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Perinatal Elimination of Genetically Aberrant Neurons from Human Cerebral Cortex

In this study, we used two independent single-cell whole-genome sequencing methods, Tn5-transposase-based amplification (TbA) and primary template amplification (PTA), to profile somatic copy number variants (CNVs) in single cortical neurons from postmortem human brain donors ranging from gestational week 14 to over 89 years of age, complemented by single-nucleus multiome (ATAC- and RNA-seq) profiling of a subset of the same donors. We found that widespread, multi-chromosomal CNVs were present in up to 46% of prenatal neurons, but this proportion dropped four- to five-fold after birth. Neurons with widespread CNVs were eliminated mostly around the time of birth, while neurons carrying smaller CNVs continued to be cleared more gradually throughout postnatal life. CNV breakpoints tracked closely with DNA replication timing, and recurrent copy losses were associated with double-strand break hotspots, implicating replication stress and NHEJ-mediated repair in dividing progenitor cells as sources of these lesions. Consistent with chromosome missegregation during development, we also observed micronuclei containing missegregated chromosomal material in the prenatal cortex, with micronuclear genomic content declining with age in parallel with the loss of CNV-bearing neurons. Neurons with a high CNV burden showed dysregulated synaptic gene expression and increased cell-death pathway activity, and the genomic regions spared from CNVs in surviving neurons were enriched for autism-risk and postsynaptic genes, evidence that this elimination is selective rather than random. Together, these findings suggest that clearance of genomically defective neurons, coupled to synapse formation, acts as a genome quality-control mechanism across brain development and aging. Through this accession, we are releasing single-cell and bulk whole-genome and multiome sequencing data for the postmortem brain donors and one iPSC-derived reference line.