Harvard University - Department of Molecular & Cellular Biology


by Cathryn Delude

September 22nd, 2011

Hopi Hoekstra

The three heads on the wall of Hopi Hoekstra’s office belong to the same species of blesboks, a South African antelope with a characteristic blaze on the snout. But one is dark brown, the second medium brown and the third pale – a dramatic example of the color pattern variation that Hoekstra studies in a smaller species, deer mice in the genus Peromyscus. “Deer mice are the most abundant mammal in North America and live in almost every habitat, so there’s great opportunity for adaptation to novel environments,” she explains. That gives her a great opportunity to look for the DNA changes responsible for adaptive variation.

“I study natural variation not just because there’s more variation in nature than in the lab, but also because I’m interested in what happens in the wild,” says Hoekstra. She strives to connect phenotypic variation to its underlying genetic, molecular and developmental changes in order to understand how evolutionary change occurs and how genes interact as they evolve. How many genes are required for, say, a brown mouse to become black or blond as it colonizes lava flows or sandy beaches? Are the same genes involved in convergent evolution, such as when lizards and shrews both evolved a similar toxin in their venom from an originally harmless digestive enzyme? Are the genetic changes regulatory or structural? Do they affect protein synthesis or gene expression?

Her innovative work in this area has earned her tenure at Harvard with a joint appointment in the Departments of Molecular and Cellular Biology (MCB) and Organismic and Evolutionary Biology (OEB). She feels at home in both the MCB and OEB habitats: “I may be the most molecular of the organismic department and the most organismal of the molecular department.” She’s equally comfortable out in nature, crouching near mouse burrows in far-flung dunes, deserts and beaches that have undergone relatively recent changes, forcing animals to evolve new traits...though these days her 6 graduate students and 8 post-doctoral researchers do more of that nitty-gritty work.

Appreciating Owl Pellets, Cockroaches and Gophers

Hoekstra began getting her hands dirty long before she settled on this sometimes-grubby line of research. Her mother, a teacher from Holland, loved the outdoors and took young Hopi on hikes in a reserve near their home in Stanford Hills, California. They collected owl pellets so they could reconstruct the skeletons of devoured mice…but that’s not what inspired Hoekstra to become a natural biologist. “I wanted to be the ambassador to Holland,” she says. She entered UC Berkeley as political science major, but switched when she discovered the thrill of discovery doing research.

She first worked with a biomechanist studying the physics of cockroaches’ running on treadmills for bio-inspired robots. Senior year, she moved up the evolutionary tree – catching gophers – while working with a mammalogist who showed her the possibility of combining lab and fieldwork. “These two research experiences were so formative that I’m committed to making research opportunities available to undergraduates here at Harvard,” she says. “The research gives a meaningful context to the class material.”

Follow the Literature

Hoekstra developed a fascination with the wealth of descriptive natural history information amassed by naturalists from previous centuries. “Although many questions are the same – how does biodiversity evolve and how is it maintained – now we can use molecular tools to tackle these questions,” she says. For her PhD work at the University of Washington on sex chromosome evolution, she studied South American mice that she had read about in the classic cytogenetic literature. For post-doctoral work at University of Arizona, she studied pocket mice that had evolved black coats after colonizing various lava flows in Arizona and New Mexico, some less than 10,000 years ago. “The mice had either tan or melanic fur with no in between,” she says. “That suggested a mutation in a single gene controls the color difference” – which she later helped identify.

But pocket mice are too territorial to breed in the lab, so when Hoekstra set up her own lab, first at UC San Diego in 2003 and then at Harvard in 2007, she began studying the more willing deer mice. “Deer mice are close enough to laboratory mice that we can borrow already establishedgenetic and genomic tools,” she says. “There’s also amazing natural history literature describing them!”

Coats of Many Color Patterns

These descriptions led her to, among other habitats, Florida, where dark-coated mice had evolved blond coats when they moved on to the sands of newly formed barrier islands about 6,000 years ago. To determine how such adaptations arose, she practices “forward genetics”: start with different phenotypes (traits) and work down to the underlying genetic variations. In this case, she captured mice with different coat color patterns and crossbred them in the lab. Next she examined the genes of parents and offspring through several generations, and then correlated the genetic differences with the phenotypic ones. In that way her lab discovered three genes that together explain most of the variation in coat color and reconstructed their evolution: selection acted on the Agouti gene first, then Mc1r and then Corin. She also learned how they interact: dark variations of Agouti trump light variations of Mc1r, for example.

