Nearly one in three fetal cortical neurons may carry genetic abnormalities, but their prevalence drops dramatically after birth, revealing a potential quality-control process that helps shape the developing human brain.
Study: Perinatal elimination of genetically aberrant human cortical neurons. Image credit: ktsdesign/Shutterstock.com
A substantial proportion of human cortical neurons carry genetic abnormalities before birth, but their prevalence falls sharply during early life, according to a study published in Nature. The findings suggest that the developing brain may selectively eliminate neurons with extensive DNA alterations, potentially through processes involving synaptic dysfunction and programmed cell death.
Researchers found that approximately 26% to 33% of prenatal cortical neurons carried widespread copy number variants (CNVs), involving gains or losses of DNA segments. After birth, this proportion fell to around 6% to 7%, a roughly 4.5-fold reduction.
The findings point to a potential genomic quality-control process that helps shape the developing brain, although the researchers have not established precisely how genetically abnormal neurons are eliminated.
Tracking genetic abnormalities from fetal development to old age
Neurons are long-lived cells that generally stop dividing once they mature. Their function depends on tightly regulated gene activity, making them particularly sensitive to changes in gene dosage. CNVs and other genetic mutations affecting brain-related genes have been associated with conditions including autism, schizophrenia, epilepsy, and intellectual disability.
Although chromosomal abnormalities are common during early embryonic development, scientists have been uncertain about how many affected neurons survive in adulthood.
To investigate, researchers analyzed postmortem brain tissue from 23 donors, ranging from 14 weeks of gestation to more than 90 years of age.
They used two independent single-cell whole-genome sequencing approaches to examine 2,357 neuronal nuclei, including 1,907 genomes that passed stringent quality-control criteria. The researchers also analyzed chromatin accessibility and gene expression in 44,861 additional nuclei to investigate how genomic abnormalities might influence neuronal function and survival.
The results revealed a pronounced difference between prenatal and postnatal brains.
Neurons with widespread CNVs were considerably more common before birth, while their prevalence remained relatively low after birth and into old age. Among infants, approximately 7.1% of neurons carried widespread CNVs, compared with 4.8% in individuals over 60.
A separate analysis of CNVs across the detectable size range also showed that genetic alterations were more prevalent in prenatal than postnatal neurons.
Combining their findings with six previous studies, the researchers estimated that approximately one-third of neurons carried a CNV at birth, with prevalence declining by around 0.27 percentage points annually thereafter.
Together, these results suggest two phases of neuronal selection: a pronounced reduction in cells carrying widespread CNVs around birth, followed by a slower decline in neurons with smaller genomic alterations throughout life.
Genetic damage may influence which neurons survive
The researchers also investigated where these abnormalities originate and why some affected neurons may be more likely to disappear.
Patterns of CNVs resembled genetic signatures previously identified in cancer cells, suggesting that at least some alterations arise when neural progenitor cells divide before developing into mature neurons.
Further evidence came from the distribution of CNV breakpoints, which were associated with DNA replication and regions vulnerable to DNA damage.
The researchers also identified micronuclei, small membrane-enclosed structures containing chromosomes or chromosome fragments separated from the main nucleus, alongside approximately 6% of nuclei in fetal cortical tissue. These structures became less common with age, broadly mirroring the decline in neurons carrying CNVs.
To explore potential mechanisms of neuronal elimination, the team examined gene-expression patterns in neurons with genomic abnormalities.
In postnatal brains, CNV-bearing neurons showed reduced activity in gene networks involved in synaptic function. One subgroup also displayed increased molecular signatures associated with apoptosis and autophagy, processes involved in cell death and cellular recycling.
This subgroup was most prevalent in infants and younger individuals and became less common with age. The researchers did not identify it in the mid-gestation samples, although the absence of third-trimester tissue prevented them from determining precisely when these changes first emerge.
The findings suggest that disrupted synaptic gene regulation may contribute to the elimination of genetically abnormal neurons during a period of extensive brain development and circuit formation.
However, the associations do not establish that synaptic dysfunction directly triggers neuronal death.
Developing brain may select against harmful genetic changes
The researchers also examined which genomic regions were more or less frequently affected by CNVs in surviving neurons.
They identified genomic coldspots, regions rarely disrupted by CNVs, that were enriched for genes involved in neurodevelopment, including autism-associated and postsynaptic genes.
These patterns are consistent with purifying selection, in which cells carrying potentially harmful genetic alterations are less likely to survive.
The results suggest that neurons with CNVs affecting dosage-sensitive genes or synaptic regulation may be preferentially eliminated, leaving a population less likely to carry disruptive changes in these regions.
This proposed selection process coincides with a well-established period of programmed neuronal death around birth, during which approximately 30% of cortical neurons may be eliminated as developing neural circuits mature.
The authors suggest that removing neurons with extensive genomic abnormalities could be one function of this developmental process.
They also estimated, using a meta-analysis, that the age-related decline in CNV-bearing neurons could correspond to approximately 13% neuronal loss over 60 years. This is broadly comparable to previous estimates of age-related neuronal loss, but the study did not directly measure such losses or establish that CNVs caused them.
Findings raise questions about brain development and aging
The researchers propose that selective elimination of genomically abnormal neurons may serve as a developmental quality-control mechanism.
If genetic or environmental factors disrupt this process, abnormal neurons might persist and potentially affect brain development. The authors also suggest that similar selection mechanisms could have implications for neurodegeneration later in life, when other forms of somatic mutation accumulate.
These possibilities remain speculative, however, and the study did not directly investigate neurological disease outcomes.
However, the study has some limitations. The analysis involved a relatively small number of donors, with no third-trimester samples to establish the precise timing of the proposed elimination process. Some genomic analyses also had limited sensitivity for detecting smaller CNVs.
Importantly, the researchers compared brain tissue from different individuals rather than following neurons over time. The proposed selective elimination was therefore inferred from age-related differences and molecular signatures, not directly observed.
Despite these uncertainties, the study provides evidence that the genomic composition of the human cerebral cortex changes substantially around birth.
The findings suggest that neurons carrying extensive genetic abnormalities become less common during early development, potentially through selective processes linked to synaptic regulation and programmed cell death. Establishing how these processes operate, and whether their disruption contributes to neurological disease, will require further investigation.
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