Somatic Mutations of Brain Cells Lead To Varying Susceptibility to Illness in Human

Every tissue in the human body develops somatic mutations during the course of a person’s life through mechanisms that rely on the physiology of the tissue itself as well as foreign substances. Quantifying cell type-specific rates and processes of somatic mutation is essential to comprehending aging and disease, beginning at the tissue level since human tissues contain various cell types with distinct features. Even though somatic mutations in aging human neurons have been the subject of prior research, mutations in glial cells have not been looked at. Glial cells make up more than half of the brain’s cellular structure and are at the root of a number of neurological illnesses. Although the reasons for these alterations are unknown, abnormalities of white matter (WM), which is mostly made up of glial cells, are a hallmark of both neurodegenerative and neuropsychiatric illnesses as well as normal aging of the brain. Furthermore, many brain cancers are derived from glial progenitor cells. Recent research has revealed that white matter (WM) in healthy human brains is more saturated with clonal oncogenic mutations than gray matter.Brain

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Oligodendrocytes are capable of mutation.

The primary cell type of white matter is the oligodendrocyte (OL), and OL dysfunction has been linked to multiple sclerosis, age-related diseases, mental problems, and several types of brain cancer. Human OL generation starts in the second trimester of pregnancy, reaches its peak at birth and in the first few years of life, and continues throughout maturity, albeit at a slower pace. Unlike neurons, which mostly develop before birth, resident oligodendrocyte-precursor cells (OPCs) replenish OLs all during postnatal life, with aging slowing the pace of replenishment. Brain cancer is associated with dysregulation of OL lineage proliferation and differentiation, and certain gliomas have been identified as having their genesis in OPCs.

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A study was carried out using single-cell whole-genome (scWGS) sequencing to compare the rates and patterns of age-related somatic mutations in OLs to those in neurons separated from the same people. The appropriate sources were used to collect all human tissues that were used for the experiment. Antibody labeling of cortical brain tissue derived from post-mortem nuclei allowed for the isolation of OLs. All protocols were duly observed. Using whole-genome sequencing, >67,000 somatic single nucleotide variations (sSNVs) and minor insertions and deletions (indels) in 51 neurons and 71 oligodendrocytes from neurotypical people aged 0.4 to 104 were discovered. Despite the fact that both cell types get mutations as they age, it was found that oligodendrocytes develop sSNVs 69% more quickly than neurons (16 per year vs. 27 per year), whereas indels develop 42% more slowly (1.8 per year compared to 3.1 per year). The work revealed the mutational dynamics of OLs during neurotypical brain aging and showed distinct disparities in somatic mutation accumulation between neurons and OLs in the same tissue.

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Clinical significance

These study-derived patterns show the distinctions between the mutagenesis processes in glia and neurons and imply cell type-specific, aging-related contributions to neurodegeneration and oncogenesis. With this knowledge, the process of neurodegenerative disorders and various cancers can be better studied, and better therapeutic interventions can be made.


Contrasting patterns of somatic mutations in neurons and glia reveal differential predisposition to disease in the aging human brain



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