Michael J McConnell
Assistant Professor of Biochemistry & Molecular Genetics
Ph.D., U. C. San Diego
The Cause and Consequence of Somatic Mosaicism in Neurons

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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

McConnell MJ, Lindberg MR, Brennand KJ, Piper JC, Voet T, Cowing-Zitron C, Shumilina S, Lasken RS, Vermeesch JR, Hall IM, Gage FH. (2013) "Mosaic copy number variation in human neurons." Science. Nov 342(6158):632-7. doi: 10.1126/science.1243472. [PubMed]

Grindberg RV, Yee-Greenbaum JL, McConnell MJ, Novotny M, O'Shaughnessy AL, Lambert GM, Ara˙zo-Bravo MJ, Lee J, Fishman M, Robbins GE, Lin X, Venepally P, Badger JH, Galbraith DW, Gage FH, Lasken RS. (2013) "RNA-sequencing from single nuclei." Proc Natl Acad Sci U S A. Dec 110(49):19802-7. doi: 10.1073/pnas.1319700110. Epub 2013 Nov 18. [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. doi: 10.1016/j.tins.2010.04.001. Epub 2010 May 12. [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. doi: 10.1073/pnas.0902018106. Epub 2009 Apr 3. [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. doi: 10.1016/j.neuron.2009.10.015. [PubMed]

McConnell MJ, MacMillan HR, Chun J. (2009) "Mathematical modeling supports substantial mouse neural progenitor cell death." Neural Dev. Jul 4:28. doi: 10.1186/1749-8104-4-28. [PubMed]

McConnell MJ, Kaushal D, Yang AH, Kingsbury MA, Rehen SK, Treuner K, Helton R, Annas EG, Chun J, Barlow C. (2004) "Failed clearance of aneuploid embryonic neural progenitor cells leads to excess aneuploidy in the Atm-deficient but not the Trp53-deficient adult cerebral cortex." J Neurosci. Sep 24(37):8090-6. [PubMed]

Rehen SK, McConnell MJ, Kaushal D, Kingsbury MA, Yang AH, Chun J. (2001) "Chromosomal variation in neurons of the developing and adult mammalian nervous system." Proc Natl Acad Sci U S A. Nov 98(23):13361-6. [PubMed]