Developing Brain Removes Neurons Carrying Widespread DNA Copy Number Variants

Neurons carrying widespread DNA copy number variants are common in the prenatal cortex, then become far less frequent around birth. A study published in Nature links that decline to abnormal expression of genes involved in forming and maintaining synapses, pointing to a possible quality-control process in the developing brain.

The change is striking: researchers report that nearly 26 percent of prenatal cortical neurons had widespread copy number variants, or CNVs, compared with an average of 6.2 percent after birth. CNVs are stretches of DNA that have been duplicated or deleted. Their presence doesn't by itself show that a neuron will malfunction, but widespread changes can alter how genes are expressed and how a cell develops.

The findings appear in “Perinatal elimination of genetically aberrant human cortical neuron.” The team found that neurons with widespread CNVs were mostly eliminated around the time of birth, while cells with smaller CNV burdens declined more gradually with age. The timing suggests that the transition around birth may be a particularly important period for sorting among developing neurons, although the study doesn't establish what triggers the loss.

Tracking genomic changes one neuron at a time

To measure how common these variants were, the scientists developed single-cell whole-genome sequencing methods. They first lightly sequenced more than 1,500 neurons from 16 individuals, then checked their results through deeper sequencing of more than 800 neurons from 12 individuals. Computational analysis identified CNVs in the sequenced cells. Looking at individual cells matters here: a bulk sample can average together neurons with different genomes and conceal how unevenly these variants are distributed.

That approach let the researchers chart where variants occurred in the genome and compare their frequency across ages, said Peter Park, PhD, co-senior author and professor of biomedical informatics at Harvard Medical School. The team also analyzed DNA and RNA from more than 44,000 individual cells to investigate what might happen to neurons carrying extensive variants. Pairing genomic information with gene-expression data gave the researchers a way to ask not only which cells carried CNVs, but also whether those cells were behaving differently at the molecular level.

Those neurons showed abnormal expression of genes involved in synapse creation and maintenance. The results suggest that difficulty forming key connections may contribute to their elimination during fetal development. The study doesn't establish that this is the sole cause of their loss, but it offers a genomic view of a process researchers have long associated with competition among neurons for synaptic connections. The connection is plausible, but it remains a proposed explanation: altered gene expression and cell loss occurring together don't by themselves prove which causes which.

A possible quality-control mechanism

Christopher Walsh, MD, PhD, co-senior author and professor of pediatrics and neurology at Boston Children’s Hospital, said the prevalence of CNVs in early development surprised the team. He connected the result to the brain’s production of excess neurons and to findings from in vitro fertilization research. That framing places the observations within a broader account of development, in which producing more cells than the mature brain will retain may create opportunities for selection as neural circuits form.

This is more significant than it looks: the study raises the possibility that variation in the genome of individual neurons is part of normal development, and that the brain's response to that variation changes over time. It doesn't mean every neuron with a CNV is harmful or destined to disappear. The scale and location of a variant, along with the cell's ability to form connections, may matter; the study's reported pattern points to those questions without answering them.

Diane Shao, MD, PhD, an HMS instructor of neurology at Boston Children’s and a co-first author, said disruption of this quality-control process could be relevant to neurodevelopmental conditions such as autism. CNVs can affect brain function and have been linked to autism, schizophrenia, epilepsy, and intellectual disability. Understanding how neurons with these variants are removed could help researchers investigate how neural development differs in people with these conditions. If you're working in this space, the distinction between finding a variant and understanding its effect in a particular cell is central.

What the findings leave open

The researchers also confirmed that neurons with genomic abnormalities continue to be eliminated in adulthood, though at a much slower pace. That finding suggests the process isn't confined to the period around birth, but the slower rate leaves open whether adult cell loss has the same causes or significance as the developmental decline. A shared pattern doesn't guarantee a shared mechanism.

They are now examining whether the process differs in developing brains of people with autism and other neurodevelopmental disorders, and whether it contributes to adult-onset conditions such as Alzheimer’s disease. Those are research questions, not conclusions from this study. Similar biological processes can have different effects depending on when they occur and which cells are involved (and this is the part most people overlook). The key next step is determining when this pruning process supports development—and when its disruption may matter.

For now, the work provides a way to study genomic variation neuron by neuron across age, alongside evidence that cells with extensive CNVs become less common near birth. The proposed quality-control interpretation is compelling, but it will need further study to establish how the cells are selected and whether that selection changes in disease. A useful lead, with important questions still unresolved.

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