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Rhesus monkey brain
A cross-section of the neocortex and cerebellum from an adult rhesus monkey brain has been labeled with a stain that highlights brain cells. (Credit: Allen Institute)

A project led by Seattle’s Allen Institute for Brain Science has mapped out how genes get fired up in key areas of a rhesus monkey’s brain as it develops – and the results could help researchers unlock the mysteries surrounding autism, microcephaly, schizophrenia and other neurological conditions.

The gene expression map, laid out today in research published by the journal Nature, shows that rhesus macaque monkeys are much better models than the usual mice for humans when it comes to brain development. It also confirms the view that different neurological disorders follow dramatically different genetic pathways.

“The sets of genes that turn on early, and the sets of genes that turn on in the adult, shift dramatically,” Allen Institute neuroscientist Ed Lein, the study’s senior author, told GeekWire.

The gene map follows up on earlier work that Lein and his colleagues have done with mice, to track how the brain develops from its fetal stage to adulthood. The Allen Institute has done similar work with adult human brains and fetal brains as well.

Like the genomes of mice and humans, a rhesus monkey genome contains all the instructions for building living tissue, including the brain. But different genes have to be turned on at different stages of development. The institute’s gene expression maps chart which genes are being expressed in which parts of the brain at a given time.

For the monkey project, five key brain regions were dissected and analyzed at 10 stages of development, ranging from 40 days into gestation to two years after birth.

The five regions are the anterior cingulate gyrus and the primary visual cortex, as well as the hippocampus, striatum and amygdala. They were selected because they’re associated with human neurological disorders. For example, abnormalities in the anterior cingulate gyrus have been linked to schizophrenia, autism and obsessive-compulsive disorder.

Researchers focused in on the genes that are also associated with such conditions, and looked for the time periods in brain development when those genes are turned on.

Brain development
This graph charts the development of a monkey brain’s neocortex before and after birth. Stained brain sections show early expansion of dividing progenitor cells (pink), followed by later generation of cortical neurons (yellow and orange). Credit: Allen Institute via Nature

They found that the timing meshed well with what other researchers have come to assume about brain development in humans. For example, the genes that are associated with microcephaly in humans tended to be turned on at an early phase of monkey brain development, when the progenitors of brain cells are dividing. Microcephaly, a condition that results in shrunken baby brains, is a hot topic nowadays because it’s the most serious health risk linked to the Zika virus.

In contrast, the genes associated with schizophrenia were expressed in the neocortex after birth. That’s consistent with the view that schizophrenia is a late-onset disorder. “It’s a completely different cell set that’s affected,” Lein said.

He said the genes associated with autism spectrum disorder are turned on during a middle period, bridging the pre-natal and post-natal stage.

One of the benefits of the gene expression map is that it shows which genes are turned on at the same time. “It’s a hook into much more complex molecular pathways,” Lein explained.

If only one gene shows an association to a brain condition, it’s like looking at the musical score for, say, the clarinet part in “Rhapsody in Blue.” But if you can see all the genes that are turned on at a given time in a given region, it’s like looking at the whole symphony.

The map also provides a metric for how much more in tune the rhesus monkey is with humans, genetically speaking. Lein said 25 percent of the genes activated in a mouse brain are substantially different from human genes. In comparison, the differences in gene regulation between monkeys and humans amount to just 9 percent.

The monkey study, known as the NIH Blueprint Non-Human Primate Atlas, was supported by $8.5 million in grants from the National Institute of Mental Health. Lein said the data would be made freely available for researchers to download and analyze via the Allen Institute’s website.

This isn’t the end of the institute’s brain-mapping work, but Lein noted that “the technology of today is shifting.” Past efforts have done genetic analysis for regions of the brain, but future efforts are likely to zoom in on gene expression in single cells, he said.

“Generally, such a big sweeping survey becomes even more resource-intensive,” Lein said.

And that means neuroscientists, data analysts and project funders – including Seattle software billionaire Paul Allen, who has put hundreds of millions of dollars into the Allen Institute – may have to start playing in a higher key.

The principal authors of the Nature study, “A Comprehensive Transcriptional Map of Primate Brain Development,” are Trygve Bakken, Jeremy Miller and Song-Lin Ding of the Allen Institute for Brain Science. They and Lein are among 99 authors of the paper.

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