Scientists from Harvard Medical School, Boston Children's Hospital, and their collaborators have uncovered a vital quality-control mechanism operating within the developing fetal brain. Published this week in Nature, the study reveals that while the human brain generates an excess of neurons during development, those carrying multiple copy number variants—such as DNA duplications or deletions—are systematically removed around the time of birth.
The research team utilized single-cell whole genome sequencing to analyze over 1,500 neurons from 16 individuals, validating findings with deeper sequencing of more than 800 neurons from 12 others. Their data indicated that nearly 26 percent of neurons in the prenatal cortex possessed widespread copy number variants. However, this figure dropped rapidly to an average of 6.2 percent after birth. The scientists observed that neurons with these extensive genetic alterations were primarily eliminated perinatally, a timeline that parallels periods of programmed cell death.
According to the study, titled "Perinatal elimination of genetically aberrant human cortical neuron," these genomic disruptions likely impair the neurons' ability to form synapses. By sequencing DNA and RNA from over 44,000 individual cells, the team found that abnormal neurons exhibited irregular expression of genes essential for creating and maintaining neural connections. This failure to establish critical links during fetal development triggers their elimination in what researchers describe as a Darwinian competition for survival.
Christopher Walsh, MD, PhD, a co-senior author and professor at Boston Children's Hospital, noted the unexpected prevalence of these variants in early development but explained that it aligns with known processes of excess neuron formation. He emphasized that this struggle for synaptic connections serves as nature's quality control mechanism. Diane Shao, MD, PhD, a co-first author, added that disruptions to this system could contribute to neurodevelopmental disorders such as autism, schizophrenia, epilepsy, and intellectual disability.
While the study confirms that flawed neurons continue to be eliminated throughout adulthood at a slower rate, the primary pruning event occurs perinatally. The researchers are now investigating whether this elimination process differs in individuals with autism and other neurodevelopmental conditions. They are also exploring the potential role of this mechanism in adult-onset neurodegenerative disorders like Alzheimer's disease, aiming to improve future treatments for conditions where neural development goes awry.