Our laboratory is interested in the genetics and genomics of behavior in health and disease. We utilize a variety of techniques, including human molecular genetics, informatics, mouse behavior, in vitro neuroscience, and neuroanatomy. We are continuously developing novel methods for transgenesis, gene manipulation, and transcriptional profiling of the brain. These tools help us to develop mouse models for discovery and modeling of genetic variations based on human patient populations, in order to understand the cellular and molecular underpinnings of behavior. We are particularly focused on neurodevelopmental disorders, including the autism spectrum. Our specific applications of these methods currently span five different, inter-related areas of research:
Transcriptional and translational regulation, and its dysregulation in neuropsychiatric disease.
- Impacts of genetic variation. Genetic variants, both those common in the population and those which are de novo—which are variations not seen in the parents but found in an offspring, due to e.g. spontaneous mutations in germ cells—have been associated with neuropsychiatric diseases by way of genome-wide association studies and genomic analysis of parent-child trios, respectively. In both cases, a vast number of the variations associated with or unique to disease fall in non-protein coding DNA, making it difficult to discern whether and how a variation begets disease. Using Massively Parallel Reporter Assays (MPRAs), we can systematically assess the effects of large sets of variants falling in a) untranslated mRNA elements, as well as b) noncoding variants falling in putative regulatory regions. We are also using this technology to explore putative transcriptional regulators of CNS cell types. We also have been performing ongoing computational genomic analysis in collaboration with the Simons Simplex Consortium, examining mutational burdens and their potential functions in family cohorts with a child suffering from ASD.
- Local and conditional translation of mRNA. Neurons have been long known to localize certain mRNAs to their axons, dendrites, and synapses for translation at the site of use. Our lab was the first to definitively show and characterize this process in astrocytes, another abundant brain cell type. Using similar techniques, including Translating Ribosome Affinity Purification (TRAP) and Ribosome Footprinting (RF), we are continuing to characterize RNA localization and translation in glial cell types and specific neuronal populations. Moreover, these methods enable us to look at e.g. effects of neuronal stimulation on mRNA occupancy, providing potential insights into mechanisms of conditional translation. Finally, using technologies such as CLIP-seq (an RNA analogue of ChIP seq), one can identify RNA binding proteins and their genes, providing another means of insight into regulation of RNA location and translation.
Genetic and behavioral mouse models of neurodevelopmental disorders and risk factors, including William’s Syndrome and Autism-Spectrum Disorders (ASDs).
- Genetic factors. While one type of genetic variation, discussed above, does not directly impact the protein-coding genome, some variations are capable of compromising one or multiple proteins—especially in the cases of large chromosomal insertions, deletions, or inversions. In these cases, a gene or a set of genes become implicitly responsible for the observed phenotypes, which makes the disease amenable to modeling by use of gene knockout mice. Current projects in this area include characterization of behaviors in mice carrying deletion variants in the orthologous William’s Syndrome deletion region (a disease that features hypersociability, in interesting contrast to ASDs). In addition, studies of behavior and varieties of the deletion region are being studied in a patient cohort.
- Sex differences. Almost all neuropsychiatric diseases appear to carry uneven incidence among males and females—for example, ASDs, ADHD, and schizophrenia more often affect men, while depression, anxiety, and PTSD tend to affect women. Animal research, as both a behavioral model and a living experimental model of the nervous system, has until recently—and often still does—only perform experiments in male animals. This has left huge gaps in knowledge about whether and how sex affects behavior, neuroanatomy, and gene expression. We have characterized and are continuing to explore sex differences in the noradrenergic projection neurons of the brain (locus coeruleus), as well as including sex as a variable in other research designs in order to close this knowledge gap.
- Environmental factors. While some cases of ASDs have evident underlying genomic disruptions, many are idiopathic. This leaves the strong possibility that environmental factors either in utero or in the first years of life can impact neurodevelopment. In this regard, we have been investigating the role of in utero exposure to selective serotonin reuptake inhibitors (SSRI, a class of antidepressant) on autism-related behaviors in mice.
We are endlessly grateful to the institutions and foundations whose funding has made–and continues to make–our work possible: