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A Genetic Map of the Brain

This new “atlas” reveals the expression pattern in the brain of every gene in the mouse genome.
September 27, 2006

A massive genetic map of the mouse brain was released yesterday, providing an invaluable new tool for understanding neural disease, memory, and other thought processes.

A three-dimensional reconstruction of the mouse brain, with the expression pattern of two different genes marked in yellow and turquoise dots. (Credit: Allen Institute for Brain Science)

Initiated in 2003, with a $100-million grant from Microsoft cofounder Paul Allen, the database–which is freely available on the Web–provides a neural map of the expression of the approximately 21,000 genes in the mouse genome.

Having access to this information, pieces of which would have taken months or years for individual neuroscientists to generate, will radically speed up research in the neurosciences, shedding light on the genetic basis of diseases such as autism and multiple sclerosis, and providing new targets for drugs.

“There’s never been anything like it before,” says Ben Barres, a neuroscientist at Stanford University who served as an advisor for the project. “It’s an incredible gift.”

The idea for the project came four years ago, when Allen gathered several prominent neuroscientists and geneticists to ask what could be done to accelerate brain research. The result was the Allen Brain Atlas. “The human genome project describes the ‘what’–what are the genes?” says Allen Jones, chief scientific officer at the Allen Institute for Brain Science, a nonprofit research institute in Seattle, WA, that did the work. “The atlas describes the ‘where’–where in the brain are these genes turned on?”

The resulting database will help researchers understand a wide range of problems in neuroscience, from neurological diseases to learning and memory and the fundamental processes of emotion and consciousness, says David Anderson, a neuroscientist at the California Institute of Technology, and a scientific advisor on the project.

Researchers at the Allen Institute created the database using a process known as in-situ hybridization. A mouse brain is sliced into thin layers and then labeled with a DNA “probe” that binds only to a single gene, highlighting the expression pattern for that gene.

In-situ maps were made for every gene in the mouse genome, then loaded into a massive database. To complete the entire database, researchers processed 170 genes per day, and produced some 1,000 gigabytes of data each day. The finished atlas cost about $41 million to produce.

While human and mouse brains look somewhat different, they share many of the same basic anatomical structures and about 90 percent of their genes. Scientists studying particular genes or brain functions can search the new database to find out where in the brain a particular gene of interest is expressed, or which genes are expressed in the brain area involved in, say, fear or the region of the brain that’s lost in Parkinson’s disease.

The researchers chose to create a mouse atlas, partly because mouse tissue is smaller and much easier to access than human tissue, but also because mice are a common lab animal and can be easily manipulated genetically.

Barres at Stanford, for example, studies the neural cells that form myelin, an insulating sheath for neurons that degenerates in multiple sclerosis (MS). “We found using the atlas that some genes involved in myelin formation are only expressed in certain parts of the myelin,” says Barres. “It’s been known that MS affects some regions of the brain and not others, so these findings suggest a new hypothesis for what’s going on.” He plans to compare gene expression patterns to gene expression in a mouse that has been genetically engineered to have a disease similar to multiple sclerosis.

At Caltech, Anderson studies the amygdala, a brain area that plays a role in fear and anxiety and has also been implicated in autism, a developmental disorder characterized by cognitive and social problems. He says the amygdala is made up of several different parts that are difficult to distinguish with a microscope. Anderson says the brain atlas shows that these subregions have distinct patterns of gene expression. Now he and other researchers can look at the development of these specific areas, to see how they might be altered in autism.

Researchers at the Allen Institute are just beginning to mine the massive database of information they’ve generated. Nonetheless, they’ve already uncovered some interesting findings. “Approximately 80 percent of the genes in the genome are expressed in the brain, which is greater than the previous estimates of 60-70 percent,” says Kelly Overly, research alliance manager at the Allen Institute. “The genome is much more represented in the brain than we thought.”

She adds that the finding has implications for drug development: if scientists are developing new drugs that target gene products found in both the brain and body, they can try to avoid targeting areas not involved in the disease.

The institute is now planning a new project focusing on the neocortex, the brain area responsible for higher thought. They will use data from the mouse atlas, as well as from human tissue samples, to try to better understand the phenomenon of complex thought. Researchers are also collaborating with other institutions to study autism, epilepsy, and ALS. Comparing gene-expression patterns in the brain atlas with that of animal models of these diseases can shed light on exactly what’s gone awry.

“That information can be a huge help in focusing research efforts to understand diseases, as well as hopefully developing new and better therapeutics,” says the Allen Institute’s Overly.

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