Cell Identity Determination In Human Brain: Somatic mutation and cell lineage

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Somatic mutations, present in some but not all cells of the brain, are increasingly implicated in neurological and psychiatric diseases. Somatic mutations that arise during the cell divisions of prenatal brain development are inherited in clonal fashion and can cause neurodevelopmental diseases such as epilepsy and intellectual disability, even when present at low levels of mosaicism. The previous funding period of this grant developed new methods and algorithms to analyze somatic mutations in postmortem human brain, and technologies to sequence the genomes of single neurons, and has shown that each neuron has a unique genome, with hundreds of developmental mutations present at birth, and dozens more mutations being added each year of life. During prenatal life, 2-3 mutations mark each cell division, so that mutations make in principal a permanent record of each cell division. Integrating the analysis of DNA marks of cell lineage with patterns of gene expression that identify the different neural types in human brain potentially now enables the discovery of the first systematic picture of the pattern of cell divisions that generates the cells of the human brain. In this project, we will apply our existing methods to provide several scientific discoveries not otherwise attainable, providing tools of widespread utility to the genetics and neuroscience communities. Our three Specific Aims will be to 1) use simultaneous analysis of DNA mutations and RNA gene expression to map the lineage of neural cell types in cerebral cortex; 2) map clonal patterns across the surface of the human cerebral cortex to see how they relate to functional subdivisions of the cortex; and 3) focus on the analysis of development of human temporal lobe, which is subject to many unique conditions like temporal lobe epilepsy. These data provide three major discoveries which have all been major goals of neuroscience and which are not presently obtainable by other means: 1) the first direct cell lineage data from the adult human brain, 2) a preliminary lineage map connecting neuronal cell classes, and 3) unique insight into temporal lobe development.