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

人脑细胞身份测定：体细胞突变和细胞谱系

• 批准号: 10259777
• 负责人: Christopher A. Walsh
• 金额: $ 70.77万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-12-16 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10259777
• 关键词: Adult; Aging; Algorithms; Animal Model; Architecture; Autopsy; Bar Codes; Birth; Brain; Brain region; Brodmann' s area; Cell Cycle; Cell Lineage; Cell division; Cells; Cerebral cortex; Cognitive; Communities; Copy Number Polymorphism; DNA; DNA Mutational Analysis; DNA Sequence Alteration; DNA analysis; Data; Development; Disease; Epilepsy; Fetal Development; Forensic Medicine; Funding; Gene Expression; Gene Expression Profile; Genetic; Genetic Transcription; Genome; Goals; Grant; Hippocampus (Brain); Human; Human Development; Human body; Inherited; Intellectual functioning disability; Life; Malignant Neoplasms; Maps; Measures; Mental disorders; Methods; Mosaicism; Mutation; Neocortex; Neuroglia; Neurologic; Neurons; Neurosciences; Pattern; Prefrontal Cortex; Primates; Publishing; RNA; RNA analysis; Retrotransposon; Sampling; Single Nucleotide Polymorphism; Somatic Cell; Somatic Mutation; Structure; Surface; Technology; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Visual Cortex; Work; autism spectrum disorder; base; brain cell; brain size; cell type; childhood epilepsy; dentate gyrus; disease-causing mutation; excitatory neuron; expectation; experimental study; genome sequencing; human disease; inhibitory neuron; insight; nervous system disorder; postnatal development; prenatal; relating to nervous system; tool

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.

体细胞突变，存在于一些但不是所有的大脑细胞中，越来越多地涉及到