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Studies Track Expression in Brain Regions During Development, Lifespan

NEW YORK (GenomeWeb News) – In today's issue of the journal Nature, two independent teams reported on their efforts to catalog gene expression patterns in different parts of the human brain over time.

Together, the studies not only track the changing gene expression landscape that exists between fetal development and late adulthood, but also illustrate expression differences between brain regions and uncover genetic variants influencing brain gene expression. As such, some say the findings may serve as a resource for interpreting information from brain-related studies in the future.

"Having at our fingertips detailed information about when and where specific gene products are expressed in the brain brings new hope for understanding how this process can go awry in schizophrenia, autism, and other brain disorders," National Institute of Mental Health Director Thomas Insel, who was not directly involved in either study, said in a statement.

In the first of these studies, an international group led by researchers with Yale University School of Medicine's neurobiology department and Kavli Institute for Neuroscience brought together exon-level gene expression data and genotyping data representing 16 regions of 57 developing and adult human brains.

The researchers found more than two-dozen distinct modules of genes that tend to be co-expressed with one another at different times and places in the brain to produce specific biological effects in the brain. By looking at the predicted functions of brains in these modules, along with when and where they are expressed, the team was able to track some of the events contributing to human brain development and aging.

While their findings suggest that some 86 percent of human genes are expressed in the human brain, most of these genes — more than 90 percent — showed variable expression depending on when and where in the brain the researchers looked. The specific exons expressed for each gene also showed spatio-temporal variation.

Although timing and brain location had the most pronounced effects on expression, the team also found evidence for some sex-based differences in the codon usage and gene expression. In particular, 159 genes appear to be differentially expressed in male and female brains, they reported, and more than three-quarters of those had male-biased expression.

Overall, though, that group found that transcriptome patterns "differ more prominently across time and space than they do between sexes, ethnicities, or individuals, despite their underlying genetic differences."

For another study appearing in Nature today, researchers from the National Institutes of Health, Illuminato Biotechnology in Baltimore, and Johns Hopkins University used microarrays to obtain gene expression and genotype information on 269 post-mortem brain samples. With this data in hand, they then looked at the nature, timing, and control of gene expression in the prefrontal cortex across development and aging, from as early as two weeks after conception to the age of 80 years old.

"Our study shows how 650,000 common genetic variations that make each of us a unique person may influence the ebb and flow of 24,000 genes in the most distinctly human part of our brain as we grow and age," senior author Joel Kleinman, a neuropathology researcher with the NIMH, said in a statement.

In the prefrontal cortex of the brain, a region known for mediating processes such as planning and judgment, the team found that the presence of certain SNPs did seem to correlate with the expression of some genes. But, they reported, each person's total repertoire of genetic variants did not significantly alter the overall transcriptional patterns in the prefrontal cortex.

"[T]he human genome produces a consistent molecular architecture in the prefrontal cortex, despite millions of genetic differences across individuals and races," the study authors noted.

Gene expression patterns were especially similar from one individual to the next during very early development and in individuals from some of the oldest age groups tested, life stages that were marked by extensive overall gene expression.

They also saw different sets of genes being expressed during specific life stages — such as infancy or childhood — or prenatally. For example, the team found that expression of genes contributing to synapse formation in the brain was elevated in prenatal and infant brains.

Data from the prefrontal cortex study is available through the Gene Expression Omnibus or through the Brain Cloud application online. Researchers involved in that effort will continue to expand on the database and are reportedly planning to assess genome-wide expression in some 1,000 post-mortem brain samples.

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