Regulatory mutations that disrupt “neighborhoods” of co-expressed neurodevelopmental genes

Many critical developmental regulators are involved in differentiation of multipotent progenitor cell types and display especially dynamic expression patterns, as their differentiation roles are deployed across in different spatial locations over developmental time.  In partcular, many genes associated with neurodevelopmental disorders are involved in basic processes – the timely replication of neuron progenitor cells (NPC), their differentiation into neurons or glia, the outgrowth of neurites, or formation of synapses – events that occur at different times in each region of the developing brain.  The deployment of these factors at the right time and place requires the precise combinatorial action of enhancers, silencers, and other regulatory elements (REs) including some located significant genomic distances from the gene.  These REs interact with each other and target promoters through the formation of chromatin loops to specify the location, time, and circumstances of the genes’ expression.

The basic mechanisms of long-distance regulation are just now beginning to be revealed, and only a few distant enhancers have been described in detail so far.  However, genetic studies in humans and mice made it clear that distal REs play a much more prevalent role.

Classically, the relationship between essential genes and long-distance REs has been identified through mutations that either involve the REs themselves, or that separate REs from their cognate promoters via genome rearrangements.  Our own studies have leveraged a unique collection of mouse translocation mutants for this same purpose, focusing on mutations that occur far from genes, but give rise to dramatic developmental effects.  Most of the translocations we have identified are associated with neurological phenotypes, and closely model certain types of human neurodevelopmental disease.

A key example is the intense current focus of our group, a translocation called 16Gso that breaks between and dysregulates the neighboring Galnt17 and Auts2 genes. Mutations in this human region have been associated with intellectual disability (ID), autistic spectrum disorder (ASD), epilepsy, as well as depression, bipolar disorder and wide range of neurological diseases, and the AUTS2 gene has been the major focus of attention.  AUTS2 is a complex gene with isoforms that are involved in different aspects of basic neuron development.  Like other essential developmental genes, AUTS2 is also expressed dynamically across the brain throughout development, reflecting the gene’s essential roles in neuron development. GALNT17 had not been characterized previously, but our data show that the gene is expressed very dynamically across the developing brain, and highly co-expressed with AUTS2. We hypothesize that the two genes operate within the same functional pathways and that their expression is coordinated by a shared system of REs spread across the genomic region. We are focused on determining the details of gene function in conditional-mutant mice and in cultured neurons, and also in the characterization of the regulatory domain that controls this “neighborhood” of co-expressed neurodevelopmental genes.

We are convinced that this research has broader implications, in that regulatory mutations within co-expressed gene “neighborhoods” (more formally called topologically associating domains, or TADs) could explain many aspects of phenotypic variation associated with human neurological disease.

Chris Seward

Chris Seward

Graduate Student, CDB


Current Project

Chris is primarily involved in the Simons Project, which is working to identify the molecular and genomic basis of social behavior.  He is focused on using ChIP-Seq to reveal the genetic regulatory mechanisms essential for social behavior in several species.  He is also working on developing bioinformatic pipelines to integrate diverse ChIP-seq and RNASeq data from this project in order to compare cross-species experimental data.

Past Projects

  • Patterns of variation in archaeal genomes from geothermal environments – Whitaker Lab, UIUC
  • Identifying a Role for Vibrio cholerae T3SS Effector VopX – Dziejman Lab, URMC

Outside the Lab

Chris grew up in Boston, MA and went to college in Rochester, NY.  He enjoys travelling, photography, sailing, skiing, weight training, driving, movies, and tinkering with new technology.  Check out his photography on Flickr.


