Perinatal Elimination of Genetically Aberrant Neurons from Human Cerebral Cortex

Human neurons are postmitotic and long-lived, requiring precise genomic regulation to maintain function over a lifetime. Normal neuronal function is highly dependent on gene dosage, with copy number variants (CNVs) and heterozygous point mutations associated with a host of neurodevelopmental and neuropsychiatric conditions [1-3]. Here, we investigated the landscape of somatic CNVs arising in fetal human brains, and how they change over development, to understand the processes that generate neurons with low rates of aneuploidy. We identified 7,725 CNVs in > 1,200 single neurons from human postmortem brain of 16 neurotypical individuals, ranging in age from gestational week 14 to 90 years old using Tn5-transposase-based single-cell whole-genome amplification. We surveyed CNVs in another 44,861 nuclei with 10X Multiome analysis. Up to 45% of postmitotic neurons in the prenatal cortex showed aberrant genomes, characterized by widespread CNVs of multiple chromosomes, but this reduces sharply after birth (p < 0.01). We identified micronuclei in the developing cortex in situ, reflecting chromosomal material missegregated during neurodevelopment [4-6]. The size of CNV appeared to define the trajectory of neuronal elimination, since cells with widespread CNVs were eliminated earlier and faster than cells with smaller CNVs. CNVs in surviving neurons were depleted for genes that are dosage-sensitive or involved in neurodevelopmental disorders (p < 0.05), suggesting selective elimination of neurons with CNVs involving these critical genes. Neurons with high CNV burdens also showed abnormal expression of synaptic gene sets, indicating that abnormal synaptic gene regulation may contribute to neuronal elimination. Elimination of defective neuronal genomes during during synaptogenesis may represent a critical process of genome quality control and a vulnerable target of factors that contribute to neurodevelopmental disease.