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Subject: OUR BRAINS ARE MADE OF THE SAME STUFF, DESPITE DNA DIFFERENCES
U.S. Department of Health and Human Services NATIONAL INSTITUTES OF HEALTH
NIH News National Institute of Mental Health (NIMH)
<http://www.nimh.nih.gov/> For Immediate Release: Wednesday, October 26,
2011
CONTACT: Jules Asher, NIMH press office,
301-443-4536,<e-mail:[log in to unmask]>
OUR BRAINS ARE MADE OF THE SAME STUFF, DESPITE DNA DIFFERENCES 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 from a pair of studies that have created databases revealing when and
where genes turn on and off in multiple brain regions through 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
(http://www.genome.gov/glossary.cfm?key=messenger%20rna%20(mrna))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, which are 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
(http://www.nimh.nih.gov/science-news/2009/atlas-will-reveal-when-and-where-
genes-turn-on-in-the-brain.shtml) -- a molecular signature that is 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 much slower rates after birth that gradually decline
and eventually level off in middle age. These rates surge again as the brain
ages in the last decades, mirroring rates seen in childhood and adolescence,
according to one of the studies. 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, if a particular version of a gene is implicated in a disorder,
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
(http://www.nimh.nih.gov/science-news/2008/genes-that-turn-on-together-hold-
secrets-of-brains-molecular-instructions.shtml)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, the area that
controls insight, planning and judgment, across the lifespan. They studied
269 postmortem, healthy human brains, ranging in age from two weeks after
conception to 80 years old, using 49,000 genetic probes. The database on
prefrontal cortex gene expression alone totals more than 1 trillion pieces
of information, according to Kleinman.
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.
-- Different types of related genes are expressed during prenatal
development, infancy, and childhood, so that each of these stages shows a
relatively distinct transcriptional identity. Three-fourths of genes reverse
their direction of expression after birth, with most switching from on to
off.
-- Expression of genes involved in cell division declines prenatally and in
infancy, while expression of genes important for making synapses, or
connections between brain cells, increases. In contrast, genes required for
neuronal projections decline after birth - likely as unused connections are
pruned.
-- By the time we reach our 50s, overall gene expression begins to
increase, mirroring the sharp reversal of fetal expression changes that
occur in infancy.
-- Genetic variation in the genome as a whole showed no effect on variation
in the transcriptome as a whole, despite how genetically distant individuals
might be. Hence, human cortexes have a consistent molecular architecture,
despite our diversity.
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
(http://www.nimh.nih.gov/science-news/2009/schizophrenia-linked-to-over-expr
ession-of-gene-in-fetal-brain.shtml). 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 genome, examining 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
(http://www.genome.gov/Glossary/index.cfm?id=61), which combine to form a
gene's protein product. This allowed them to pinpoint changes in these
combinations that make up a protein, as well as to chart the gene's overall
expression.
Among key findings:
-- Over 90 percent of the genes expressed in the brain are differentially
regulated across brain regions and/or over developmental time periods. There
are also widespread differences across region and time periods in the
combination of a gene's exons that are expressed.
-- Timing and location are far more influential in regulating gene
expression than gender, ethnicity or individual variation.
-- Among 29 modules of co-expressed genes identified, each had distinct
expression patterns and represented different biological processes. Genetic
variation in some of the most well-connected genes in these modules, called
hub genes, has previously been linked to mental disorders, including
schizophrenia and depression.
-- Telltale similarities in expression profiles with genes previously
implicated in schizophrenia and autism are providing leads to discovery of
other genes potentially involved in those disorders.
-- Sex differences in the risk for certain mental disorders may be
traceable to transcriptional mechanisms. More than three-fourths of 159
genes expressed differentially between the sexes were male-biased, most
prenatally. Some genes found to have such sex-biased expression had
previously been associated with disorders that affect males more than
females, such as schizophrenia, Williams syndrome, and autism.
The Sestan study was also funded by NIH's National Institute on Child Health
and Human Development, National Institute on Neurological Disorders and
Stroke, and National Institute on Drug Abuse. Data for the Sestan study are
posted at <www.humanbraintranscriptome.org> and at
<http://www.developinghumanbrain.org/>, as part of a larger ongoing study,
BrainSpan, funded by NIMH under the American Recovery and Reinvestment Act
to create an Atlas of Human Brain Development
(http://www.nimh.nih.gov/science-news/2009/atlas-will-reveal-when-and-where-
genes-turn-on-in-the-brain.shtml).
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_id=phs0004
17.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>.
The mission of the NIMH is to transform the understanding and treatment of
mental illnesses through basic and clinical research, paving the way for
prevention, recovery and cure. For more information, visit the NIMH website
<http://www.nimh.nih.gov/> .
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NINDS <http://www.ninds.nih.gov/> is the nation's leading funder of research
on the brain and nervous system. The NINDS mission is to reduce the burden
of neurological disease -- a burden borne by every age group, by every
segment of society, by people all over the world.
About the Eunice Kennedy Shriver National Institute of Child Health and
Human Development (NICHD): The NICHD sponsors research on development,
before and after birth; maternal, child, and family health; reproductive
biology and population issues; and medical rehabilitation. For more
information, visit the Institute's Web site at <http://www.nichd.nih.gov/>.
About the National Institutes of Health (NIH): NIH, the nation's medical
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------------
The html version of this release contains graphics of:
"genetic difference vs. transcriptional distance colored by race comparison"
at <http://www.nimh.nih.gov/images/news-items/kleinmanlifespanfig4.jpg>
"ZSWIM7 expression colored by gene type" at
<http://www.nimh.nih.gov/images/news-items/zswim7%20expression%20colored%20b
y%20gene%20type>.jpg
"genetic expression change across lifetime" at
<http://www.nimh.nih.gov/images/news-items/kleinmanexpressionchangeacrosslif
espan.jpg>
"males show more sex-biased gene expression" at
<http://www.nimh.nih.gov/images/news-items/sestanfig2a.jpg>
"expression data trajectories" at
<http://www.nimh.nih.gov/images/news-items/cell_synapse_dendrite.jpg>
---------------
REFERENCES:
Colantuoni c, Lipska BK, Ye T, Hyde TM, Tao R, Leek JT, Colantuoni EA,
Elkahloun AG, Herman MM, Weinberger DR, Kleinman JE. Temporal Dynamics and
Genetic Control of Transcription in the human prefrontal cortex. Nature
2011. Oct 27
Kang HJ, Kawasawa1YI, Cheng F, Zhu Y, Xu X, Li M, Sousa1 AMM, Pletikos M,
Meyer KA, Sedmak G, Guennel G, Shin Y, Johnson MB, Krsnik Z, Fertuzinhos
MS, Umlauf S, Lisgo SN, Vortmeyer A, Weinberger DR, Mane S, Hyde TM, Huttner
A, Reimers M, Kleinman JE, ©estan N. Spatiotemporal transcriptome of the
human brain. Nature 2011. Oct 27.
---------------
The activities described in this release are funded in part through the
American Recovery and Reinvestment Act. More information about NIH's
Recovery Act grant funding opportunities can be found at
<http://grants.nih.gov/recovery/>. To track the progress of HHS activities
funded through the Recovery Act, visit <www.hhs.gov/recovery>. To track all
federal funds provided through the Recovery Act, visit <www.recovery.gov>.
##
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