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Investigation of genes important in neurodevelopment disorders in adult human brain

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Abstract

Several neurodevelopmental disorders (NDDs) are caused by mutations in genes expressed in fetal brain, but little is known about these same genes in adult human brain. Here, we test the hypothesis that genes associated with NDDs continue to have a role in adult human brain to explore the idea that NDD symptoms may be partially a result of their adult function rather than just their neurodevelopmental function. To demonstrate adult brain function, we performed expression analyses and ChIPseq in human neural stem cell(NSC) lines at different developmental stages and adult human brain, targeting two genes associated with NDDs, SATB2 and EHMT1, and the WNT signaling gene TCF7L2, which has not been associated with NDDs. Analysis of DNA interaction sites in neural stem cells reveals high (40–50 %) overlap between proliferating and differentiating cells for each gene in temporal space. Studies in adult brain demonstrate that consensus sites are similar to NSCs but occur at different genomic locations. We also performed expression analyses using BrainSpan data for NDD-associated genes SATB2, EHMT1, FMR1, MECP2, MBD5, CTNND2, RAI1, CHD8, GRIN2A, GRIN2B, TCF4, SCN2A, and DYRK1A and find high expression of these genes in adult brain, at least comparable to develo** human brain, confirming that genes associated with NDDs likely have a role in adult tissue. Adult function of genes associated with NDDs might be important in clinical disease presentation and may be suitable targets for therapeutic intervention.

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Abbreviations

NSC:

Neural stem cells

FBC:

Fetal brain cells

iPSC-NPC:

Induced pluripotent stem cell-neural progenitor cells

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Acknowledgements

This work was funded by grants from the Scottish Rite Charitable Foundation of Canada and the Canada Research Chairs program to CE.

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    Authors and Affiliations

    1. Department of Psychiatry, McGill University, Montreal, QC, H4H 1R3, Canada

      Gilles Maussion, Alpha B. Diallo, Liam Crapper, Jean-Francois Théroux, Gary G. Chen, Cristina Vasuta & Carl Ernst

    2. McGill Group for Suicide Studies, Douglas Hospital, Montreal, QC, H4H 1R3, Canada

      Gilles Maussion, Alpha B. Diallo, Carolina O. Gigek, Elizabeth S. Chen, Liam Crapper, Jean-Francois Théroux, Gary G. Chen, Cristina Vasuta & Carl Ernst

    3. Disciplina de Genética, Departamento de Morfologia e Genética, Escola Paulista de Medicina/Universidade Federal de São Paulo, São Paulo, SP, Brazil

      Carolina O. Gigek & Elizabeth S. Chen

    4. Department of Human Genetics, McGill University, Montreal, QC, H4H 1R3, Canada

      Carl Ernst

    5. Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Verdun, QC, H4H 1R3, Canada

      Carl Ernst

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    1. Gilles Maussion
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    G. Maussion and A. B. Diallo contributed equally to this work.

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    Maussion, G., Diallo, A.B., Gigek, C.O. et al. Investigation of genes important in neurodevelopment disorders in adult human brain. Hum Genet 134, 1037–1053 (2015). https://doi.org/10.1007/s00439-015-1584-z

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