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Genes and the Brain

Two related studies revealed gene activity in the brains of people of different genders and ethnicities, from fetal development to old age. The accomplishment provides a broad foundation for understanding both normal brain development and what goes awry in mental disorders.

Messenger RNAs, or transcripts, are transient copies of genes that carry instructions to the protein-making machinery within cells. Transcripts are made, or “expressed,” in patterns that are influenced by the approximately 1.5 million DNA variations unique to each of us. Dr. Joel Kleinman of NIH's National Institute of Mental Health (NIMH) and NIMH grantee Dr. Nenad Sestan of Yale University led a broad survey to find which genes are active in different areas in the brain at different stages of life. The sister studies appeared in the October 27, 2011, issue of Nature.

One team focused on how genetic variations are linked to the expression of transcripts in the brain's prefrontal cortex — the area that controls insight, planning and judgment — across the lifespan. The researchers studied 269 postmortem, healthy human brains ranging in age from 2 weeks after conception to 80 years old. The other study looked at expression across 16 brain regions in 57 postmortem brains — from 40 days post-conception to 82 years old — from males and females of multiple ethnicities.

The researchers found that different sets of genes are expressed during prenatal development, infancy and childhood. Three-fourths of genes change expression levels immediately after birth, with most decreasing. Gene expression gradually declines from there, eventually leveling off in middle age. It then surges again as the brain ages in the last decades of life.

Individual genetic variations are profoundly linked to expression patterns. However, despite differences in the genetic code across individuals and ethnicities, the transcriptomes — the complete set of expressed transcripts — of human brains are generally similar.

Over 90% of the genes expressed in the brain are differentially regulated across brain regions and/or over developmental periods. Brain location and timing, the researchers found, affect gene expression far more than gender, ethnicity or individual variation.

The researchers have now created large databases that reveal when and where genes turn on and off in multiple brain regions throughout development. This information will help to show how genetic variations affect development and how they might lead to mental illness.

“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,” says NIMH Director Dr. Thomas R. Insel.