Somatic Mosaicism in the Aging Brain
Somatic mosaicism is the result of the random mutational damage that occurs to stem cells and progenitor cells, leading to a spread of different mutation patterns throughout the descendant cells making up a tissue. It is thought to be involved in aging, a way for random mutation, different in every cell, to lead to specific dysfunctions occurring throughout a tissue, and potentially prime a tissue for a later combination of mutations that gives rise to cancer. This commentary on recent research discusses somatic mosaicism in the brain, intending to see whether there were differences in neurological disease states, but the findings are more relevant to cancer risk.
Mutagenesis occurs in human cells starting from the fertilized egg and continuing throughout life, resulting in somatic mutations. Most somatic mutations are functionally benign and have neither harmful nor beneficial effects on health. In rare cases, they change cell functions and may lead to diseases. Cancer is the most common example of a genetic disorder caused by somatic mutations.
In our recent study, we analyzed 131 post-mortem human brains from 44 healthy individuals, 19 with Tourette syndrome, nine with schizophrenia and 59 with autism spectrum disorder. The study reported several interesting findings by whole-genome sequencing of the brains to a depth of over 200X. First, most brains had 20-60 detectable single-nucleotide mutations that likely arose in early development. There were no differences in the somatic mutation burden between diseased and normal brains. Unexpectedly, seven brains, about 6% of the total, carried an abnormally large number - at least 100 but as many as 2000 - of somatic mutations. This phenomenon was termed hypermutability. Hypermutability increased with age, reaching ∼16% among old brains (older than 60 years of age), while it was only ∼2% among younger brains (less than 40 years of age). Interestingly, 10 damaging mutations in cancer-driving genes were found in four of the other six hypermutable brains, therefore implying clonal expansion. Consistently, hypermutability is typically localized to one brain region, although that estimate could be biased as no more than two regions per brain were analyzed.
Age is known to be the major factor associated with cancer occurrence. As such, the observed hypermutability carries two major hallmarks of cancers: clonal expansion and age association. This suggests that hypermutability generally represents pre-cancer or undiagnosed cancer cases, implying a theoretical possibility of cancer monitoring and early detection based on genomics. Association with aging also implies that hypermutability could be relevant in other aging-associated diseases such as Parkinson's and Alzheimer's. If proven, they theoretically could be diagnosed early before symptoms develop, using hypermutability as a genomic biomarker. However, it is currently unclear how this could be achieved, given that brain tissue is hardly accessible.
The question of which cell type expanded remains open. It could be interneurons. However, since the cell fractionation experiment may not isolate pure interneurons, clonally expanded cells could theoretically be some other cell type. Unlike post-mitotic neurons, glial cells continue to divide in adult brains. Given previous studies reporting increased glial cell fraction with age, the hypothesis of clonal gliogenesis is consistent with the observation that hypermutable brains are older. Clonal hematopoiesis with infiltration of blood into the brain could be yet another possibility. This hypothesis emerges from the observation that mutated cancer-driving genes in hypermutable brains are frequently associated with clonal hematopoiesis. In aging adults, clonal hematopoiesis increases, and the blood-brain barrier also becomes leakier. So, expanded cell lineages in the blood could be detected in the brain. Further studies are required to determine which hypothesis is correct, but it is possible that all could be correct, and there could be different causes of hypermutability in different individuals.