This study investigates the patterns of somatic mutations in human oligodendrocytes (OLs) and neurons, two major cell types in the brain, to better understand the mechanisms of aging and disease. Using single-cell whole-genome sequencing (scWGS), the researchers identified over 92,000 somatic single-nucleotide variants (sSNVs) and small insertions/deletions (indels) in 86 OLs and 56 neurons from individuals aged 0.4 to 104 years. They found that OLs accumulate sSNVs at a rate 81% faster than neurons and indels at a rate 28% slower than neurons. The distribution of mutations in OLs and neurons differs significantly: OL mutations are enriched in inactive genomic regions and are distributed across the genome similarly to mutations in brain cancers, while neuronal mutations are enriched in open, transcriptionally active chromatin. These differences suggest distinct mutagenic processes in OLs and neurons, with OLs potentially undergoing more active mutagenesis related to DNA replication and positive selection for cancer insurgence. The study also highlights the importance of understanding cell-type-specific mutational patterns in aging and disease.This study investigates the patterns of somatic mutations in human oligodendrocytes (OLs) and neurons, two major cell types in the brain, to better understand the mechanisms of aging and disease. Using single-cell whole-genome sequencing (scWGS), the researchers identified over 92,000 somatic single-nucleotide variants (sSNVs) and small insertions/deletions (indels) in 86 OLs and 56 neurons from individuals aged 0.4 to 104 years. They found that OLs accumulate sSNVs at a rate 81% faster than neurons and indels at a rate 28% slower than neurons. The distribution of mutations in OLs and neurons differs significantly: OL mutations are enriched in inactive genomic regions and are distributed across the genome similarly to mutations in brain cancers, while neuronal mutations are enriched in open, transcriptionally active chromatin. These differences suggest distinct mutagenic processes in OLs and neurons, with OLs potentially undergoing more active mutagenesis related to DNA replication and positive selection for cancer insurgence. The study also highlights the importance of understanding cell-type-specific mutational patterns in aging and disease.