The mosaic patterns of mutation present across the brain, in an illustration inspired by Gustav Klimt’s “Portrait of Adele Bloch-Bauer I." | Concept by Gilad Evrony / Illustration by Erik Jacobsen of Threestory Studio
Gilad Evrony is the 2016 grand prize winner in the annual international competition for The Eppendorf & Science Prize for Neurobiology. Evrony developed new techniques for sequencing and analyzing the genomes of individual brain cells, revealing that diverse mutations occur during brain development — some of which may impact the brain and cause neurologic disease.
Although it has previously been assumed the billions of cells in the brain all have the same genome, other research suggests the brain may harbor genetic diversity, stemming from errors that cause variations in the genetic makeup of different cells and can also lead to the onset of illnesses like cancer. Evrony was intrigued by the idea that these so-called somatic mutations might drive neuropsychiatric diseases whose causes remain unknown. Together with colleagues in the laboratory of Christopher Walsh at Boston Children's Hospital, he developed a way to detect these mutations by sequencing the genomes of single brain cells.
Evrony and his team were able to use the mutations they found as markers to trace how cells migrate across the brain as it is formed. The analysis uncovered interesting patterns showing that every brain is a remarkable patchwork of mosaic mutations. These methods can now be used to study unexplained neuropsychiatric diseases, such as epilepsy, autism and schizophrenia, to determine whether somatic mutations may be involved.
"As a physician-scientist, I wanted to pursue research that could help patients with diseases whose causes are not known. I hope our findings inspire more research to bring light to unsolved neurologic diseases," Evrony said.
The Eppendorf and Science Prize in Neurobiology recognizes outstanding international neurobiological research based on current methods and advances in the field of molecular and cell biology by a young, early-career scientist, as described in a 1,000-word essay based on experiments performed within the last three years. The grand prize winner receives $25,000 from Eppendorf.
Evrony's needle-in-haystack-like approach provided a first-ever detailed look at somatic mutations in the brain. It also provided an important revelation — many types of mutations occur and accumulate during normal brain development, "such that every cell in a person's brain, in fact, has a unique genome," said Evrony, who obtained his M.D. and Ph.D. from Harvard Medical School during his time in Walsh's laboratory."Sequencing brain cells one at a time is challenging but necessary, because somatic mutations may be present in only a very small fraction of cells or even just one cell — making them undetectable by standard DNA sequencing."
The brain is built from cells that replicate many times, each time making a copy of their genome. "Our brains are a mix of cells with copies of copies, and copies of copies of copies, and so on, of the genome. Imagine you were building a house and every brick was made by copying the previous brick rather than making all the bricks from the same original mold. That is, in a sense, the challenge of building a brain where each cell must have a relatively faithful copy of the genome," Evrony stated. "Inevitably, mistakes in DNA replication and other mutational forces accumulate and create imperfect copies."
In his award-winning essay, "One brain, many genomes," which was published in the 4 November issue of Science, Evrony describes how single-cell sequencing was used to study the first brain-specific somatic mutations causing a rare congenital brain malformation known as hemimegalencephaly.
The discovery provided an initial glimpse into the unexplored landscape of somatic mutations and subsequent brain dysfunction, which had been overlooked as most genetic analyses only examine the sequence of blood DNA. Because neurons and their genomes must keep working for an entire person's lifetime, this same technology could also measure how many mutations might creep into our brains as they age.
The patchwork patterns of somatic mutations that Evrony and his fellow researchers uncovered could mean that rare, as-yet unrecognized brain disorders may exist. In these instances, a somatic mutation may subtly affect only one small part of the brain — that is involved with the ability to speak, for example — while sparing the rest of the brain. "We might be especially prone to such mutations because of the high number of cell divisions that it takes to build a large human brain," Evrony suggested.
The findings will ultimately paint a clearer picture of the brain's inner workings, Evrony said, noting, "Our work is part of the broader effort in the neuroscience community to develop new tools to study the brain. The brain is incredibly complex, and I believe that our progress in understanding it largely depends on the development of new technologies."
Evrony and the following finalists will be recognized at the annual meeting of the Society for Neuroscience on Sunday, 13 November, in San Diego, California.
Anna Beyeler, for her essay "Parsing reward from aversion." Beyeler received her undergraduate degree from the University of Bordeaux, in southern France, where she then completed her Ph.D. degree requirements. As a postdoctoral fellow at the Massachusetts Institute of Technology, she has been exploring the neural circuit mechanisms underlying rewarding and aversive memories. Beyeler is currently establishing an independent research program aimed at identifying neural substrates of anxiety disorders.
Arjun Krishnaswamy, for his essay "Building connections." Krishnaswamy received undergraduate and Ph.D. degrees from McGill University. As a postdoctoral fellow at Harvard University, he has been using molecular, electrophysiological and genetic approaches to learn how developing neurons in the mouse retina choose synaptic targets and establish wiring patterns important for retinal function.
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