A Critical Window into the Developing Human Brain Profiled in Nature

First major report using data from the BrainSpan Atlas of the Developing Human Brain shines a light on where genes are turned on in the brain during mid-pregnancy, what goes wrong in developmental disorders like autism, and what makes human brains unique

April 2, 2014 View PDF

Researchers at the Allen Institute for Brain Science have generated a high-resolution blueprint for how to build a human brain, with a detailed map of where different genes are turned on and off during mid-pregnancy at unprecedented anatomical resolution. This first major report using data from the BrainSpan Atlas of the Developing Human Brain is published in the journal Nature this week. The data provide exceptional insight into diseases like autism that are linked to early brain development, and to the origins of human uniqueness. The rich data set is publicly available to everyone via the Allen Brain Atlas data portal.

“Knowing where a gene is expressed in the brain can provide powerful clues about what its role is,” says Ed Lein, Investigator at the Allen Institute for Brain Science.  “This atlas gives a comprehensive view of which genes are on and off in which specific nuclei and cell types while the brain is developing during pregnancy. This means that we have a blueprint for human development: an understanding of the crucial pieces necessary for the brain to form in a normal, healthy way, and a powerful way to investigate what goes wrong in disease.”

This paper represents the first major report to make use of data collected for the BrainSpan Atlas of the Developing Human Brain, a big science consortium initiative which seeks to create a map of the transcriptome across the entire course of human development. “Coming on the first anniversary of the BRAIN Initiative, this is a terrific example of the potential for public-private partnerships to accelerate progress in neuroscience,” says Lein.

Thomas R. Insel, Director of the National Institute of Mental Health, praises the BrainSpan Atlas as an already invaluable tool to researchers. "While we have had previous reports of molecular and cellular changes during human brain growth, the BrainSpan Atlas is the first comprehensive map of the dramatic trajectory of gene expression across prenatal and postnatal development,” he says. “This atlas is already transforming the way scientists approach human brain development and neurodevelopmental disorders like autism and schizophrenia.  Although the many genes associated with autism and schizophrenia don't show a clear relationship to each other in the adult brain, the BrainSpan Atlas reveals how these diverse genes are connected in the prenatal brain."

Spotlight on Autism

Though virtually all developmental diseases and disorders can benefit from increased knowledge about how genes are expressed in the developing brain, the researchers pointed to autism as a disorder with particularly pertinent links to early brain development. The research team used the BrainSpan Atlas to examine a number of genes linked to autism in prior scientific studies during development.

“We used the maps we created to find a hub of genetic action that could be linked to autism—and we found one,” says Lein. “These genes were associated with the newly generated excitatory neurons in the cortex, the area of the brain that is responsible for many of the cognitive features affected in autism such as social behavior. This discovery is an exciting example of the ability of the BrainSpan Atlas to generate meaningful hypotheses about the origins of brain developmental disorders.”

What Makes Humans Unique?

Understanding what makes humans unique involves deciphering a complex puzzle—one that begins during the earliest phases of development. The richness of the BrainSpan Atlas gives scientists a new set of tools to assess how the human brain develops compared to other species.

“We know that some important regions of the genome show striking sequence differences in humans compared to other species. Since where a gene is expressed in the brain can give insight into its function, we can use our map to begin to figure out the roles of those genes in making humans distinct,” says Lein. “Our analysis of the data showed that these genes are enriched in the frontal cortex, as well as in several specific specialized cell types including inhibitory GABAergic interneurons and neurons of the transient subplate zone that serves as a scaffold during early circuit formation.  These features are all known to be expanded or show developmental differences in humans compared to other species, so our data gives unprecedented clues about the molecular underpinnings of what makes human neocortex unique.”

A Precious Resource Freely Available

As with all the resources produced at the Allen Institute for Brain Science, sharing the data with the public was a fundamental goal from the very beginning. The BrainSpan Atlas enables researchers around the world to conduct research and ask questions about the early human brain that many would not be able to do otherwise, due to the highly limited availability of prenatal tissues. 

