BRAINcode

BRAINCODE: How Does the Human Genome Function in Specific Brain Neurons? The human brain comprises about 86 billion neurons whose function is central to human biology. How does the human genome program high performing neurons and neural networks in response to experience? What subprograms does the genome express in physiologically and morphologically distinct brain cells? The goal of the BRAIN Cell encyclOpeDia of transcribed Elements Consortium (BRAINcode) is to provide a map of gene expression - both protein-coding and non-coding - in specific cell types, not in culture, but in situ in brains of people. Going beyond traditional mRNA sequencing, polyadenylated and non-polyadenylated transcripts were ultra deeply sequenced using ribo-depleted RNA from neurons laser-captured from human post-mortem brains. Three prototypical neuron types, dopamine neurons, pyramidal neurons, and Betz cells, were prioritized because of their key biologic roles and differential vulnerability to important neurodegenerative diseases such as Parkinson's or Alzheimer's disease. Genetic variation between individuals was examined for correlation with differences in transcribed sequences to identify regions of the genome that influence whether, how, and how much a transcript is expressed in specific cell types in human brains. Our results indicate a vast universe of annotated and novel non-coding RNAs expressed in brain cells and suggest a more diverse and much more complex transcriptional architecture than previously imagined. ]]>
The brain samples represented 93 subjects without a clinical or neuropathological diagnosis of neurodegenerative disease meeting the following stringent inclusion and exclusion criteria. Inclusion criteria: (1) absence of clinical or neuropathological diagnosis of a neurodegenerative disease e.g. Parkinson's disease according to the UKPDBB criteria, Alzheimer's disease according to NIA-Reagan criteria, dementia with Lewy bodies by revised consensus criteria; (2) PMI /= 6.0 by Agilent Bioanalyzer (good RNA integrity); (4) visible ribosomal peaks on the electropherogram. Exclusion criteria were: (1) a primary intracerebral event as the cause of death; (2) brain tumor (except incidental meningiomas); (3) systemic disorders likely to cause chronic brain damage. We also included eight non-brain tissue samples as controls, including five samples of peripheral blood mononuclear cell (PBMC) and three fibroblasts (FB), provided by Harvard Biomarker Study and Coriell Institute. This study was approved by the Institutional Review Board of Brigham and Women's Hospital.]]>