Howard Hughes Medical Institute 2010 Annual Report

HHMI investigator Catherine Dulac

HHMI investigator Catherine Dulac

Understanding Our Biased Genes

In an ambitious feat that coupled scientific collaboration with sheer labor, HHMI investigator Catherine Dulac took a big step this year toward understanding the complicated genetic underpinnings of behavior in the brain. For more than 1,300 genes active in the mouse brain, her team found, there is a significant bias as to which copy is active—the one inherited from the mother or the one that came from the father.

For the most part, the cells of sexually reproducing organisms bear two copies of every gene, one from each parent. Usually, both copies behave similarly. But sometimes, one parent’s copy dominates while the other stays silent, never producing a protein, or producing many fewer than the other copy.

This phenomenon, called imprinting, was first recognized 20 years ago as an epigenetic mode of gene regulation unique to mammals and flowering plants. The list of genes to which it applies has since grown steadily—albeit too slowly to satisfy Dulac.

A neuroscientist at Harvard University, Dulac suspected imprinting was particularly influential in the brain. According to a popular theory proposed by evolutionary biologist David Haig, imprinted genes in mammals reflect evolutionary conflicts of interest between an organism’s mother and father. An infant that suckles aggressively, for example, might have a better chance of surviving to pass on both parents’ genes but places a disproportionate burden on the mother so that she is less likely to bear more young.

Such asymmetry could be important in a variety of traits, but Dulac suspected it would be especially so for genes that influence behavior.

Until recently, about 100 imprinted genes had been discovered in mice, but the necessary labor and expense had discouraged a systematic search. Dulac was convinced that understanding the relationship between genes and behavior required an understanding of which genes are subject to imprinting, so she rallied her lab for a comprehensive survey of the mouse brain.

The work would require not just additional resources but also new kinds of expertise. So she assembled a team of Harvard scientists that together would be well equipped for the job.

Naoshige Uchida would use his lab’s tools to measure how the imprinted genes influence the activity of specific neurons as mice make decisions. Geneticist Bill Carlezon would measure the influence of genes on specific behaviors and test the roles of imprinted genes in addiction, depression, anxiety, and other disorders and visualize activity in the animals’ brains. And Dulac recruited Haig, who would be instrumental in fitting the team’s findings into a theoretical framework for genomic imprinting.

A Collaborative Innovation Award from HHMI ensured that each team member would have the resources needed for the project.

The first findings to emerge from the collaboration have altered the scale on which Dulac and her colleagues think about imprinting. Before the analysis, the team had speculated that several hundred genes in the brain might be subject to imprinting. Instead, they found 1,308. Furthermore, their results indicate that, even for a single gene, imprinting does not always work the same way: A gene’s bias can shift from favoring one parent to the other during an animal’s life and may differ depending on the region of the brain or whether the offspring is male or female.

With Uchida and Carlezon’s expertise, the team is now working toward understanding how widespread gene imprinting in the brain affects the way neurons communicate with one another.

Their work already suggests that imprinting has a strong influence on embryonic development and postnatal behavior, which is consistent with Haig’s evolutionary theory. Ultimately, the team also hopes to understand how imprinted genes contribute to disease.

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Photo Credit: Matt Kalinowski