Not every cell in a person’s body has identical versions of that person’s genome. There are tens of trillions of cells in the human body, so this is maybe not so surprising. However, because each single neuron connects to thousands of other neurons, single neurons with variant genomes could directly alter neural circuit performance and, thereby, influence an individual’s behavior. Understanding the circuit-wide consequences of diversity among neuronal genomes motivates single cell analysis of human neurons in the McConnell lab.
We think that genetic mosaicism – that is, the composite collection of neuron-to-neuron genetic diversity in one brain – can help explain why one identical twin may be autistic, when the other one is not. Or why another identical twin develops schizophrenia, while their sibling doesn’t. We hypothesize that neuron-to-neuron genetic differences “individualize” behavioral phenotypes by creating wiggle-room at the interface of nature and nurture. Most importantly, we want to know if numerous, weak genetic links to neuropsychiatric disorders can be refined by measuring genetic mosaicism.
Our laboratory uses human induced pluripotent stem cells (hiPSCs) to make and study the neural circuits that can be built from different human genomes. In parallel, we develop single cell approaches to understand the cause and consequence of genetic mosaicism among neurons.
We have three immediate research goals.
1) Determine if genetic mosaicism leads to somatic selection during the development of neural circuits.
2) Understand how genetic mosaicism affects the performance of neural circuits.
3) Discover genes that mediate the propensity for genetic mosaicism.