The goal of this project is to understand the role of somatic mutations in neurodegeneration, specifically in neurodegenerative disorders Alzheimer's Disease (AD) and Ataxia Telangiectasia (AT), using single-cell analysis. AD is a progressive neurodegenerative disorder leading to the loss of memory and other cognitive functions; AT is another neurodegenerative disorder with inherited defects in DNA double strand break (DSB) repair. Somatic mutations have been studied most extensively in cancer, but they also cause neurodevelopmental disorders such as epilepsy and hemimegalencephaly. Previous studies have found somatic mosaic mutations in causally implicated genes in some neurodegenerative diseases, such as presenilin-1 in AD. Other studies, including our work, have suggested that the lack of proper DSB repair in AT may allow increased accumulation of somatic mutations, including those in repetitive DNA, and lead to neuronal cell death. Our recent single-neuron genomic studies showed that even neurologically normal human brains are a patchwork of somatic mutations that occur throughout one's life, and that active transcription may play a role in generation of rare somatic mutations. We therefore hypothesize that late-development or even post-mitotic mutations in a small number of neurons may have a functional role in the loss of synaptic function and cell loss in neurodegenerative diseases. To overcome the limited detection sensibility for low frequency variants in current bulk-cell analysis, we will employ single-cell genomics to test our hypothesis, using novel computational tools to circumvent the noise in the data introduced by the genome amplification process necessary in current single-cell sequencing protocols.
In Aim 1, we propose to develop robust analytical methods to mitigate the impact of genome amplification bias in detecting multiple forms of somatic mutations, including repeat aberrations (tandem repeats such as telomere and retrotransposons).
In Aim 2, we will analyze somatic mutations in post-mortem brains of patients with AT and AD using single-neuron whole genome sequencing.

Public Health Relevance

The aim of this proposal is to characterize multiple forms of somatic mutations in Ataxia-Telangiectasia and Alzheimer's disease, two neurodegenerative disorders that do not have effective treatments, by using single- cell genomic analysis. This project will not only enable a better understanding of the role of somatic mutations in these neurodegenerative diseases but also provide a framework for single-cell genomic analysis that can be applied to other neurodevelopmental and neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01AG051791-01A1
Application #
9179977
Study Section
Neuroscience of Aging Review Committee (NIA)
Program Officer
Wise, Bradley C
Project Start
2016-08-01
Project End
2021-04-30
Budget Start
2016-08-01
Budget End
2017-04-30
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
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Jung, Hyunchul; Lee, Donghoon; Lee, Jongkeun et al. (2015) Intron retention is a widespread mechanism of tumor-suppressor inactivation. Nat Genet 47:1242-8