Abstract

Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of 900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography—the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function.

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Acknowledgements

We wish to thank the Allen Institute founders, P. G. Allen and J. Allen, for their vision, encouragement, and support. We express our gratitude to past and present Allen Institute staff members R. Adams, K. Aiona, A. Alpisa, J. Arnold, C. Bennet, K. Brouner, S. Butler, E. Byrnes, S. Caldejon, J. Campiche, A. Carey, J. Chen, C. Copeland, C. Cuhaciyan, T. Desta, N. Dotson, S. Faber, T. Fliss, E. Fulfs, G. Gee, T. Gilbert, L. Gourley, G. Gu, J. Heilman, N. Ivanov, K. Keyser, A. Kriedberg, J. Laoenkue, F. Lee, S. Levine, L. Luong, N. Mastan, N. Mosqueda, E. Mott, N. Motz, D. Muzia, K. Ngo, A. Oldre, E. Olson, J. Parente, J. Phillips, L. Potekhina, T. Roberts, K. Roll, D. Rosen, M. Sarreal, S. Shapouri, N. Shapovalova, C. Simpson, D. Simpson, M. Smith, N. Stewart, K. Sweeney, A. Szafer, L. Velasquez, U. Wagley, W. Wakeman, C. White and B. Youngstrom for their technical assistance. We thank C. Long for mechanical engineering contract work. We thank R. Gullapalli, A. McMillan and R. Morales for post-mortem magnetic resonance imaging and radiology interpretation of MR data; J. Cottrell, M. Davis, R. Johnson, K. Moraniec, R. Vigorito, A. Weldon and the NICHD Brain and Tissue Bank for Developmental Disorders for tissue acquisition and processing; J. Davis for donor coordination; F. Mamdani, M. Martin, E. Moon, L. Morgan, B. Rollins and D. Walsh for tissue processing and psychological autopsy (DW); D. Patel for magnetic resonance imaging; and J. Sonnen for consultation on tissue microneuropathology. We also thank the External RNA Controls Consortium (ERCC), the US National Institute of Standards (NIST) and Technology, and M. Salit for access to ERCC transcripts during Phase V testing. We are grateful to Beckman Coulter Genomics (formerly Cogenics) and their staff P. Hurban, E. Lobenhofer, K. Phillips, A. Rouse and S. Beaver for microarray data generation and design of the custom Agilent array. We also wish to thank the Allen Human Brain Atlas Advisory Council members D. Geschwind, R. Gibbs, P. Hof, E. Jones, C. Koch, C. Saper, L. Swanson, A. Toga and D. Van Essen for their scientific guidance and dedication to the successful execution of this project. The project described was supported in part by Grant Numbers 1C76HF15069-01-00 and 1 1C76HF19619-01-00 from the Department of Health and Human Services Health Resources and Services Administration Awards and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Health and Human Services Health Resources and Services Administration Awards. S.G.N.G and L.V.L. were supported by the MRCD, Wellcome Trust and European Union Seventh Framework Programme under grants 241498 EUROSPIN, 242167 SynSys, and 241995 GENCODYS Projects.

Author information

Author notes

    • Michael J. Hawrylycz
    •  & Ed S. Lein

    These authors contributed equally to this work.

Affiliations

  1. Allen Institute for Brain Science, Seattle, Washington 98103, USA

    • Michael J. Hawrylycz
    • , Ed S. Lein
    • , Angela L. Guillozet-Bongaarts
    • , Elaine H. Shen
    • , Lydia Ng
    • , Jeremy A. Miller
    • , Kimberly A. Smith
    • , Amanda Ebbert
    • , Zackery L. Riley
    • , Chris Abajian
    • , Amy Bernard
    • , Darren Bertagnolli
    • , Andrew F. Boe
    • , M. Mallar Chakravarty
    • , Mike Chapin
    • , Jimmy Chong
    • , Rachel A. Dalley
    • , Chinh Dang
    • , Suvro Datta
    • , Nick Dee
    • , Tim A. Dolbeare
    • , Vance Faber
    • , David Feng
    • , Jeff Goldy
    • , Benjamin W. Gregor
    • , Zeb Haradon
    • , John G. Hohmann
    • , Robert E. Howard
    • , Jayson M. Jochim
    • , Marty Kinnunen
    • , Christopher Lau
    • , Evan T. Lazarz
    • , Changkyu Lee
    • , Tracy A. Lemon
    • , Yang Li
    • , John A. Morris
    • , Caroline C. Overly
    • , Patrick D. Parker
    • , Sheana E. Parry
    • , Melissa Reding
    • , Joshua J. Royall
    • , Clifford R. Slaughterbeck
    • , Andy J. Sodt
    • , Susan M. Sunkin
    • , Beryl E. Swanson
    • , Derric Williams
    • , Paul Wohnoutka
    • , Christof Koch
    •  & Allan R. Jones
  2. Genes to Cognition Programme, Edinburgh University, Edinburgh EH16 4SB, UK

