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IGB Biologists & Bioinformaticians to Explore Origins of Social Behavior

September 3, 2013

IGB Biologists and Bioinformaticians Unite to Explore the Origins of Social Behavior

An animal’s success in nature depends in part on its ability to navigate social situations—to find a mate, defend a territory, or work with others to obtain a meal.  Social interactions are also crucial for humans, not only for survival, but for the exploration of space or the complex systems within our own bodies.

A new $3 million grant from the Simons Foundation to the Institute for Genomic Biology will fund a multidisciplinary collaborative effort by Gene Networks in Neural & Developmental Plasticity (GNDP) theme members to search for similarities in the ways that the brains of many different species, including our own, produce social behavior.  “Our goal,” said GNDP Theme Leader and Principal Investigator Lisa Stubbs, “is to tie the truths we extract from each species together, into a fundamental model of how animal brains respond to social stimulus.”  Stubbs is a Professor of Cell and Developmental Biology.

GNDP members (left to right) Saurabh Sinha, Jian Ma, Yoshi Oono, Lisa Stubbs, Gene Robinson, and Alison Bell.

The project arose naturally from the varied areas of strength and common interests of GNDP.  Theme members Alison Bell, Jian Ma, Yoshi Oono, Gene Robinson, and Saurabh Sinha, are also co-investigators.  “Our theme was brought together originally because of our shared interest in what regulatory network architecture can teach us about biology,” said Stubbs.  “We are especially excited about how conserved network[s of genes] are reused, and reshaped, throughout evolution.”  Now, theme members will be working together to understand how gene networks in the brains of animals respond to social stimuli, and develop new ways to compare those network responses.

Stubbs, Bell, and Robinson and their laboratories will be primarily responsible for conducting experiments in mice, stickleback fish, and honey bees, respectively; these animals exhibit interesting social behaviors that are easy for researchers to manipulate.  Oono, as well as Ma, Sinha, and their teams will be innovating novel ways to analyze the genomic data produced by the experimental work.

Why do GNDP researchers believe that diverse animal species, even humans, may share molecular mechanisms that direct sociality?  Inspiration for the project comes from the highly successful efforts of the past several decades to understand how genes direct anatomical development.

The remarkable outcome of this work was the realization that underlying the anatomical diversity observed across animal species are shared sets of genes that direct development.  These sets of genes are conserved across many different species.  Morphological differences between species are directed by differences in their spatial and temporal patterns of gene expression, rather than differences in gene sequence.  This shared genetic “toolkit” directs development of common structures underlying anatomical diversity, such as body segments and appendages.

Just as there is diversity in the physical structure of animals, there is great variation in the structure of their social interactions with other members of their own species.  These interactions can often be grouped into the same broad categories—aggression, mate selection, care of young—but the dynamics vary widely between species.  A female prairie vole mates with one male for life; in contrast, a female mouse shows no such fidelity, while a female stickleback fish allows herself to be chased away by her mate, and a praying mantis female might make a meal of hers.

On a basic level, though, there are shared principles of social behavior across species, just as there are in anatomy.  Animals rely on information from others to guide their behavior during social interactions, and that information, received as primary input, is processed by sets of connected neurons that operate via molecular actions that are deeply conserved, even if the identities of those sets of neurons are not.

IGB researchers will be taking advantage of these commonalities—shared categories of social interactions, and conserved brain biochemistry—to ask whether there are also shared gene actions that guide social behavior.  Alison Bell, Associate Professor of Animal Biology, described the planned study: “we will measure the response to what we think are comparable behaviors in honey bees, stickleback fish, and mice, and look for responses in the same genes, networks, or pathways in each of these organisms.”

The study will initially focus on the brain genomic response to aggressive social encounters.  Researchers will expose individual bees, mice, or fish to an intruder, an unfamiliar individual of the same species.  They will then use high-throughput RNA sequencing methods to quantify gene expression in brain regions that based on prior work are believed to be involved in producing social behavior.  Similarities in the molecular response within the brain of all three species would suggest that the social behaviors of each, although quite distinct, may have evolved from the traits of an ancient common ancestor.

