The genetic makeup of any given brain cell differs from all the others (Scientific American, 2017). This realisation may provide clues to a range of psychiatric diseases.

The past few decades have seen intensive efforts to find the genetic roots of neurological disorders, from schizophrenia to autism. But the genes singled out so far have provided only sketchy clues. Even the most important genetic risk factors identified for autism, for example, may only account for a few percent of all cases.

A lot of frustration stems from the realisation that the key mutations elevating disease risk tend to be rare, because they are less likely to be passed on to offspring. More common mutations confer only small risks, although those risks become more significant when calculated across an entire population.

However there are several other places to look for the missing burden of risk, and one surprising possible source has recently emerged. Accepted dogma holds that, although every cell in the body contains its own DNA, the genetic instructions in each cell nucleus are identical. But new research has revealed that there are actually several sources of spontaneous mutation in somatic (non-sex) cells, resulting in every individual containing a multitude of genomes, a situation researchers term somatic mosaicism.

“The idea is something that ten years ago would have been science fiction,” said biochemist James Eberwine of the University of Pennsylvania. “We were taught that every cell has the same DNA, but that’s not true.” There are reasons to think somatic mosaicism may be particularly important in the brain, not least because neural genes are very active.

A paper published on April 27th in Science by a group founded two years ago, The Brain Somatic Mosaicism Network (BSMN), outlines a research agenda for using new technologies to explore the genetic diversity found in each cell, and to investigate what links, if any, tie such mutations to a variety of neurological conditions.

“The field was abuzz with interest in exploring mosaicism but there was no money,” said Thomas Lehner, director of the Office of Genomics Research Coordination at the National Institute of Mental Health, which is now devoting $30m in funding to BSMN over the first three years, two of which have elapsed.

The consortium consists of eighteen research teams at fifteen US institutions with access to repositories of post-mortem brain tissue taken from healthy people and people with schizophrenia, autism, bipolar disorder, Tourette’s syndrome and epilepsy. Each team is tackling different samples.

“There’s a lot of new technology application and development involved, and a ton of data that will become a resource” Thomas Lehner said. “We also wanted to understand if there’s an association with new technology, so we encouraged researchers to include brain banks of individuals with various neurological conditions.”

Studies that preceded the consortium have confirmed mosaicism is commonplace. One report estimated there may be hundreds of changes in single letters of genetic code (single nucleotide variants, or SNVs) in each neuron in mouse brains. Another found over a thousand in human neurons. These findings suggest somatic mosaicism is the rule, not the exception, with every neuron potentially having a different genome than those to which it is connected.

A primary cause of somatic mutations has to do with errors during the DNA replication that occurs when cells divide. Neural progenitor cells undergo tens of billions of cell divisions during brain development, proliferating rapidly to produce the eighty billion neurons in a mature brain. The idea of each cell carrying a carbon copy of the genetic material of all other cells is starting to fade, and for good reason. Genetic sequencing does not normally capture the somatic mutations in each cell.

“You get a sort of average of the person’s genome, but that doesn’t take into account any brain-specific mutations that might be in that person” said study lead author Michael McConnell of the University of Virginia.

A 2012 study found somatic mutations in the brains of children with hemimegalencephaly, a developmental disorder in which one hemisphere is enlarged, causing epilepsy and intellectual disability. The mutations were found in brain tissue, but not always in blood or in cells from unaffected brain areas, and only around 8 to 35% of cells from affected areas. Studies like this, showing somatic mutations can cause specific populations of cells to proliferate, leading to cortical malformations, had researchers wondering whether somatic mutations may also play roles in more complex conditions.

Mature neurons stop dividing and are among the longest living cells in the body, so mutations will stick around in the brain. “In the skin or gut, cells turn over in a month or week so somatic mutations aren’t likely to hang around unless they form cancer” said Michael McConnell. “These mutations are going to be in your brain forever.” This could alter neural circuits, thereby contributing to the risk of developing neuropsychiatric disorders. “In psychiatric disease we don’t know that much yet, and that’s largely the goal [to find an answer]” said Michael McConnell. “It’s a good hypothesis but it’s going to require this big, multi-team effort to really address it.”