    • Louie N. van de Lagemaat
    •  & Seth G. N. Grant
  3. MIRA Institute, University of Twente & Donders Institute, Radboud University Nijmegen, Nijmegen, Netherlands

    • Christian F. Beckmann
  4. Department of Psychiatry & Human Behavior, University of California, Irvine, California 92697, USA

    • Preston M. Cartagena
  5. Kimel Family Translational Imaging-Genetics Laboratory, Centre for Addiction and Mental Health Toronto, Ontario M5S 2S1, Canada

    • M. Mallar Chakravarty
  6. University of Maryland School of Medicine, Department of Diagnostic Radiology, University of Maryland Medical Center, Baltimore, Maryland 21201, USA

    • Barry David Daly
  7. Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA

    • David R. Fowler
  8. Department of Radiology, University of Washington, Seattle, Washington 98195, USA

    • David R. Haynor
  9. Department of Human Genetics, Gonda Research Center, David Geffen School of Medicine, Los Angeles, California 90095, USA

    • Steve Horvath
  10. Banyan Biomarkers, Inc., Alachua, Florida 32615, USA

    • Andreas Jeromin
  11. Office of the Chief Medical Examiner, Baltimore, MD, Department of Pediatrics, University of Maryland, Baltimore, Maryland 21201, USA

    • Ling Li
  12. Department of Neuroscience, Georgetown University, School of Medicine, Washington DC 20007, USA

    • Jay Schulkin
  13. Functional Genomics Laboratory, Department of Psychiatry & Human Behavior, School of Medicine, University of California, Irvine, California 92697, USA

    • Pedro Adolfo Sequeira
    •  & Marquis P. Vawter
  14. Histion LLC, Everett, Washington 98204, USA

    • Simon C. Smith
  15. The Eunice Kennedy Shriver NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland, Baltimore, Maryland 21201, USA

    • H. Ronald Zielke
  16. Program in Neurogenetics, Department of Neurology and Department of Human Genetics, and Semel Institute, David Geffen School of Medicine-UCLA, Los Angeles, California 90095, USA

    • Daniel H. Geschwind
  17. Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, New York 10029, USA

    • Patrick R. Hof
  18. FMRIB, Oxford University, Oxford OX3 9DU, UK

    • Stephen M. Smith
  19. Computation & Neural Systems, California Institute of Technology, Pasadena, California 91125, USA

    • Christof Koch

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Contributions

A.R.J., A.L.G.-B., E.H.S. and K.A.S. contributed significantly to overall project design. A.L.G.-B., E.H.S., K.A.S., A.E. and P.W. managed the tissue and sample processing in the laboratory. D.B., A.F.B., R.A.D., J.G., B.W.G., R.E.H., M.K., T.A.L., P.D.P., S.E.P., M.R., J.J.R. and B.E.S. contributed to tissue and sample processing. E.H.S. and Z.L.R. contributed to establishing the tissue acquisition pipeline. P.M.C., B.D.D., D.R.F., L.L., P.A.S., M.P.V. and H.R.Z. contributed to tissue acquisition and MR imaging. Z.L.R., A.B., M.M.C., N.D., A.J., J.M.J., E.T.L., S.C.S. and P.R.H. contributed to protocol development. S.D., J.M.J., C.R.S. and D.W. provided engineering support. A.L.G.-B., R.A.D., P.D.P., J.G.H., J.A.Mo., J.J.R. and B.E.S. contributed to the neuroanatomical design and implementation. L.N. and C.D. managed the creation of the data pipeline, visualization and mining tools. L.N., C.D. and C.C.O. contributed to the overall online product concept. L.N., C.A., M.C., J.C., T.A.D., D.F., Z.H., C.La., Y.L. and A.J.S. contributed to the creation of the data pipeline, visualization and mining tools. M.J.H., E.S.L., J.A.Mi., D.H.G., L.N.L., C.F.B., S.M.Sm., S.G.N.G., A.LG.-.B., E.H.S., K.A.S., A.B., D.B., V.F., J.G., D.R.H., S.H., C.Le., J.S., S.M.Su., P.R.H. and C.K. contributed to data analysis and interpretation. A.R.J. supervised the overall project, and the manuscript was written by M.J.H. and E.S.L. with input from other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michael J. Hawrylycz.

Supplementary information

PDF files

  1. 1.

    Supplementary Methods

    This file contains Supplementary Methods 1-3 (see pages 1-2 for details), which describe in detail the methodology of tissue preparation, data generation and data analysis techniques utilized for both the project and the manuscript.

  2. 2.

    Supplementary Information

    This file contains Supplementary Figures 1-14 and legends for Supplementary Tables 1-10.

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  1. 1.

    Supplementary Tables

    This file contains Supplementary Tables 1-10 (see Supplementary Information file for legends).

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https://doi.org/10.1038/nature11405

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