Her lab also discovered an example of convergent evolution of the Agouti gene by studying other blond deer mice inhabiting Nebraska’s Sand Hills, which formed around 8,000 years ago. Both the Florida and Nebraska mice have changes that affect Agouti gene expression, but in a different way and at different developmental stages. In Florida mice, the change in Agouti slows down the maturation of the pigmented melanocytes and their migration to hair follicles, which affects the distribution of pigments across the body. Thus, small changes in the expression pattern of Agouti in a developing embryo lead to large changes in the adult color pattern. In Nebraska mice, by contrast, Agouti affects the distribution of pigment on individual hairs, which makes the mouse appear more golden, and this change occurs in adults.

Now Hoekstra’s lab is trying to identify the precise DNA base-pair changes responsible for these changes in Agouti expression. Do they result from the evolution of new regulatory elements, an increase in the binding affinity of existing elements, or a deletion mutation in a repressor element? “The ultimate test is to see if we can insert a mutation from a light colored mouse into a dark mouse and make them lighter.”

Adapting Behaviors

Few people doubt that genetic variations underlie various physical traits, but what about behavior? Mice in different habitats, it turns out, also have different behaviors. For example, they build burrows of different sizes and shapes, perhaps due to different predators. They also produce different “songs” – high pitch ultrasonic vocalizations that her lab records and analyzes. These are instinctive songs, not learned, so the variations among populations of mice must be genetic. Hoekstra’s lab is using the same crossbreeding and genetic analysis approach to determine the contribution of genes to the natural variation in these behaviors too.

Deer mice also differ in mating behavior – some populations are monogamous and some promiscuous – and in parenting styles. Similar variations in the prairie vole’s social behavior have been traced to changes in a cellular receptor for the hormone vasopressin, which binds the hormone oxytocin. Hoekstra’s group has ruled out this mechanism in deer mice and is working to understand how monogamy can evolve through a different set of genetic changes.

Racing Sperm and Choosy Females

Some of Hoekstra’s findings just can’t help but amuse. In 2010, her lab reported that a male deer mouse in promiscuous populations does not just compete for access to females before mating. After mating, his sperm also compete for access to the female’s egg – and a chance to pass of genes to a new generation. To help in this race, the sperm from one male form clumps, which allows them to swim faster. To form these bands of brothers, the sperm discriminate kin from competitor sperm, by mechanisms Hoekstra is still investigating. This sperm clumping does not occur in monogamous populations, presumably because it carries no evolutionary advantage.

For female mice, though, there is an evolutionary advantage to being choosey. Hoekstra is looking at the role of olfaction in this selective female behavior with Catherine Dulac, an expert on olfaction. They hope to determine its genetic control and the evolution of olfactory receptors. Hoekstra is collaborating with several other MCB researchers to complement their work on laboratory model animals.

Amazing Teaching

In addition to being an outstanding scientist, Hoekstra also excels at teaching. She has just received a 2011 Fannie Cox Prize for Excellence in Science Teaching, which recognizes outstanding teaching in introductory science courses – in her case evolutionary biology (OEB 53). A faculty committee comprised of members from across the sciences at Harvard recommends recipients based on their ability to inspire students, instill in them a passion for science, and effectively communicate complex ideas. The committee noted that enrollment in OEB 53 has more than doubled since she began co-teaching it with Andrew Berry in 2008. “Students think she is fantastic,” the committee wrote, and they call the class “awesome” and “amazing.” The award consists of a $10,000 personal award and $40,000 in unrestricted support for teaching and research.

Curating Mammals

These are just some of Hoekstra’s diverse studies, and she has already published more than 40 papers since completing her PhD in 2000. Though she still likes spending time out in the field, she also enjoys working in another habitat: Harvard’s Museum of Comparative Zoology, where she is curator of the mammal collection. This collection has specimens going back to the 1830s, including hippopotamus skulls and gorilla skeletons. She is currently developing a public exhibit to highlight the molecular and genetic studies of these specimens. In what may come as no surprise, she is working on a piece on the language of color and how natural selection causes color variation.

[September 22nd, 2011]

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