Somatic mosaicism, the phenomenon whereby not all cells of the human body have identical DNA sequence, occurs as part of the normal developmental process. Retrotransposon activity, replication errors during rapid mitotic expansion of neurons during fetal brain development, and electrophysiological activity of the neurons have been implicated in the generation of somatic variations. Recent studies suggest that such variations might accumulate throughout the lifespan and be widespread in the brain.
Somatic genomic variations could occur in the form of single nucleotide variants (SNVs), copy number variants (CNVs), structural variants (SVs), or retrotransposon insertions. Such variations could alter epigenetic and transcriptome patterns, creating functional diversity among brain cells which could result in alteration of cell signaling pathways and neural circuit function leading to behavioral perturbations and disease. Somatic mosaicism has been studied extensively in the context of cancer, but this work has only recently begun to focus on brain disorders, particularly neurodevelopmental disorders. For example, in hemimegalencephaly (HMG), mutations in ATK3, PI3KCA, and mTOR genes in as few as 8% of the brain cells were found to result in cortical perturbations in an entire cerebral hemisphere. Recent technological progress in single-cell genome sequencing has made it possible for researchers to explore somatic variations at a single-cell level. Through such single-cell approaches, studies have identified several somatic Long Interspersed Nuclear Elements (LINE-1) insertions that occur in neural cell lineages during normal brain development.
Although there is increasing evidence of somatic mosaicism in the brain, the extent of such variation and its functional significance in normal brain development and in psychiatric disorders remain poorly understood. Elucidating the architecture of genetic perturbations in somatic cells of normal and diseased brains may provide new insights into genetic susceptibility of complex psychiatric disorders and lead to the identification of novel therapeutic targets.
An integral part of this FOA is identifying somatic variations in human brain and characterizing their role in one or more psychiatric disorders. Under the scope of this FOA, specific areas of research interest include, but are not limited to the following:
- Identify, characterize and validate the frequency and distribution of a range of somatic variations, including CNVs, SNVs, SVs, and retrotransposon insertions in different cell types, across brain regions, from diseased and healthy control brains.
- Identify whether somatic variations are differentially represented in diseased brains compared to healthy brains, with reference to the extent, frequency, location, and types of somatic variations, as well as the brain regions and cell types in which they occur.
- Apply state-of-the-art methods to prioritize somatic variants in coding and non-coding regions of the genome, based on their functional relevance to brain and psychiatric disorders.
- Identify whether and how such somatic variants interact with genes and gene networks reported to be associated with psychiatric disorders (e.g., using computational approaches).
- Trace the origin of such prioritized somatic variations across a range of developmental stages to identify how and when the variations occurred and assess their effects on downstream neurodevelopmental events.
- Pursue follow-up functional characterization of prioritized somatic variants through a variety of approaches, such as transcriptome analysis, epigenetic profiling, engineering somatic mutations in neural progenitor cells or iPSC lines to assess phenotypes, or by using other novel in vitro or in vivo model systems.
Applications submitted to this FOA should include the following elements: 1) comprehensive characterization and comparison of somatic variations in healthy control and diseased brains, and 2) determination of functional roles for these variations in psychiatric disorders. Since the primary focus of this FOA is to identify and characterize somatic variations in diseased human brains, the projects could utilize a phased approach. For example, the initial focus of the applications might be discovery of somatic variations across human brain; subsequent aims might focus on functional follow-up experiments to investigate the role of somatic mosaicism in the development of psychiatric disorders.
Research applications could explore the extent of somatic variations across neuronal cell types and lineages, from different brain regions, and/or for one or more psychiatric disorders. For example, one approach might be to combine state-of-the-art genomic, computational, single-cell and other relevant approaches to rapidly characterize and generate a high resolution map of different types of somatic variations across multiple brain regions implicated in the pathophysiology of psychiatric disorders.
Applications are encouraged to apply unbiased genomic approaches to evaluate somatic mosaicism using appropriate human brain samples from patient populations to correlate findings with psychiatric disorders. Comprehensive assessments could include identifying a range of somatic variations in different cell types or cell lineages, across brain regions in a large number of individuals covering one or more lifetime periods. For initial discovery of somatic genomic variations, applicants are encouraged to propose studies using brain samples from human patient populations, rather than induced pluripotent stem cell (iPSC) lines or model organisms as primary source. However, iPSC cell lines or animal models could be employed for functional follow-up analysis.
To the extent possible, investigators are encouraged to leverage existing large-scale, genome-wide data sets and brain sample collections from publicly available resources, including but not limited to Brainspan, The Genotype-Tissue Expression Project (GTEx), NIH NeuroBiobank, CommonMind Project, and Autism Tissue Program (ATP).
This FOA should be used when two or more collaborating sites are essential to complete the proposed research. It is required that Research Strategy must be identical across linked collaborative U01 applications, with the exception of a short section describing specific function of each application under “elements unique to that site.” For a linked set of collaborative U01 applications, each application must have its own Program Directory/Principal Investigator (PD/PI) and the program must provide a mechanism for cross-site coordination, quality control, data and sample sharing among BSM Network members, as appropriate, database management, statistical analysis, and reporting.
Deadlines: February 24, 2015; October 23, 2015; June 24, 2016; February 24, 2017
Filed Under: Funding Opportunities