His postdoc Michael Lodato sequenced the genomes of 36 single neurons, extracted from the preserved brains of three healthy people who had died in accidents. He found that each neuron contains around 1,500 unique mutations, making them more variable than the team had anticipated. Contra Pahlaniuk, each neuron really is a beautiful and unique snowflake.
These mutations are different than those that typically exist in, say, skin cells or cancer cells. Those arise when cells divide and make mistakes when duplicating their DNA, or when that DNA is bombarded by damaging stimuli like ultraviolet radiation or tobacco chemicals. By contrast, neurons pick up most of their mutations through the simple act of switching on their genes. “When DNA isn’t being used, it is packed up and put away,” explains Walsh. “When a cell wants to use a gene, it unwinds the DNA and opens it up, and that unwinding is a little dangerous. It makes the DNA more vulnerable and can induce damage.”
“The field will look back as this paper as a landmark study,” says Alexander Urban from Stanford University School of Medicine. “They have taken a phenomenon that was only vaguely known to exist and put it on a very firm foundation with solid numbers. Based on this foundation, we can now start to investigate the possible consequences of these [mutations] in health and in disease, during brain development, and in aging.”
Lodato also sequenced the genomes of 226 neurons from a single brain, known simply as Brain B. He found that these cells belonged to at least five distinct lineages, all of which were spread throughout the organ. More surprisingly, those lineages also included cells from other parts of the same person, including their liver, heart, lung, and pancreas.
To understand that weird pattern, cast your mind back by several decades to a time when Brain B’s owner was a recently conceived ball of embryonic cells. Five of those cells would eventually give rise to the lineages that Lodato discovered, and they had already acquired mutations that distinguished them from each other. As they divided, their progeny intermingled and gave rise to all kinds of tissues. Some produced neurons and found their way to the same pocket of prefrontal cortex that Lodato studied. Others made a living in distant organs.
Why such a complicated pattern? Imagine if that wasn’t the case, and that a single early cell could give rise to all the neurons in a specific chunk of brain. If that cell developed a mutation in a critical gene, the resulting brain region would be in serious trouble. Indeed, in earlier studies, Walsh’s team showed that mutations in small clusters of neurons can lead to debilitating disorders involving abnormal brain development and epileptic seizures.
So perhaps, by dispersing the descendants of early cells around the brain (and the body), we also spread the risk of neurological disease. “That’s just a speculation,” says Walsh—but a very plausible one. Given his new results, it seems likely that every site in every gene is mutated in at least one neuron, somewhere in the brain. Indeed, Lodato found that brain B harbored single neurons with mutations that confer a high risk of schizophrenia, seizure disorders, and other disorders. If these cells are few and far between, the consequences might be minimal.