Post by Former NIMH Director Thomas Insel: BrainSpan – Mapping the Developing Brain
Every cell in your body has the same DNA with about 23,000 genes. Yet blood cells and brain cells look different, have different proteins, and serve very different functions. How can the identical genome create such diversity? The answer is that only a fraction of the genome is expressed in any given cell and the specific genes that are expressed define the cell’s identity, one expression pattern defining blood cells and another defining brain cells.
The key translator between DNA and protein is RNA. Every cell type has a distinct RNA profile—called its transcriptome. RNA is such a precise translator, you can identify the type of cell by knowing its transcriptome. Which is why a new report mapping the brain’s transcriptome, called the BrainSpan Atlas, is so important.1 Previous studies have shown that the brain expresses more of the genome than other organs, and that brain transcriptomes are especially complex.2 BrainSpan maps how the genome is translated throughout development of the human brain. The bottom line: the fetal brain is profoundly different from the adult brain. In fact, so many genes are translated differently in the fetal brain, the fetal brain at a molecular level could almost be considered a different organ.
To understand how this map will be used, consider some recent results. Over 100 genetic variants have been associated with schizophrenia and autism. While one might hope that these variants would tell a story, there really is no simple narrative to explain how they are related based on where these genes are found in the adult brain. But when Willsey and colleagues used the BrainSpan Atlas, they discovered that genes that seemed to be functionally unrelated in the adult brain were expressed in the same cells in one layer of the developing fetal cortex at a key interval during the second trimester.3 Gulsuner and colleagues found a similar network in the fetal brain when they looked at genes implicated in schizophrenia.4 Perhaps this should not be surprising: neurodevelopmental disorders should be studied in a developing brain. But prior to BrainSpan we did not have a comprehensive picture of how different the developing brain would be. Now some of the mysteries emerging from genetics can be solved.
There is one other aspect of the BrainSpan Atlas that deserves notice. Although the paper describing the results was only published this week in the journal Nature, the results have been available on the web for anyone to use for the past year. In fact, the papers on autism and schizophrenia mentioned above were published last year and did not involve the creators of the BrainSpan Atlas. This reflects a new culture of making data public to accelerate research. BrainSpan was a joint effort of the Allen Institute for Brain Science and academic investigators funded by NIMH. The Allen Institute, a private research institute established by Microsoft co-founder Paul Allen, has transformed neuroscience by creating atlases of mouse, monkey, and human brain that are freely available for anyone, anywhere. The NIMH investment, made possible because of the American Recovery and Reinvestment Act, was intended to create a resource for the global community working on neurodevelopmental disorders. Seeing the papers last year, months before BrainSpan was published, might have previously raised concerns about academics scooping each other, but in the new culture this rapid use of data was a welcome sign of a new way of doing business.
The figure depicts the location and expression level of three different genes in the developing human brain.
Source: Allen Brain Atlas
1 Miller JA et al. Transcriptional landscape of the prenatal human brain. Nature. 2014 April 2. doi: 10.1038/nature13185. Epub ahead of print.
2 Hawrylycz MJ et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature. 2012 Sep 20;489(7416):391-9. doi: 10.1038/nature11405.
3> Willsey AJ et al. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell. 2013 Nov 21;155(5):997-1007. doi: 10.1016/j.cell.2013.10.020.
4 Gulsuner S et al. Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell. 2013 Aug 1;154(3):518-29. doi: 10.1016/j.cell.2013.06.049.