By analyzing genomic data from neurons, scientists from Harvard Medical School (HMS), Boston Children’s Hospital, and their collaborators have gained insights into a critical quality-control mechanism that takes place in the developing fetal brain.
During development, the human brain generates an excess of neurons, most of which are eliminated around when the baby is born. According to a study published this week in Nature, scientists report that neurons with multiple copy number variants, including DNA duplications or deletions, are widespread in the developing brain. However they are selectively eliminated shortly before or after birth likely because the genomic alterations disrupt their ability to form synapses.
Full details are provided in a paper titled “Perinatal elimination of genetically aberrant human cortical neuron.” The findings reported there are significant because copy number variants can impact brain function and may contribute to neuropsychiatric conditions, including autism, schizophrenia, epilepsy, and intellectual disability. A better understanding of the pruning process in the developing brain could improve how autism and other disorders in which neural development goes awry are treated.
As Diane Shao, MD, PhD, HMS instructor of neurology at Boston Children’s and a co-first author on the study noted, “If that quality control system can be disrupted, that could be part of what goes wrong in neurodevelopmental disorders like autism. Understanding the mechanism could eventually point us toward what to look for, and maybe what to protect.”
One of the first steps in the study was exploring the prevalence of copy number variants in developing human brains. To do that, the scientists designed single-cell whole genome sequencing approaches that allowed them to lightly sequence the genomes of single neurons. They used this method to sequence over 1,500 neurons from 16 individuals. They then validated the results with deeper sequencing of over 800 neurons from 12 individuals. They then used various computational methods to identify copy number variants in each sequenced genome. With their approach, it was possible to see the genomic changes “one neuron at a time, map where in the genome they occur, and compare how common they are from before birth to old age,” explained Peter Park, PhD, co-senior author on the paper and professor of biomedical informatics at HMS.
The data showed that an average of nearly 26 percent of neurons in the prenatal cortex had widespread copy number variants, but this rapidly decreased to an average of 6.2 percent after birth. Specifically, “neurons with widespread CNVs were mainly eliminated perinatally, timed roughly parallel to periods of programmed cell death, whereas neurons with smaller CNV burdens declined slowly in frequency with postnatal age,” the scientists wrote.
“We were totally unprepared for how common these were in early development,” said Christopher Walsh, MD, PhD, a co-senior author on the paper and professor of pediatrics and neurology at Boston Children’s Hospital. “But it makes sense in the context of what we know about the formation of excess neurons and in the context of the IVF literature.”
Next, the team explored the pathways through which the abnormal neurons are eliminated. By sequencing and analyzing DNA and RNA from over 44,000 individual cells, they found that neurons with widespread copy number variants also had abnormal expression of the genes involved in the creation and maintenance of neural synapses. It suggests that unlike healthy brain cells, these abnormal neurons fail to make critical connections during fetal development which causes them to die off.
“This competition for synapses has been described for years, but without the benefit of a genomic understanding,” Walsh noted. We didn’t realize that this struggle for survival—this Darwinian competition—was nature’s quality control mechanism in the brain.”
As part of the study, the team also confirmed some earlier findings that flawed neurons continue to be eliminated throughout adulthood, albeit at a much slower rate. Currently, they are looking into whether this neural elimination process is different in developing brains of people with autism and other neurodevelopmental disorders. They are also exploring whether this process plays a role in development of adult-onset neurodegenerative disorders like Alzheimer’s disease.