Perinatal Reduction of Genetically Aberrant Neurons from Human Cerebral Cortex

Since human neurons are postmitotic and long-lived, the regulation of their genomic content is crucial. Normal neuronal function is uniquely dependent on gene dosage, with diverse genome copy number alterations (CNA) associated with neurodevelopmental and neuropsychiatric conditions ^1–3 . In this study, we evaluated the landscape of CNA arising in normal human brains, focusing on prenatal and perinatal ages. We surveyed ∼5,897 CNA in >1,200 single neurons from human postmortem brain of individuals without a neurological diagnosis, ranging in age from gestational week (GW) 14 to 90 years old. Using Tn5-based single-cell whole-genome amplification (scWGA) and informatic advances to validate CNAs in single neurons, we determined that a striking proportion of neurons (up to 45%) in human prenatal cortex showed aberrant genomes, characterized by large-scale CNAs in multiple chromosomes, which reduces significantly during the perinatal period (p<0.1). Furthermore, we identified micronuclei in the developing cortex, reflecting genetic instability reminiscent of that described in early embryonic development ^4–6 . The scale of CNA appeared to alter the trajectory of neuronal elimination, as subchromosomal CNAs were more slowly eliminated, over the course of a lifetime. CNAs were depleted for dosage-sensitive genes and genes involved in neurodevelopmental disorders (p<.05), and thus represent genomic quality control mechanisms that eliminate selectively those neurons with CNA involving critical genes. Perinatal elimination of defective neuronal genomes may in turn reflect a developmental landmark essential for normal cognitive function.