Systematic Analysis of Genetic Mosaicism in FTD/ALS Brains
Abstract
Our major goal is to reveal the potential roles of genetic mosaicism in the etiology and progression of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), a Fiscal Year 2019 Peer Reviewed Medical Research Program Topic Area. FTD and ALS are increasingly recognized as a spectrum disorder because of overlaps in their clinical, genetic, and pathological features. FTD/ALS has a strong genetic basis, and about 30 disease-related genes have been identified in familial FTD/ALS patients during the past two decades due to advances in next-generation sequencing. However, familial cases only account for approximately 30% of FTD and 10% of ALS, while the majority of cases are sporadic and lack a family history of the disease. Therefore, it is critical to understand the etiology of the sporadic FTD/ALS and identify risk factors that are associated with it. Genetic mosaicism, either clonal or non-clonal, has been proposed to play a potential role in the pathogenesis of sporadic FTD/ALS. This is supported by the focal onset, stereotyped patterns of spread and late-age onset of sporadic FTD/ALS. In contrast to inherited germline mutations, genetic mosaicism or somatic mutation arises from errors in DNA damage repair that occurs during development or postnatal life. A somatic mutation that occurs in one cell during development is inherited by all its daughter cells and becomes a clonal mutation in the body. Distribution of such clonal mutations can be restricted in the brain if they occur at the late stage of development, and this restricted distribution prevents the somatic mutations from being detected in non-brain tissues including blood, hair, and skin through traditional genetic screening. To discover the presence of rare clonal mutations in FTD/ALS brains directly, the first goal of our project will be devoted to high-throughput screening of clonal mutations in a panel of 90 neurodegeneration related genes in the prefrontal cortex, motor cortex, and cerebellum of a cohort of sporadic FTD/ALS and age-matched normal cases. Clonal mutations of previously identified FTD/ALS genes will be identified and evaluated based on their predicted pathogenicity. Potential crossover between FTD/ALS and other neurogenerative diseases can also be evaluated because our targeted gene sequencing panel also contains genes that are related to Alzheimer’s disease, Parkinson’s disease and other rare types of dementia. Results of our project will reveal the frequency of pathogenic clonal mutation in FTD/ALS and may change our understanding of the genetics of the disease. Non-clonal somatic mutation can also arise in post-mitotic neurons during the normal aging process as a result of error-prone DNA damage repair. This kind of somatic mutation is unique to each cell and cannot be detected through regular genomic sequencing of bulk tissues. Although cells normally can tolerate and accumulate somatic mutations, accelerated accumulation of somatic mutation may be detrimental to the cell. Indeed, a recent study showed that Cockayne syndrome (CS) and xeroderma pigmentosum (XP), two human progeroid diseases characterized by accelerated aging and premature neuronal loss, exhibit faster accumulation of somatic single-nucleotide variant (sSNV). Given the fact that TDP-43, FUS, and C9ORF72 expansions, the three major genetic causes of FTD/ALS, are all implicated in DNA damage repair, it is very likely that neuronal cell death in FTD/ALS is a consequence of intolerable accumulation of somatic mutations. Our second goal is to compare the rate and pattern of non-clonal somatic mutations in neurons of FTD/ALS brains to neurons of normal brains. Various types of mutation, including SNV, indel, retrotransposon insertion, and double-strand break, will be evaluated through single-cell whole-genome and targeted sequencing. These approaches allow us to define ultra-rare mutations at the single-cell level. An increased burden of soma
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010028
Entities
People
- Zinan Zhou
Organizations
- United States Army