To investigate, the consortium will sequence brain DNA from control and patient samples. “Before you can get to your destination you have to have a map, and this is going to help build that map of somatic mutations that have potential for influencing neural functioning and disease” said James Eberwine, who was not involved in the new research. “So this consortium is critically important for neuroscience.”

One question to be explored is whether genes associated with a brain disorder may harbour somatic mutations. The fact specific genes only explain a small proportion of cases may be because researchers have only been looking in the germ line (sex cells) said Michael McConnell. He said “Maybe the person doesn’t have the mutation in their germ line, but some percentage of their neurons have it.”

Somatic mosaicism may also contribute to neural diversity in general. “It might explain why everybody’s different—it’s not all about the environment or genome. There’s something else” said neuroscientist Alysson Muotri of the University of California, San Diego, who is not part of the consortium. “As we understand more about somatic mosaicism, I think the contribution to individuality as well as the spectrum [of symptoms] you find in, for example, autism, will become clear.”

Somatic mutations can occur in multiple circumstances. They may emerge during DNA replication or from DNA damage (caused by free radicals or environmental stresses) combined with imperfect repair machinery. In addition to SNVs, mutations known as indels, involving insertions and deletions of small DNA sequences (typically tens of nucleotides), also occur frequently.

Larger, rarer mutations include structural changes in chromosomes, either in the form of gains or losses of whole chromosomes or copy number variants (CNVs), in which the number of repetitions of long chunks of DNA (covering multiple genes) is altered. Within genomes there are also “mobile genetic elements” that act almost like parasites, jumping around or making copies of themselves and inserting themselves elsewhere in the genome, seemingly to ensure their survival. These strange entities are an active field of research in their own right. They are important here because they can cause somatic mutations, including a type known as mobile genetic element insertions, or MEIs. They are switched on in the same way as genes involved in producing new neurons, making them especially active in the brain during development.

The paper outlines three methods for studying these mutations. The first involves using technologies to sequence a whole genome from bulk brain tissue. This technique can detect many variants but the rarest types are diluted by the mass of cells in bulk tissue. “Large CNVs and mobile elements are much more difficult to detect in bulk tissue than SNVs” said Michael McConnell. Also, this method cannot reveal how mutations vary between cell types.

This can be partly solved using a technique known as “sorted pools,” which sorts out neurons from other unwanted cell types. The most important recent advance that will aid the consortium, however, is the advent of technologies that allow the genomes of individual cells to be sequenced. “By going into single cells we can compare [what we find] to the neighboring cell, and say: ‘Aha, they’re different!’ That’s the advance that allows us to really move forward” said Alysson Muotri. “I’m very excited—this is the beginning of something completely new in biology and neuroscience.”

The project is funded until 2020, and will make all data publicly available, and for some results that should be in twelve to twenty four months. “Around 10,000 sequencing data sets will be generated, and we’ll be making that available in a database for the scientific community to dig in more deeply” said Michael McConnell.

There are also plans to collaborate with other NIMH initiatives including BrainSpan, which maps gene expression during brain development, and psychENCODE, which is mapping the brain epigenome (environmentally driven modifications of DNA that influence gene activity without changing the genetic code).

“This is supposed to initiate an important area of research” said Thomas Lehner. “We hope it will give us a landscape of mosaicism in the brain and insights into the contribution of mosaicism to mental disorders, but I don’t expect to have all the answers.” These insights may ultimately lead to the discovery of new genetic targets for treating a range of hard to treat disorders.

“This is exploratory research, we’re learning about the phenomenon” said Alysson Muotri. How important it will be is not clear at this stage but “by figuring out how it works we may reveal new therapeutic opportunities.”