Human Study Finds Perinatal Decline in Neurons With Widespread CNVs

Researchers sequenced 2,357 single neurons from human postmortem brains spanning fetal to postnatal life, using two single-cell whole-genome sequencing approaches. They also analyzed 44,861 nuclei with single-nucleus chromatin-accessibility and RNA-sequencing methods to investigate gene regulation associated with copy number variants (CNVs). The study focused on somatic CNVs—DNA copy-number changes arising in individual neurons—and their frequency across developmental stages.

An average of 25.9% of prenatal cortical neurons (range, 12.7%–46%) had widespread CNVs involving multiple chromosomes. This proportion was about 4.5 times lower after birth across the two sequencing approaches (Fisher meta-analysis P=3.5×10⁻⁶). Neurons with the most widespread CNVs were mainly absent by the perinatal period, while neurons with smaller CNV burdens declined more gradually with postnatal age. CNVs in surviving neurons were depleted for dosage-sensitive genes and genes associated with neurodevelopmental disorders. Neurons with high CNV burdens also showed abnormal synaptic gene expression.

The authors propose that selective elimination of neurons with genomic abnormalities may be part of normal developmental quality control. The postmortem, observational analyses cannot establish the mechanisms causing neuronal loss or show that this process is altered in people with neurodevelopmental disorders. The findings are mechanistic and do not currently support a change in clinical care.