As organs go, the brain seems to harbor an abundance of somatic mutations — genetic variants that arise after conception and affect only some of our neurons. In a recent study in Science, researchers found about 1,500 variants in each of neurons they sampled.
New research revealing the propensity of DNA to break in certain spots backs up the idea of a genetically diverse brain. Reported in Cell last month, it also suggests a new avenue for thinking about brain development, brain tumors and neurodevelopmental/psychiatric diseases.
Investigators from the Program in Cellular and Molecular Medicine (PCMM) at Boston Children’s Hospital, Harvard Medical School and the Howard Hughes Medical Institute, show that the genome of developing brain cells harbors 27 clusters or hotspots where its DNA is much more likely to break in some places than others. The hotspots appear in genes associated with brain tumors and a number of neurodevelopmental and neuropsychiatric conditions.
“In our dreams we couldn’t have found a set of genes to better fit the hypothesis that breaking DNA in neural cells is important,” says Frederick Alt, PhD, director of PCMM and senior author on the study.
DNA breakage: from cancer cells to neurons
The study’s roots go back more than 30 years, when Alt and his colleagues first started investigating the links between tumors, oncogenes, DNA breaks and DNA repair, particularly in immune and nerve cells. Alt’s lab discovered that neurons lacking a DNA repair pathway called non-homologous end joining (NHEJ) either die off early in development or give rise to brain tumors called medulloblastomas.
In recent years, Alt’s laboratory engineered a method for mapping DNA breaks throughout the genome at very fine resolution. The method, called high-throughput genome-wide translocation sequencing (HTGTS), was first developed to understand how genes reshuffle (translocate) in cancer. The Alt lab has also used HTGTS to measure the precision of CRISPR gene editing.
In last month’s Cell study, Alt, lab members Pei-Chi Wei, PhD, Amelia Chang, Bjoern Schwer, MD, PhD and their colleagues used HTGTS and informatics to map DNA break patterns in neural stem and progenitor cells from mice — the cells that produce the brain’s neurons, astrocytes and oligodendrocytes — under conditions of replication stress (aberrant DNA replication that is prone to introduce errors).
Strikingly, the 27 hotspots for DNA breakage were spread across the bodies of 27 individual genes. These genes share a number of characteristics:
- All are long, mostly more than 100 kilobases, with multiple exons (coding segments) and long introns (non-coding segments).
- Most are copied late in the cell division process.
- The proteins they encode are on the surface of neurons and mostly perform functions that help neurons communicate (e.g., synapse formation, cell-cell adhesion).
- Twenty-four of the 27 genes have been linked to tumor suppression and/or neurological conditions such as autism spectrum disorder, schizophrenia and bipolar disorder.
DNA breaks, neuronal diversity and brain circuitry
Because the breaks appeared most frequently in the gene’s non-coding segments, they could potentially allow the coding portions to be spliced in different ways to produce different variations of the protein encoded by the gene, the researchers say. The neurons that develop from the neural stem/progenitor cells could then wire themselves into unique neural circuits.
Wei, a postdoctoral fellow in Alt’s laboratory, gives one example. “The protein encoded by one of the genes we identified, neurexin, potentially has more than 1,000 different forms, some of which may make connections between neurons of different strengths,” she says. “What we found could provide a mechanism for making a diversity of synaptic connections and make contacts between neurons different.”
Consider that our entire brains — with some 100 billion neurons — arise from a relatively limited number of neural stem/progenitor cells. Could recurrent DNA breaks help make the brain what it is?
“It could be a way to sample different combinations of circuits and synapses, almost like evolution in miniature,” says Schwer. “We don’t know for sure that this is the case, but we now show that these replication stress–associated breaks that occur during neural development could be a way to contribute to the perceived diversity of neural cells that end up in the mature brain.”
The team also speculates that DNA damage associated with replication stress during neural development could, by affecting these genes, promote neurodevelopmental or neuropsychiatric diseases.
“Virtually all of these genes have been associated with diseases that have a neurodevelopmental component,” says Schwer. “It could be that when you can’t efficiently repair breaks within genes, it could predispose the individual to neurodevelopmental disease.”
Wei PC, Chang AN, Kao J, Du Z, Meyers RM, Alt FW, & Schwer B (2016). Long Neural Genes Harbor Recurrent DNA Break Clusters in Neural Stem/Progenitor Cells. Cell, 164 (4), 644-55 PMID: 26871630