marks. For example, ancestral great apes may have had genetic variants that protected them from HIV infection but lost bouts with similar PtERV viruses 4 million years ago. Humans apparently were never exposed to the PtERV viruses or evolved to defeat them but today are susceptible to HIV.
Malik sees the human genome as a tapestry documenting past evolutionary conflicts, whether with internal parasites like retrotransposons or external threats like viruses. The structure of our genome reflects a "negotiated truce," he says, and the best way to understand that truce is to reconstruct the events that produced it. "Understanding the terms of this armistice is essential," he argues "because the respite is likely short-lived and, when broken, will lead to human disease."