It is possible that some of the same genes, or genes with similar functionality, will be responsive to social stimuli in all three species.  Because of the known complexity of brain genomic responses to behavior, however, researchers will probably need more sophisticated ways to identify similarities.  Said Associate Professor of Computer Science Saurabh Sinha, “We will probably realize that the shared molecular basis across the different species is not as simple as a gene or a set of genes being common to all of them and playing a big role, but that there is a more complex notion of molecular similarity.”

To do this, researchers will combine experimental data about gene expression and the structure of the genome with computational and statistical methods.  Genes called transcription factors produce proteins that work within the cell to help control the activity of many other genes. Sophisticated analyses that take into account experimental data, along with prior knowledge about how genes are regulated, will produce a model of which transcription factors are most important for directing gene activity after a social encounter.  These models, called gene regulatory networks, will be developed for the brain genomic response to aggression in mice, fish and bees.

A novel and valuable aspect of the study will be the innovation of new computational methods that allow the comparison of gene regulatory networks of different species.  Sinha identified such methods as one of the important outcomes of the project: “Tools to compare this basic construct of a regulatory network across different species will play a huge role in that act of comparative genomics.”

These novel computational methods will enable researchers to detect conservation of molecular mechanisms on a yet-unexplored level of analysis, the level of gene regulatory networks.  “The possibility that the same gene networks have been involved in multiple and independent evolutions of social behavior is very exciting because it would provide a new appreciation of the unity of life,” said IGB Director and Professor of Entomology Gene Robinson.  Professor of Physics Yoshi Oono also emphasized the potential power of the study to yield major evolutionary insights: “The molecules and their organizations responsible for sociality will be recognized to be much older than we now naively expect; [they] could be older than Metazoa, could go back at least to Filozoa,” that is, several hundred millions of years old.

Discovering deeply conserved mechanisms of social response will also further efforts to understand human brain function and social behavior.  “The findings would also provide new insights into human neurobiology and mental illnesses,” said Assistant Professor of Bioengineering Jian Ma.

The Simons Foundation, in addition to funding basic life and physical science studies, supports a funding initiative for autism research, making the GNDP study with its potential connections to human social behavior particularly aligned with the Foundation’s aims.  Said Robinson, “If there are gene networks that play a strong role in social responsiveness in different species, these networks might be the ones that get perturbed in mental illnesses that involve social behavior.”

Theme members are energized by the freedom and exploration the grant will support: “Here the focus is on the grander vision of getting insights by comparing whatever we learn from each species . . . [the grant] allows us some breathing space to really think on a grand scale, which normal projects don't often do,” said Sinha. 

This energy, and the strong collaborative aspect of the project, will help GNDP continue to establish itself as a theme.  “The Simons proposal grew directly out of discussions we had last summer to formulate the focus of our new theme,” said Stubbs.  “This project is an almost perfect embodiment of our theme.” 

In addition to the faculty mentioned, many other theme members are playing important roles in the project.  Annie Weisner contributed to pilot studies in mice, and Derek Caetano-Anolles will conduct ongoing mouse behavioral and molecular work.  Dr. Clare Rittschof contributed to pilot studies in bees, and will be joined by Drs. Hagai Shpigler and Matt McNeill for ongoing bee behavioral and molecular work.  Abbas Bukhari may assist in conducting behavioral experiments in stickleback fish, in addition to his main role performing bioinformatics analyses.  Joe Troy will also contribute bioinformatics analyses.  Current IGB Fellow Dr. Ken Yokoyama, Charles Blatti, Laura Sloofman, and Yang Zhang will be involved in computational aspects of the project.  Former IGB Fellow Dr. Qiuhao Qu will help direct work in human stem cells, and Drs. Huimin Zhang and Amy Cash-Ahmed will oversee molecular experiments.

September 3, 2013
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