NIH Common Fund Selects New York Genome Center as Multi-Grant Recipient Under SMaHT Network

The National Institutes of Health (NIH) Common Fund has selected the New York Genome Center (NYGC) as a multi-grant recipient under the Somatic Mosaicism across Human Tissues (SMaHT) Network.

The awarded grants will fund two research projects led by Soren Germer, PhD, Vice President of Genome Technologies, Sam Aparicio, BM, BCh, PhD, FRCPath, FRSC, Senior Scientific Director of Cancer Genomics, Dan Landau, MD, PhD, NYGC Core Faculty Member and Associate Professor of Medicine in the division of Hematology and Medical Oncology at Weill Cornell Medicine, and Rahul Satija, PhD, NYGC Core Faculty Member and Associate Professor of Biology at New York University.

The SMaHT Network, funded by the NIH Common Fund with $140 million over five years, is a trans-NIH initiative aimed at the discovery and systematic cataloging of somatic mosaicism in humans. The SMaHT Network encompasses five interconnected initiatives; the research led by Drs. Germer and Aparicio, falls under the umbrella of the Somatic Variant Discovery Initiative Genome Characterization Centers (GCCs), while the research led by Drs. Landau and Satija falls under the Technology and Tools Development Initiative

The human genome is composed of the DNA sequence we inherit from our parents at fertilization, but also includes changes (or variants) that occur over time in individual cells, referred to as somatic mosaicism. Somatic mosaicism has the potential to alter how cells function and may influence human development, disease, aging, and other physiological measures across a person's lifespan, including their susceptibility to certain diseases and disorders. In collecting data from normal human tissues, the SMaHT Network will establish the foundational knowledge necessary to enable a better understanding of the role that somatic genetic variation plays in human biology, aging, and disease.

The SMaHT Network will sample tissues from human donors with diverse ancestries, across life stages, and from different tissue types throughout the body. The collected data from the GCCs will generate a tissue-specific catalog of human somatic variation that will be made available to the community through a bespoke SMaHT Variant Catalog Portal and Integrated Data Workbench.

New York Genome Center's SMaHT Genome Characterization Center

The NYGC GCC, led by Dr. Soren Germer and co-PI Dr. Sam Aparacio, is funded by a two-year grant (Grant Number 1UM1DA058236). In collaboration with other GCCs and SMaHT Network Centers, the NYGC GCC will generate a high-quality somatic variant catalog leveraging three core sequencing assays: mRNA sequencing, long-read Oxford Nanopore whole genome sequencing (WGS), and ultra-deep duplex WGS, which was developed by the Landau Lab at the NYGC. In addition, for a select number of tissues the team will sequence the genomes from individual single cells, using DLP+, a method developed by the Aparicio Lab. These assays will provide an unprecedented and comprehensive view of somatic mutations across a variety of healthy tissues.

The team will utilize the newest high-throughput sequencing platform, the Ultima Genomics UG100, to perform deep, short-read WGS for variant discovery supplemented by long-read genome sequencing using the Oxford Nanopore Technologies platform. Long-read genome sequencing will further enhance the discovery of large variants, including mobile elements, copy number changes, and structural events. The team will also perform RNA sequencing to analyze the expression of those variants in cells and evaluate the functional effects of somatic mosaicism.

We are very excited to participate in this important initiative and collaborate with other Network Centers to bring our sequencing and analysis expertise to the creation of a comprehensive catalog of somatic mutations in human tissues. The importance of somatic mutations is increasingly being recognized beyond the realm of cancer research. Creating a comprehensive catalog contributes to, and lays the groundwork for, explorations of the role of somatic mutations in disease and aging processes."

Dr. Soren Germer, Vice President of Genome Technologies

The "Single-Cell Multi-Omics" Approach

The research team led by Dr. Dan Landau and co-PI Dr. Rahul Satija has received a two-year grant (Grant Number 1UG 3NS132139) to develop innovative tools for the study of somatic mosaicism in detail using a "single-cell multi-omics" approach. These novel technologies are capable of measuring multiple molecular layers of information from the same individual cell (e.g., DNA, RNA, protein etc.). Taking this approach, researchers can examine the co-dependence of these different layers and how they influence one another.

"Our overarching goal is to be able to make detailed comparisons between normal and mutant cells to comprehensively identify the underpinnings of fitness advantage in clonal outgrowths," said Dr. Landau.

This project falls under the component of the SMaHT Network dedicated to creating new DNA sequencing and analysis technologies that directly address challenges in detecting rare genetic variants that occur in regions of repetitive DNA sequences and in small populations of cells.

All NIH Common Fund grant recipients will work closely under the highly-collaborative SMaHT Network.