Tracking Gene Mutations across the Lifespan: the Somatic Mosaicism Across Human Tissues (SMaHT) Network

Tracking Gene Mutations across the Lifespan: the Somatic Mosaicism Across Human Tissues (SMaHT) Network

Each of us is born with a unique genome made up of DNA that we inherit, and changes to that DNA sequence occur in individual cells over our lifetimes. Somatic mosaicism refers to the post-conception changes to our DNA that cause genetic variation among cells within an individual, but which can differ from cell to cell or from one tissue to another. These somatic variants contribute to numerous neurological disorders including epilepsies, nervous system tumors, and neurodevelopmental and neurodegenerative disorders. Leveraging recent advances in genomic technologies, researchers have begun to determine the role of somatic variants in disease processes, which will enhance our understanding of disease mechanisms and potential therapeutic strategies. However, our overall understanding of the functional consequences of somatic mosaicism remains incomplete. To transform our understanding of how somatic mosaicism in human cells influences biology and disease, I am excited that NINDS is participating in the Somatic Mosaicism across Human Tissues (SMaHT) Network, an NIH Common Fund program.

The purpose of the SMaHT Network is to facilitate the discovery of new biological processes in human health and disease that are mediated by genomic variation in somatic tissues. Somatic mosaicism is challenging to study because low frequency variants are hard to detect, and repetitive regions of DNA that can move within the genome (transposable elements) are difficult to sequence reliably. Achieving this ambitious goal requires assessing somatic variation across different cell types, life stages, and a diverse cohort of donors, as well developing tools and technologies that will reduce the technical and biological barriers for somatic variant detection.

The first five years of the program will focus on three key areas: Building a scaffold from foundational datasets that catalog somatic variation across a set of common tissues from a diverse donor pool; developing tools focused on increasing the sensitivity of detection and specificity of the pipelines to detect multiple types of variations; and creating a variant catalog, portal, and integrated workbench that facilitates access to the tools, technologies, and data developed by the Network.

Five Funding Opportunity Announcements have recently been issued to realize these goals, all with a receipt date of July 8, 2022:

  • Technology and Tools Development Projects (RFA-RM-22-011) will develop next generation tools focused on significantly improving detection and characterization of somatic variants.
  • The Tissue Procurement Center (RFA-RM-22-012) will collect, process, and distribute a set of at least 15 high quality human tissues from a diverse donor cohort of 150 people;
  • The Genome Characterization Centers (RFA-RM-22-013) will use state-of-the-art genomics sequencing technologies to identify all types of somatic variation in tissues from the Tissue Procurement Center;
  • The Organizational Center (RFA-RM-22-009) will coordinate Network activities and establish strong links with related NIH and international programs;
  • The Data Analysis Center (RFA-RM-22-010) will integrate the data generated by the Network to build the variant catalog, portal, and workbench.

To learn more about these funding opportunities and for more information, there will be a Technical Assistance Webinar on April 29th from 12:00 – 1:00 pm EDT.

Creating a comprehensive catalog of somatic variants from diverse human donors, with innovative tools that optimize variant detection will be important outcomes of the SMaHT network. The Somatic Variant Catalog will serve as the foundation for the SMaHT Data Workbench, which will seamlessly integrate somatic variation within the current human genome, accelerating our understanding of the functional consequences of somatic variation on human biology through new technologies, analysis methods, and extensive datasets.

The knowledge generated from this catalog will enable the SMaHT Network to deepen our understanding of how much variation there is within our personal genomes and what the consequences are on human health. It will catalyze research on the extent to which somatic mosaicism within our unique genomes is associated with environmental exposures, influences human development and aging, and contributes to diseases and disorders, including undiagnosed diseases and disorders in the skin, muscle, brain, and immune system.

Thursday, April 28, 2022