Sequence analysis of 131 human brains has revealed the mutagenesis processes that take place throughout life, from development to senescence. In a new study published in the July 29, 2022, issue of Science, the authors described how high rates of brain somatic mutations (what they call hypermutability) correlated with age. Their work includes certain neuropsychiatric diseases, where they found some genetic signatures that could be used for an early clinical diagnosis of different pathologies.

To know how somatic mosaicism is distributed in the brain, researchers from Yale University, the Lieber Institute for Brain Development (LIBD) and Harvard University extracted samples of frozen postmortem brain tissue. Tissues were dissected from at least one or two brain regions (cortex, striatum or hippocampus) in 131 individuals.

Of these, 44 of the samples belonged to people without neurological pathologies and 87 came from patients affected by neuropsychiatric disease: 19 with Tourette syndrome (TS), 9 with schizophrenia (SCZ) and 59 with autism spectrum disorder (ASD).

The DNA came from neurons and glial cells analyzed by whole genome sequencing (WGS). After data alignment, researchers recorded somatic point mutations for all samples.

To distinguish these mutations, they examined the frequency of the annotation and the lack of overlap compared to the catalog of human germline variations. And to validate the data, they analyzed the mutations of two of the brains (NC7 and LIBD82) using the single-cell RNA sequencing (scRNAseq) technique.

Their results showed that there were between 20 to 60 somatic mutations of a single nucleotide for each brain. In these cases, there were no differences between the number of somatic mutations between the brains that come from samples without pathologies and those from patients with neuropsychiatric diseases. However, 6% of the brains, and at least one of the brains in each cohort, had an atypically high count of somatic mutations. The authors have described these cases as hypermutable brains.

Somatic mutations are not inherited but originate early in development. This is consistent with the finding of somatic mutations that do not correlate with age, as occurs in these samples. However, in the case of hypermutable brains, the number of somatic mutations did increase with age. The data indicate that only 2% of people under 40 years of age had brain hypermutability, while 16% of brains over 60 years of age were hypermutable. Therefore, these mutations not only originate during development but are also established during aging.

The LIBD82 brain came from a patient with SCZ. This case presented the highest number of mutations (validated by scRNAseq) and several genomic alterations in the hippocampus, including duplication of chromosome 7 and deletion of chromosome 10. These aneuploidies constitute a characteristic signature in glioblastoma-type tumors.

Since there was no prior clinical evidence of this disease for this patient, the data suggest that hypermutability or some mutations could serve as a diagnosis of cancer several years before it even develops, as is the case of this brain with an incipient glioblastoma.

When asked what other diagnostic applications are deduced from this study, coauthors Flora Vaccarino (Yale University) and Alexej Abyzov (Mayo Clinic) remarked that this depends upon the cells harboring the mutations causing lineage expansion. "They may be detected in peripheral tissues. If such cells proliferate and apoptose (we don't know about that) one may hope to detect duplications and deletion in the cell-free DNA in the blood," they told BioWorld Science.

Researchers have also found that autism samples were associated with mutations that create transcription factor binding motifs in enhancer-like regions in the developing brain. These corresponded to myeloid ectopic viral integration site transcription factors (MEIS), suggesting a relationship between their role in gene regulation and autism.

On the origin of hypermutability

Hypermutability is present in both control brains and neuropsychiatric patients. A high mutation rate is correlated with age, but it is not related to the disease state. What is the cause of such a degree of mutation? Could it be associated with genomic instability? "Causes of hypermutability are unclear. We think that genomic instability is not likely the cause," they said. These authors have deduced that hypermutability is not innate, but rather occurs at some point in an individual's life.

They hypothesized that the cell lineage carrying these mutations undergoes clonal expansion that allows other mutations from the previous lineage to increase until they reach a detectable frequency. "Likely all cases of hypermutability result from lineage expansion. Potentially, any somatic mutation could confer competitive advantage and lineage expansion," they remarked. Mutations in nonhypermutable brains do not correlate with age but those in hypermutable brains do. "Possible explanations are: mutations causing lineage expansion are more frequently acquired during aging, or cells harboring those mutations are less frequently eliminated during aging, or it takes time for lineage expansion so that we can only see it in aging. Implications are that these expanded lineages may evolve into cancer," they explained.

Researchers' next steps will focus on "assessing the cell type(s) harboring mutations causing lineage expansion; improving assays and technologies to detect somatic mutations in living persons; and identifying mutations leading to lineage expansion," they commented.