Evolutionary Biology, Genetics
Dr. Hoekstra is also Alexander Agassiz Professor of Zoology in the Department of Organismic and Evolutionary Biology and the Department of Molecular and Cellular Biology as well as Curator of Mammals at Harvard's Museum of Comparative Zoology.
The Molecular Basis of Evolutionary Change in Morphology and Behavior
Like many biologists, Hopi Hoekstra works with mice. But she does not use laboratory strains bred specifically for experimental consistency. Rather, she is unraveling the tangled, messy, adaptive genetics of wild deer mice. By studying them in the lab and in their natural environments, Hoekstra's research touches on evolution, development, behavior, neurobiology, and genetics.
It's not where she thought she'd be when she started college. As an undergraduate at the University of California, Berkeley, Hoekstra began as a political science major. She wanted one day to be the US ambassador to Holland, where her parents grew up. After a stint in a biomechanics lab, however, where she spent time running cockroaches on treadmills, she caught the science bug. "I didn't particularly like cockroaches or even physiology or biomechanics," she says, "but I fell in love with the research process itself."
For Hoekstra, it's all about discovery. "I want to know how things work—not just at the molecular level, not just at the ecological level, but everything in between. I want a complete story." She's been working to fill in that story ever since and is linking genetic variation to behavioral variation in both lab and natural mouse populations. "In some ways," she says, "I see this as a next major frontier."
As part of her postdoctoral work in Michael Nachman's lab at the University of Arizona in Tucson, she helped identify the molecular basis of coat-color variation in rock pocket mice. Rock pocket mice are found in two color variants, light and dark, which affect their vulnerability to owls and other predators. The dark mouse is better camouflaged among dark lava rock, and the light mouse blends into a light sandy desert. Hoekstra and colleagues found that a mutation in a cellular receptor for melanin altered the protein's activity, thereby changing the rodents' pigmentation and affecting their survival. The findings were the first to show how a simple DNA base-pair change can influence fitness in a natural population.
In starting up her own lab—first at the University of California, San Diego and then at Harvard University—Hoekstra wanted to establish a new animal-model system in which she could study the genetics of adaptation more deeply. She decided to study deer mice (Peromyscus) for several reasons: they can be bred in the lab, they're closely related to lab mice (and can therefore share their genomics resources), yet—unlike lab mice—deer mice are incredibly diverse, with numerous species in a variety of habitats.
Hoekstra began by using both field and lab approaches to show how individual and cumulative genetic changes can cause fast, dramatic variation in the animals' coat color. "One of the hallmarks of work in our lab is that it's very integrative," she says. "We did experiments in the field that show that color matters for survival. We did genetics in the lab to identify the genes, pharmacological assays to show how mutations cause change in receptor function, and population genetics to unravel the evolutionary history of the mutations. It's an example of how we try to understand the complete story, from organism and environment down to genetics and molecular mechanism."
Hoekstra's emphasis on integrative studies has potential implications for understanding human disease, too. One of the genes involved in mouse coat color turned out to be similar to a gene that, in humans, contributes to skin pigmentation and skin cancer susceptibility.
Now her lab is veering into even more difficult territory: the genetics and evolution of behavior. To quantify behavior—something usually categorized as qualitative—Hoekstra has been studying mouse burrows, which vary in length and the presence or absence of an escape route. She has identified four genetic regions involved in the building of large, complex burrows. She's also looking at sexually selected traits, such as sperm morphology and behavior, to understand how the involved genes affect not just survival but the reproductive ability of mice.
Hoekstra knows that her work has an expansive range, but that's how she likes it. On the grand scale, she says, she's interested in the biggest possible question: "How do you go from a genome to producing an organism?" she asks. "We're interested in the genes that matter for an organism to survive and reproduce in the wild. And, with the genes in hand, we can then go after mechanism—understanding how these changes evolve and work at the molecular level."