Exploring the Role of Somatic Mosaicism in Human Biology
We’ve long known that understanding our genes is one of the keys to unraveling the causes of mental illnesses. Indeed, gene mapping has identified hundreds of genetic mutations that predispose individuals to mental illnesses, explaining a significant chunk of why mental illnesses run in families and pointing the way to biological targets for potential new therapies.
Most of us think about genetic risk in just this way—that the genes that we inherit from our parents explain why certain diseases run in families. But more recently, a whole new area of science has emerged, thanks to brand-new technologies that allow scientists to characterize the genetic makeup of individual cells in the body—as opposed to previous technologies, which measured the genetic makeup of an entire individual, essentially “averaged” across many such cells. Using this technology, researchers have shown that the DNA sequences that make up our genes can differ from one cell to the other. Sometimes these differences are subtle or meaningless, but sometimes they can affect the function of these cells. Scientists supported by NIMH have shown that these differences can even occur in neurons and glia, the cells that make up our brains. Whether and how these changes might contribute to mental illnesses are unclear and something we at NIMH are trying to figure out.
These cell-to-cell differences in our genes are called “somatic mosaicism.” “Somatic” means it occurs in the cells of the body itself, rather than in the germline (sperm or eggs). We use the term “mosaicism” because the differences make each cell a bit distinct from the others, like the tiles of a mosaic. Of course, somatic mosaicism occurs not just in the brain but throughout the body. Consequently, it is not just brain disorders like mental illnesses that might be influenced by somatic mosaicism, but all illnesses. Therefore, understanding the extent of somatic mosaicism in the population and its potential role in many illnesses is of interest to all 27 institutes and centers of the NIH.
Accordingly, the NIH Common Fund has launched an NIH-wide initiative to study somatic mosaicism called the Somatic Mosaicism across Human Tissues (SMaHT) Network . This program aims to transform our understanding of how somatic mosaicism in human cells influences biology and disease. NIMH recognizes the particular importance of understanding somatic mosaicism in the brain and characterizing its role in mental illnesses, which is why our institute is helping lead this critical initiative.
To realize its goal, the SMaHT Network is taking a multipronged approach to discovering the role of somatic mosaicism in human biology. The Network comprises three initiatives that will work together to develop a systematic catalog of somatic mosaicism in humans.
Somatic Variant Discovery
The Somatic Variant Discovery initiative will systematically document genetic variants from human tissues using state-of-the-art DNA sequencing technologies. Through this initiative, the Network will collect a set of 15 tissues from a diverse cohort of 150 people. Somatic variants will be analyzed from different cell types, disease states, and life stages, leading to new understandings of how much somatic variation influences fetal development, disease processes, and aging.
Technology and Tool Development
The SMaHT Network will also address challenges that hamper the ability of the scientific community to research somatic variants. Somatic variants often occur in small numbers of cells and regions of the genome that are understudied, including regions with repetitive DNA sequences. Somatic variants that occur at low frequencies are hard to detect, and variants that occur in repetitive DNA regions are challenging to sequence reliably. Through the Technology and Tool Development initiative, the SMaHT Network will spur technological developments that seek to overcome these challenges and facilitate the detection of different types of genetic variation, including rare mutations. These technological improvements may enhance our understanding of how large and small variants influence human biology and development.
Data Analysis and Organization
To further bolster somatic variant research in the scientific community, the SMaHT Network’s Data Analysis and Organization initiative will integrate data generated from the Network with genome browsers and other tools to develop a data workbench and study DNA sequences. The data workbench will also enable the analysis of somatic variation within the current human genome. Additionally, this initiative will ensure that the somatic variants characterized through the Somatic Variant Discovery initiative will be available as a catalog that is high quality, accessible to researchers, and interoperable with other datasets. To facilitate the use of the resources generated by the SMaHT Network, the Data Analysis and Organization initiative will also disseminate training materials and hold demonstration sessions for the biomedical research community.
The SMaHT Network is poised to transform our understanding of the contribution of somatic variation to human biology by generating new datasets, technologies, and analysis methods. The knowledge generated by the Network will likely not only enrich our understanding of the extent of somatic variation in our genomes but also provide insight into the association of somatic variation with environmental exposures and the functional consequences of somatic variation in human health and disease. This knowledge aims to catalyze research on the influence of somatic variation on mental illnesses and other types of conditions and disorders.
The first awards of the SMaHT Network will be announced in Spring 2023.