In mammals, cells carry out their work driven by two copies of nearly every gene, one inherited from each parent. If something happens to one gene, the other is usually there to compensate. But for a small number of genes, the two copies rule does not apply. For those genes, only one parent’s copy is turned on,and the other is shut off. This regulatory process leaves little room for error because there is no gene to act as a backup if problems arise.
In mammals, cells carry out their work driven by two copies of nearly every gene, one inherited from each parent. If something happens to one gene, the other is usually there to compensate. But for a small number of genes, the two copies rule does not apply. For those genes, only one parent's copy is turned on, and the other is shut off. This regulatory process leaves little room for error because there is no gene to act as a backup if problems arise.
Although this type of gene regulation, called imprinting, was discovered more than 20 years ago, there are still many unanswered questions about how it works and why it appears to be so important for development. Scientists would like to know more about which types of genes are imprinted and whether imprinting is most important during the early phases of development or whether it is necessary throughout a mammal's lifetime. There is no estimate about how many genes are controlled through imprinting, although recent studies have identified nearly 60 imprinted human and rodent genes.
When you start thinking about genes and behavior, this is one of the very interesting questions. I've been thinking about it for many years, and now is the time when I can work on it.
HHMI investigator Catherine Dulac has long been interested in how genes govern behavior. In recent years, Dulac's research team has identified individual neural circuits in mouse brains that govern behaviors such as courtship and aggression. She and other researchers have wondered to what extent imprinted genes contribute to brain development and behavior. Now, with funding from an HHMI Collaborative Innovation Award, Dulac has assembled a team of Harvard University scientists to sort out how imprinted genes affect brain function.
Dulac and her colleagues will perform the most extensive genome-wide analysis of imprinting ever undertaken. They will perform a scan of every gene expressed in the mouse brain to search for imprinted genes that influence behavior. The researchers—experts in mouse genetics, neuroscience, evolutionary theory, and motivational behavior—will then sort out the contributions that imprinted genes make to brain development and behavior.
“Human and mouse genetics seem to provide some interesting information already about gene imprinting and gene behavior,” says Dulac, citing the human diseases—Angelman and Prader-Willi syndromes—and several mouse disorders controlled by imprinted genes that are linked to behavior problems.
Imprinting is an inherited chemical mark on a gene that shuts it off but does not delete it. Sometimes that mark shuts off the mother's gene, sometimes the father's gene. Which gene is turned on or off appears to be consistent from generation to generation, and it is always inherited from the same parent.
Scientists have some ideas about which parent's gene is activated during imprinting. The most prominent theory—proposed by David Haig, one of Dulac's collaborators on the HHMI project—suggests that the conflicting biological interests of the mother and father are reflected in imprinted genes. For example, Haig posits that it is in the father's interest for his genes to create the largest possible offspring, which would give them the best chance for survival. But for the mother, it is better to promote genes that keep the fetus from getting too big, which saps the mother's strength and could potentially hurt her chances of having more progeny.
So far, research on imprinting has focused on its impact on an animal's fetal development. But, Dulac says, “it is not a big jump to say that these conflicts over getting the resources of mom could also occur in a newborn animal.” Any gene that might represent a conflict between the mother's interests and the father's interests—for example, a gene that regulates how aggressively a newborn suckles its mother—may be subject to inherited imprinting, she says. Genes influencing pain, stress, reward, feeding, sleep, or sexual behavior can all be thought of in this way, Dulac points out.
This idea that behavioral genes might be particularly susceptible to regulation by imprinting has intrigued Dulac for years. In particular, she would like to find out whether the neural circuits in the brain that govern social and motivational behavior are, as she expects, hotspots for the expression of imprinted genes. But as members of her laboratory began studying imprinting, “it was clear that we needed to have more people involved, people with different sets of expertise if we really want to go to the core of the influence of these genes on behavior,” she explained.
In developing a proposal for the HHMI Collaborative Innovation Award, Dulac sought to assemble a team of researchers that could look across the genome to identify specific examples of imprinting's role in shaping or altering behavior—from its evolution to its impact on day-to-day decisionmaking to its role in behavioral diseases. Even the first step of their project is an ambitious one: Dulac and her colleagues plan to sequence all of the genes expressed in the brains of male and female mice, then do the same in their offspring so that her team can trace whether one or both parents' copies of specific genes are turned on. Once they have a catalogue of all of the imprinted genes in the brain, the team will produce genetically modified animals and other tools that they can use to determine the functions of the imprinted genes.
To complete the project, the team will rely on the expertise of each of its members. Naoshige Uchida, an assistant professor in Harvard's Center for Brain Science, studies how neurons combine sensory information with memories of past experience to make decisions. Uchida will use his lab's tools to measure the activity of specific neurons as mice make decisions. By conducting these experiments with genetically modified animals with the imprinted genes turned on or off, he aims to determine precisely how those genes impact neural circuits and behavior.
Bill Carlezon, director of the Behavioral Genetics Laboratory at Harvard's McLean Hospital, studies the role of genetics in behavior and neurological disorders. His lab has developed tests to quantitatively measure the influence of genes on specific behaviors. Using the genetically modified mice developed in Dulac's laboratory, Carlezon will test the roles of imprinted genes in addiction, depression, anxiety, and other disorders by examining how the mice respond to reward or punishment. His lab will also visualize activity inthe animals' brains using magnetic resonance imaging (MRI). The team hopes this effort will turn up genetic pathways that could be targeted for new treatments for these disorders.
These experiments will likely to generate an enormous amount of data, she says, and it will be important to fit their findings into a theoretical framework for genomic imprinting. Haig, one of the world's experts on the evolutionary role of imprinting in promoting the conflicting interests of mother and father in the embryo, will lead this component of the study.
Dulac doesn't really know what the team will find—or even how many genes they will find. Some estimates suggest 600 genes or more could be controlled through imprinting. They also don't know whether they will find differences in the number or type of imprinted genes by sex or age, for example. “When you start thinking about genes and behavior, this is one of the very interesting questions,” she says. “I've been thinking about it for many years, and now is the time when I can work on it.”