Gene expression databases reveal ‘consistent molecular architecture’
Despite vast differences in the genetic code across individuals and ethnicities, the human brain shows a “consistent molecular architecture,” say researchers supported by the National Institutes of Health. The finding is based on a pair of studies that have created databases revealing when and where genes turn on and off in multiple brain regions during development.
“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,” explained Joel Kleinman, M.D., Ph.D., of the National Institute of Mental Health (NIMH) Clinical Brain Disorders Branch.
Kleinman and NIMH grantee Nenad Sestan, M.D., Ph.D. of Yale University, New Haven, Conn., led the sister studies in the Oct. 27, 2011 issue of the journal Nature.
“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,” said NIMH Director Thomas R. Insel, M.D.
Both studies measured messenger RNAs or transcripts. These intermediate products carry the message from DNA, the genetic blueprint, to create proteins and differentiated brain tissue. Each gene can make several transcripts, expressed in patterns influenced by a subset of the approximately 1.5 million DNA variations unique to each of us. This unique set of transcripts is called our transcriptome—a molecular signature unique to every individual. The transcriptome is a measure of the diverse functional potential that exists in the brain.
Both studies found that rapid gene expression during fetal development abruptly switches to slower rates after birth that gradually decline and eventually level off in middle age. According to one of the studies, these rates surge again as the brain ages in the last decades, mirroring rates seen in childhood and adolescence. The databases hold secrets to how the brain’s ever-changing messenger chemical systems, cells, and development processes are related to gene expression patterns through development.
For example, suppose a particular gene version is implicated in a disorder. In that case, the new resources might reveal how that variation affects the gene’s expression over time and by brain region. By identifying even distant genes that may be turning on and off in-sync, the databases may help researchers discover whole modules of genes involved in the illness. They can also reveal how variation in one gene influences another’s expression.
Prefrontal cortex
Kleinman’s team focused on how genetic variations are linked to the expression of transcripts in the brain’s prefrontal cortex, which controls insight, planning and judgment across the life studied 269 postmortem, healthy human brains, ranging in age from two weeks after conception to 80 years old, using 49,000 genetic probes. According to Kleinman, the prefrontal cortex gene expression database alone totals more than 1 trillion pieces of information.
Among key findings in the prefrontal cortex: Individual genetic variations are profoundly linked to expression patterns. The most similarity across individuals is detected early in development and again as we approach the end of life.
In previous studies, Kleinman and colleagues have found that all genetic variations implicated to date in schizophrenia are associated with transcripts that are preferentially expressed in the fetal brain. This adds to evidence that the disorder originates in prenatal development. By contrast, he and his colleagues are examining evidence that genetic variation implicated in affective disorders may be associated with transcripts expressed later in life. They are also extending their database to include all transcripts of all the genes in the human gpostmortemining 1000 post-mortem brains, including many of people who had schizophrenia or other brain disorders.
Multiple brain regions
Sestan and colleagues characterized gene expression in 16 brain regions, including 11 areas of the neocortex, from both hemispheres of 57 human brains that spanned from 40 days post-conception to 82 years – analyzing the transcriptomes of 1,340 samples. Using 1.4 million probes, the researchers measured the expression of exons, which combine to form a gene’s protein product. This allowed them to pinpoint changes in these combinations that make up a protein and to chart the gene’s overall expression.
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The Kleinman study data on genetic variability are accessible to qualified researchers at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id5phs000417.v1.p1, while the gene expression data can be found at http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc5GSE30272.
In addition, BrainCloud, a web browser application developed by NIMH to interrogate the Kleinman study data, can be downloaded at http://www.libd.org/braincloud.
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