  1. Shpigler, Hagai; Saul, Michael; Murdoch, Emma; Corona, Frida; Cash-Ahmed, Amy; Seward, Christopher; Chandrasekaran, Sriram; Stubbs, Lisa; Robinson, Gene. Honey bee neurogenomic responses to affiliative and agonistic social interactions, Genes, Brains and Behavior 2018.  doi:10.1111/gbb.12509
  2. Michael Saul*, Charles Blatti, Wei Yang, Syed Abbas Bukhari, Hagai Y. Shpigler, Joseph M. Troy, Chris Seward, Lisa Stubbs, Gene E. Robinson, Sihai Dave Zhao* and Saurabh Sinha*. Cross-species systems analysis of evolutionary toolkits of neurogenomic response to social challenge, Genes, Brains and Behavior 2018. doi:10.1111/gbb.12502
  3. Abbas Bukhari, Michael Saul, Chris Seward, Dave Zhao, Sriram Chandrasekaran, Lisa Stubbs, Alison M. Bell. Temporal Dynamics of Neurogenomic Plasticity in Response to Social Interactions in Male Sticklebacks, PLOS Genetics 2017. doi:10.1371/journal.pgen.1006840
  4. Rika Anderson, Angela Kouris, Chris Seward, Kate Campbell, and Rachel Whitaker. Structured populations of Sulfolobus acidocaldarius with susceptibility to mobile genetic elements, Genome Biology and Evolution 2017. doi:10.1093/gbe/evx104
  5. Chris Seward*, Michael Saul*, Saurabh Sinha, and Lisa Stubbs, et al. Transcriptional regulatory dynamics set the stage for a coordinated metabolic and neural response to social threat in mice, Genome Research 2017. doi:10.1111/gbb.12379
  6. Younguk Sun, Huimin Zhang, Majid Kazemian, Joseph M Troy, Chris Seward, Xiaochen Lu, Lisa Stubbs. ZSCAN5B and primate-specific paralogs bind RNA polymerase III genes and extra-TFIIIC (ETC) sites to modulate mitotic progression, Oncotarget 2017. doi:10.18632/oncotarget.12508
  7. Hagai Shpigler, Michael Saul, Emma Murdoch, Amy Cash‐Ahmed, Chris Seward, Saurabh Sinha, Lisa J Stubbs, Gene E Robinson, et al. Behavioral, transcriptomic and epigenetic responses to social challenge in honey bees, Genes, Brains and Behavior 2017. doi:10.1111/gbb.12379
  8. Chris Seward*, Huimin Zhang*, Zuowei Wu, Huiyan Ye, Youjun Feng. Genomic insights into the ESBL and MCR-1-producing ST648 Escherichia, Science Bulletin 2016. doi:10.1007/s11434-016-1086-y
  9. Kelly Miller, Madeline Sofia, Jacob Weaver, Chris Seward, and Michelle Dziejman.  Regulation by ToxR-like proteins converges on vttRB expression to control T3SS-dependent Caco2-BBE cytotoxicity in V. cholerae, Journal of Bacteriology, 2016. doi:10.1128/JB.00130-16
  10. Christopher H. Seward, Alexander Manzella, Ashfaqul Alam, J. Scott Butler and Michelle Dziejman. Using S. cerevisiae as a Model System to Investigate V. cholerae VopX-Host Cell Protein Interactions and Phenotypes, Toxins 2015. doi:10.3390/toxins7104099

Email Chris

seward2 [at] illinois [dot] edu

Annie Weisner

Annie Weisner, Neuroscience

Annie Weisner, Neuroscience

History Annie is a native Nashvillian who started her research career at Vanderbilt University, where she earned her Bachelors of Arts in Neuroscience and Theatre. During her time as an undergraduate, she worked in the Center for Human Genetics, where she investigated the role of heavy-metal processing in autism by screening patients and families for polymorphisms in heavy-metal transport genes. Additionally, she worked on projects investigating the role of glutathione during oxidative injury through site-directed mutagenesis of the gamma-glutamylcysteine gene, and performed large-scale screening of patient populations for polymorphisms in urea cycle genes.

She joined the UIUC Neuroscience Program and Medical Scholars program in 2009, and is working toward her M.D. and Ph.D. Upon completion of her degrees in 2018, she plans to pursue a career as a physician-scientist specializing in Pediatric Neurology, and she intends to continue her research in developmental neuroscience.

Current Project Annie is investigating the role of newly discovered neurodevelopmental gene, Auts2, in abnormal neurodevelopment. Mutations in the Auts2 locus cause autism, epilepsy, and mental retardation in humans, but little is known about the function of this gene or its role during neurodevelopment. She is analyzing the role of AUTS2 in differentiation of neurons in culture to ask what the function of AUTS2 is in normal neurodevelopment. As well, Annie utilizes a unique translocation mutant called 16Gso which displays epilepsy and autistic-like behaviors resulting from a reduction in AUTS2 expression to how AUTS2 disruption can lead to abnormal neurodevelopment.

Annie also works on the Simons Project, investigating the genetic pathways underlying evolutionarily conserved social behaviors, such as aggression and maternal caring, through RNA-sequencing and protein expression analysis of mouse brain after acute social stimuli.

Past Projects Annie began her work in the Stubbs lab studying the role of Pax6 alternative transcripts in development of the eye through histological analysis of the 1Gso translocation mutant.


Elso, C; Lu, X; Weisner, PA; Thompson, HL; Skinner, A; Carver, E; Stubbs, L (2013). A reciprocal translocation dissects roles of Pax6 alternative promoters and upstream regulatory elements in the development of pancreas, brain, and eye. Genesis, 51:9, 630-646.

Le, TM; Magarik, JA; Cunningham, GR, Weisner, A et al (2008).  gamma-Glutamylcysteine co-migrates at the peak typically assigned to L-aspartate in ion-exchange chromatography-based amino acid analysis.  Molecular Genetics and Metabolism, 93:3, 255-255.

Outside the Lab Annie is the Grants Director of Champaign-Urbana’s only free charitable clinic, Avicenna Community Health Center, and manages a team of 12 graduate, medical, undergraduate student, and faculty volunteers to secure funding for the clinic. She also has twice organized the Illinois Summer Neuroscience Institute, a weeklong research program for undergraduates from underrepresented groups who are interested in pursuing a career in Neuroscience research. She has taught the Medical College’s Cell and Tissue Biology laboratory course since Fall of 2012, and last year ranked in the top 10% of all University instructors, as rated by her students.

In her free time, Annie is an avid powerlifter, cyclist, and climber. She loves to garden and to cook, and teaches healthy cooking classes at the Common Ground Food Co-op. She also volunteers with several organizations for special needs children in town, including taking students on the Swann School’s nature walks, volunteering for the Challenger softball league, and teaching at the CIRCLE Academy.

Email Annie