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Genome-wide investigation of somatic mutation in the developing and aging brain

发育和衰老大脑体细胞突变的全基因组研究

基本信息

批准号：
9105769
负责人：
Kristin Kay Baldwin
金额：
$ 65.55万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9105769
关键词：
Address Adult Age Aging Autistic Disorder Awareness Bioinformatics Brain Cancer Model Cell Aging Cell Line Cell Lineage Cell Nucleus Cells Clonal Expansion Cloning Complex Copy Number Polymorphism DNA Insertion Elements DNA Sequence Alteration DNA Sequence Rearrangement DNA amplification Detection Development Disease Equilibrium Event Exhibits Fertilization Fibroblasts Fluorescence Future Genes Genetic Genome Genome Mappings Genomics Germ-Line Mutation Health Hippocampus (Brain)Human Individual Inherited Intellectual functioning disability Investigation Knowledge Link Loss of Heterozygosity Malignant Neoplasms Mammals Maps Methods Micromanipulation Mitotic Morphologic artifacts Mosaicism Mus Mutation Mutation Spectra Neonatal Neurons New York Nucleotides Oncogenic Oocytes Pattern Play Point Mutation Population Prevalence Process Publications Publishing Recurrence Reporting Research Resolution Role Schizophrenia Science Sister Somatic Cell Somatic Mutation Sorting - Cell Movement Stem cells Surveys Technology Time Tissues Tube Validation Variant Work aged aging brain base cell age cell type chromothripsis cost effective design embryo cell frontier genome sequencing genome-wide human disease innovation insight interest nervous system disorder nuclear transfer olfactory bulb rare variant relating to nervous system self renewing cell sequencing platform single cell sequencing somatic cell nuclear transfer whole genome

项目摘要

DESCRIPTION (provided by applicant): Mutations that arise after fertilization in somatic cell lineages are linked to cancer and aging an have been shown to contribute to an increasing number of human disorders. Similarly, de novo germline mutations in neuronal genes are responsible for cases of autism, schizophrenia and intellectual disability, suggesting that similar types of somatic mutations could contribute to these and other neurological disorders by providing large-effect mutations in specific cell types, that may act alone or in concert with inherited variants. Despite the growing awareness of the importance of genomic mosaicism for human health, our present understanding of somatic mutation in different cellular lineages of the body and brain is minimal. This question has been difficult to address because conventional genome-wide methods cannot detect variants that are rare within a cell population, and most tissues are composed of diverse cell types and intermixed lineages. Single cell sequencing offers one solution, however, current methods suffer from high error-rates and low resolution, and do not allow for independent validation of mutations detected in merely one cell. A second means to amplify genomes from single cells is through clonal expansion. This is feasible for cancer and some self-renewing cell types, but not for many interesting or aged cell types such as post-mitotic neurons. Here, we propose to use two innovative strategies to profile genomes from individual neurons and control fibroblasts from young and aged mice. First, we take advantage of the only known method to amplify neuronal cells without use of oncogenic factors: cloning by somatic cell nuclear transfer. This will enable deep whole genome sequencing and comprehensive mutational profiling of neuron-derived cell lines. Second, we will use nuclear transfer to produce pairs of sister cells derived from single neurons after one division. Single cell sequencing of replicate sister cells will enable sensitive and accurate detection of de novo copy number variation in a context where bona-fide mutations can be clearly distinguished from DNA amplification artifacts. Our application of these complementary technologies will reveal the full spectrum of genome variation that arises in different cell lineages during development and aging, and will help resolve longstanding hypotheses regarding the extent, impact and origins of neuronal genome diversity.

描述（由申请人提供）：