All animal species exhibit certain fundamental similarities in form and behavior, but also many striking differences despite very similar complements of genes. It is likely that conserved networks that regulate gene expression underlie most of the similarities, and that alterations in those regulatory networks can explain many aspects of biological diversity. Understanding the structures of conserved regulatory networks, and how they can be modified to yield biological diversity both between and within species, are major challenges in biology and the focus areas of our theme.
Even small differences in genome sequence - for example, between individual humans - can translate into an amazing diversity of form, function and behaviors. Small sequence differences have especially large impact when they alter the function regulatory molecules that coordinate genomic response to environmental signals. These “first responders,” including transcription factors, signaling molecules, and regulatory RNAs, interact within regulatory networks to control sequential cascades of downstream genes. Perturbing regulatory network components or their connectivity can thus have potent effects on development and behavior.
Regulatory networks can be altered by genetic mutation, but they can also be “rewired” in response to experience and other environmental factors through epigenetic modification of the DNA. Mutation of regulatory network components determines inborn aspects of interspecies and individual diversity, while epigenetic modifications in response to environment and experience fine-tune inborn diversity and underlie processes of developmental and behavioral plasticity. Our goal is to define gene regulatory networks that underlie the expression of complex patterns of development and behavior, and to understand how those networks are shaped by mutation and epigenetic events to craft individual and species diversity.
The theme draws together a team of researchers from neuroscience, developmental biology, evolutionary biology, mathematics, bioinformatics, and physics to collaboratively tackle the following interrelated questions:
- How does the genome respond to developmental signals and environmental stimuli, especially those related to social experience?
- What mechanisms control and modulate those responses? What are the major components of those mechanisms, and how are they integrated into gene regulatory networks?
- How do alterations in regulatory networks - through mutation, epigenomic changes, or other – translate into behavioral and developmental diversity and plasticity?
- Are these regulatory networks conserved between species, either in their components and the details of direct interactions among network elements, or at a higher level of organization?
- How does diversity in regulatory network architecture contribute to interspecies and individual diversity?
The theme addresses these issues by studying conserved behaviors and key developmental events in a diverse set of animal models, developing gene expression, transcription-factor binding, epigenomic, and other types of genome-scale datasets with high-throughput techniques. Theme members develop computational tools and infrastructure to integrate these data, to compare them across species, and to predict the outcome of structural variation in network components. The theme also develops molecular methods, as well as cell-based and animal models, to test hypotheses arising from computational predictions. By employing a range of diverse biological systems, researchers aim to extract the essential features of networks that have evolved to control plasticity in neural and developmental contexts. Practical applications may include the development of medical therapeutics for mental health, aging, and developmental disorders. Funding for several aspects of theme research provided by the Simons Foundation.