The brain is a genetic mosaic. Neuron-to-neuron genomic differences - brought about by endogenous mobile element activity, by idiosyncratic sub-chromosomal amplifications and deletions, and by whole chromosome gains and losses – are hypothesized to “individualize” behavioral phenotypes. To explore the causes and consequences of genetic mosaicism in neural circuits, my laboratory develops high-throughput single cell approaches and employs these approaches to study human induced pluripotent stem cell (hiPSC)-derived neurons, as well as transgenic mice. 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; and 3) discover genes that mediate the propensity for genetic mosaicism. Moreover, altered levels of mosaicism have been associated with neurodegenerative (e.g., Ataxia-telangiectasia) and neuropsychiatric disorders (e.g., schizophrenia and Rett's syndrome). A deeper understanding of these and other neurological disorders is expected from ever-increasing understanding and measurement of neuronal genomic diversity.

Selected References

MacMillan HR, McConnell MJ. (2011) "Seeing beyond the average cell: branching process models of cell proliferation, differentiation, and death during mouse brain development." Theory Biosci. 130:31-43. Epub 2010 Sep 8. [PubMed]

Singer T, McConnell MJ, Marchetto MC, Coufal NG, Gage FH. (2010) "LINE-1 retrotransposons: mediators of somatic variation in neuronal genomes?" Trends Neurosci. 33:345-54. Epub 2010 May 12. [PubMed]

Datwani A, McConnell MJ, Kanold PO, Micheva KD, Busse B, Shamloo M, Smith SJ,Shatz CJ. (2009) "Classical MHCI molecules regulate retinogeniculate refinement and limit ocular dominance plasticity." Neuron. Nov 64:463-70. [PubMed]

McConnell MJ, MacMillan HR, Chun J. (2009) "Mathematical modeling supports substantial mouse neural progenitor cell death." Neural Dev. Jul 4:28. [PubMed]

McConnell MJ, Huang YH, Datwani A, Shatz CJ. (2009) "H2-K(b) and H2-D(b) regulate cerebellar long-term depression and limit motor learning." Proc Natl Acad Sci U S A. Apr 106(16):6784-9. Epub 2009 Apr 3. [PubMed]