Human genomes harbor significant variation both between and within individuals. Numerous studies have explored inherited variation across human populations and linked various germline polymorphisms to human traits and disease susceptibility. However, genomic sequences also vary within a single individual after zygote formation, resulting in somatic mosaicism. This mosaicism leads to genomic variants that range from individual cells to entire tissues and developmental lineages. We have recently begun to explore this mosaicism within the human prefrontal cortex, a region of the brain associated with numerous neuropsychiatric disorders including Alzheimer’s disease, schizophrenia, and bipolar disorder. Using a combination of single cell DNA sequencing and bulk tissue analysis from post-mortem human brains, we have identified numerous somatic copy number variants and retrotransposon insertions as well as evidence of ongoing somatic transfer of mitochondrial DNA into the nuclear genome. Our findings reveal intriguing attributes of these somatic variants, including regions of enrichment and depletion within the neuronal genome and associations with aging. Our work contributes to the growing body of research that suggests an ongoing accumulation of mitotic and post-mitotic somatic genomic variation, challenging the concept of a static human genome.
“Exploring the Mosaic Nature of Neuronal Genomes”
