Human brain eliminates genetically aberrant neurons perinatally, study shows

Scientists investigated somatic copy number variants (CNVs) across human neurodevelopment using postmortem brain samples ranging from 14 gestational weeks to over 90 years of age, as reported by nature.com. The researchers sequenced 2,357 single postmitotic cortical neurons across two independent whole-genome sequencing methods nature.comnature.comnature.comOpen source ↗. The data showed that an average of 25.9% of prenatal cortical neurons possessed widespread CNVs across multiple chromosomes.

Perinatal selection

The proportion of neurons carrying severe genomic abnormalities decreased by approximately 4.5-fold after birth (Fisher meta-analysis P = 3.5 × 10⁻⁶) nature.comnature.comnature.comOpen source ↗. This elimination occurred primarily during the perinatal period, coinciding with developmental programmed cell death. Neurons carrying smaller CNV burdens exhibited a much slower decline in frequency across postnatal aging.

Surviving postnatal neurons showed a depletion of CNVs within dosage-sensitive genes and genes linked to neurodevelopmental disorders (hypergeometric test P < 0.05) nature.comnature.comnature.comOpen source ↗. This depletion indicates selective purifying elimination during cortical maturation rather than random cell loss.

Synaptic gene regulation

To identify potential clearance pathways, researchers profiled 44,861 single nuclei using single-nucleus RNA sequencing and assay for transposase-accessible chromatin (snATAC) nature.comnature.comnature.comOpen source ↗. Neurons harboring high CNV burdens exhibited disrupted synaptic gene expression. The authors concluded that abnormal synaptic regulation likely contributes to the selective removal of genomically defective cells during human development.