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Unlocking the Genetic Code

Dr. Joel Kleinman explains when and where genes turn on in the brain


Announcer: The human genome has 2 ½ billion bases, chemicals that make up our genetic code. Every 1,000 bases there is a slight variation that makes each of us a unique person. This means that each of us has about 2 ½ million common variations all of which contribute to making us genetically diverse. Dr. Joel Kleinman, of the NIMH Clinical Brain Disorders Branch, together with NIMH grantee Nenad Sestan of Yale University, have been studying messenger RNAs, the products that carry the messages from DNA, the blueprint of the human genome, to make the many different types of cells throughout our brain.

Dr. Joel Kleinman: What we wanted to do in this study is see how genetic variation - how those common genetic variations might affect expression of the messenger RNAs in a particularly part-particularly human part of the brain, the dorsolateral prefrontal cortex. This is a part of the brain that is involved in insight, planning and judgment - characteristics that are peculiarly human. The genetic code that you're born with is what you're going to have all your life, but obviously the cells change over time. And the way they're going to change over time is the amount of messenger RNA and protein that are made are going to change as you develop, mature, age.

Announcer: To carry out the study, Kleinman's team analyzed 650,000 common genetic variations and expression of all 24,000 genes of the human genome in 269 normal postmortem brains.

Dr. Joel Kleinman: And the first thing that you can see from this is that the largest changes of expression are occurring before you're born in the fetal or prenatal period. Then the teens are still less than the child… the 20s are still less … the 30s its beginning to level off… and the 20s and 40s are pretty much the same… and the 50s, 60s and 70s… it's going in the opposite direction. So there's big change again but everything that is basically falling apart again.

Announcer: The database that Kleinman has created on the genes expressed in the prefrontal cortex totals more than 1 trillion pieces of information. These stores of information will allow scientists to have at their fingertips data which may lead to new hope for understanding how such processes in the brain can go awry in schizophrenia, autism, and other brain disorders.

Dr. Joel Kleinman: The genetic variation that's increasing risk for schizophrenia is almost- not almost -in every instance we've examined in detail - has been associated with transcripts which were preferentially expressed in fetal human brain. Makes me think that this illness is probably beginning right from the early parts of brain development.

Announcer: As Dr. Kleinman and his colleagues expand their study to discover every messenger RNA expressed in every gene in the human genome, they are hoping to at last unlock the mysteries surrounding the mental illnesses that affect so many people.

Dr. Joel Kleinman: We're measuring every base of every gene in these brain specimens. And we're doing it in about 1000 brains, which cover disease as well as normals. And we're hoping to generate enough data so we can get to the bottom of these illnesses for good.