“The work behind creating this atlas could not have been done anywhere else,” says Allan Jones, Chief Executive Officer at the Allen Institute for Brain Science. “The scope of the project, and the level of detail in the data we collected, could only be accomplished thanks to the highly collaborative and interdisciplinary project-based approach of the Allen Institute team. And now, since the data are publicly available, the entire scientific community can take advantage of our efforts to drive their own investigations forward and in exciting new directions.”

The founding principal investigators in the consortium behind the BrainSpan project include Ed Lein and Michael Hawrylycz at the Allen Institute for Brain Science, Nenad Sestan and Mark Gerstein at Yale University, Jim Knowles at USC , Pat Levittat at The Saban Research Institute of Children’s Hospital Los Angeles and USC, Dan Geschwind at UCLA, and Bruce Fischl at Massachusetts General Hospital.

 

Reference

Miller JA, Ding S-L, Sunkin SM, Smith KA, Ng L, Szafer A, Ebbert A, Riley ZL, Aiona K, Arnold JM, Bennet C, Bertagnolli D, Brouner K, Butler S, Caldejon S, Carey A, Cuhaciyan C, Dalley RA, Dee N, Dolbeare TA, Facer BAC, Fend D, Fliss TP, Gee G, Goldy J, Gourley L, Gregor BW, Gu G, Howard RE, Jochim JM, Kuan CL, Lau C, Lee C-K, Lee F, Lemon TA, Lesnar P, McMurray B, Mastan N, Mosqueda NF, Naluai-Cecchini T, Ngo N-K, Nyhus J, Oldre A, Olson E, Parente J, Parker PD, Parry SE, Player AS, Pletikos M, Reding M, Royall JJ, Roll K, Sandman D, Sarreal M, Shapouri S, Shapovalova NV, Shen EH, Sjoquist N, Slaughterbeck CR, Smith M, Sodt AJ, Williams D, Zöllei L, Fischl B, Gerstein MB, Geschwind DH, Glass IA, Hawrylycz MJ, Hevner RF, Huang H, Jones AR, Knowles JA, Levitt P, Phillips JW, Sestan N, Wohnoutka P, Dang C, Bernard A, Hohmann JG, Lein ES. Transcriptional landscape of the prenatal human brain. Nature, April 10, 2014 DOI: 10.1038/nature13185

 

About the Allen Institute for Brain Science

The Allen Institute for Brain Science is an independent, 501(c)(3) nonprofit medical research organization dedicated to accelerating the understanding of how the human brain works in health and disease. Using a big science approach, the Allen Institute generates useful public resources used by researchers and organizations around the globe, drives technological and analytical advances, and discovers fundamental brain properties through integration of experiments, modeling and theory. Launched in 2003 with a seed contribution from founder and philanthropist Paul G. Allen, the Allen Institute is supported by a diversity of government, foundation and private funds to enable its projects. Given the Institute’s achievements, Mr. Allen committed an additional $300 million in 2012 for the first four years of a ten-year plan to further propel and expand the Institute’s scientific programs, bringing his total commitment to date to $500 million. The Allen Institute’s data and tools are publicly available online at www.brain-map.org.

About the BrainSpan Atlas of the Developing Human Brain

This project was supported by Award Numbers RC2MH089921 (PIs Ed Lein & Michael Hawrylycz, Allen Institute for Brain Science), RC2MH090047 (PI James A. Knowles, University of Southern California) and RC2MH089929 (PI Nenad Sestan, Yale University), totaling $16.2M, $8.9M and $9.9M, respectively, from the National Institute of Mental Health. This project is funded with 100% federal funds.  No non-government funds support the project.  The content is solely the responsibility of the respective authors and does not necessarily represent the official views of the National Institute of Mental Health or the National Institutes of Health.