DNA Damage During Neural Development May Lead to Neurological Conditions

News Brief by Helen Mizrach

 Researchers from the Program in Cellular and Molecular Medicine (PCMM) at Boston’s Children’s Hospital, Harvard Medical School, and the Howard Hughes Medical Institute found that the genome of developing brain cells contains 27 hotspots where DNA is likely to break. These hotspots appeared in genes directly associated with brain tumors and other neurodevelopmental and neuropsychiatric conditions. PCMM director and senior study author Frederick Alt and his colleagues started investigating the links between tumors, oncogenes, DNA breaks, and DNA repair more than 30 years ago. His lab discovered that without the DNA repair pathway called non-homologous end joining, nerve cells cannot repair DNA breaks and either die off early in development or give rise to brain tumors. Alt’s laboratory maps DNA breaks in the genome through the use of high-throughput genome-wide translocation sequencing (HTGTS). In their current study, the team used HTGTS and found that the 27 break hotspots were spread across the bodies of 27 individual genes with a number of shared characteristics, including links to tumor suppression and neurological conditions.

            The DNA break hotspots the team identified appeared most frequently in the genes’ introns, leading the team to believe that the hotspots may help the brain generate diverse circuitry. By splicing exons in different ways, the genome could create several variations of its encoded proteins, leading to the formation of unique neural circuits. Having recurrent DNA breaks could potentially be evolutionarily advantageous, as it may be a way to sample different combinations of circuits and synapses. It’s likely that DNA replication stress-associated breaks that occur during neural development contribute to the diversity of neural cells in the mature brain. Alt and his team speculate that when this DNA damage is not repaired, it may predispose an individual to neurodevelopmental or neuropsychiatric disease.

 

Boston Children's Hospital. (2016, February 11). DNA breaks in nerve cells' ancestors cluster in  specific genes: Study reveals new avenue for thinking about brain development, brain tumors   and neurodevelopmental/psychiatric diseases. ScienceDaily. Retrieved February 18, 2016 from www.sciencedaily.com/releases/2016/02/160211184955.htm