Perinatal Elimination of Genetically Aberrant Neurons from Human Cerebral Cortex

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Human neurons are postmitotic and long-lived, making genomic content regulation critical.
• Gene dosage is vital for neuronal function, and copy number alterations (CNAs) are linked to neurodevelopmental and neuropsychiatric disorders.

Purpose of the Study:

• To investigate the landscape of CNAs in normal human brains, focusing on prenatal and perinatal periods.
• To understand the prevalence and impact of CNAs on neuronal development and elimination.

Main Methods:

• Surveyed approximately 5,897 CNAs in over 1,200 single neurons from postmortem human brains (gestational week 14 to 90 years old).
• Employed Tn5-based single-cell whole-genome amplification (scWGA) and advanced informatics to validate CNAs in single neurons.

Main Results:

• Up to 45% of prenatal cortical neurons exhibited aberrant genomes with large-scale CNAs, significantly decreasing during the perinatal period.
• Identified micronuclei in the developing cortex, indicating genetic instability.
• Subchromosomal CNAs were eliminated more slowly throughout life, and CNAs involving dosage-sensitive or neurodevelopmental genes were depleted.

Conclusions:

• A significant proportion of neurons with CNAs are eliminated during human brain development, particularly in the perinatal period.
• This genomic quality control mechanism removes neurons with critical gene alterations, essential for normal cognitive function.
• The elimination of defective neuronal genomes is a key developmental landmark for healthy brain function.