Researchers establish best methods to measure genetic variation within the body
Quantifying mutations that accumulate over time could give clues to diseases of aging, cancer development
Sara Moser/WashU MedicineWashU Medicine researchers have verified the accuracy of genetics tools to correctly identify all the rare DNA changes that make up an individual’s genomic mosaic, paving the way to understanding these variants’ impact on health and disease.
In Brief
- Scientists at WashU Medicine are testing the best ways to understand small genetic changes that build up in our cells as we age.
- These changes can raise the risk of aging-related diseases and cancer.
- Three methods combined provide the most comprehensive picture.
Researchers at Washington University School of Medicine in St. Louis are leading national efforts to investigate small DNA changes over time that create genetic differences between tissues within the same person. Called somatic mosaicism, these variations alter how cells operate and play a critical role in aging and disease — especially cancer risk — across the lifespan.
Despite their importance, such DNA changes are rare and difficult to measure. Now, a package of papers publishing in Cell Press journals demonstrates new and innovative strategies to accurately measure and assess the significance of these types of DNA changes across multiple tissue types. WashU Medicine investigators led three of these studies, one published in Cell and two in Cell Genomics.
The research is part of the Somatic Mosaicism across Human Tissues (SMaHT) Network, which is supported by the National Institutes of Health’s (NIH) Common Fund.
WashU Medicine serves as the national organizing center, led by principal investigator Ting Wang, PhD, the Sanford C. and Karen P. Loewentheil Distinguished Professor of Medicine and head of the James S. McDonnell Department of Genetics. WashU Medicine is also the largest of five data production centers, also led by Wang, contributing more than 25% of all the data produced by the network since it launched in 2023.
A person’s genome sequence — all the “letters” making up a person’s complete set of DNA — is often thought of as identical in each cell throughout the body. In practice, DNA is far more complex, with various cells across multiple tissues accumulating different changes, or variants, over time. Much genetic research into disease has focused on inherited variants, which are passed from parents to offspring through the reproductive cells (sperm and eggs) and are a bit easier to identify because they are present in each cell throughout the body.
These new efforts are focused on genetic changes that emerge over the course of a person’s lifetime and in just some cells, which are known as somatic mutations or somatic variants.
“Many of these variations are neutral and harmless, but we also know a lot of diseases are directly linked to somatic variation, especially cancer,” Wang said. “We have a broad understanding that individuals are a genetic mosaic, but we need to define the spectrum of normal somatic variation. Once we have that reference spectrum of normal, we can start to delve into what may lead to disease with the goal of finding ways to mitigate it.”
According to Wang, only recently has genomic sequencing technology advanced to the point that scientists can study the distribution of somatic variants. The major goal of this first set of studies is to verify the accuracy of computational tools the scientists developed to correctly identify — with high statistical sensitivity and specificity — all the rare DNA changes that make up an individual’s genomic mosaic.
How to dissect the effects of genetic changes sprinkled throughout our bodies
In one of the two Cell Genomics studies, led by Wang, the researchers harnessed the extensive sequencing data from the Human Pangenome Reference Consortium, another national genomics effort, this one intended to increase the diversity of the human genome sequences that are pooled into the widely used reference human genome.
WashU Medicine also serves as the national coordinating center for this project, which is led by Wang. The pangenome project data has been heavily used in the past to find inherited genetic variants, but this study is the first to show that the data can also be used to identify somatic DNA variation across any tissue.
In the second Cell Genomics study, led by WashU Medicine’s Sheng Chih (Peter) Jin, PhD, an assistant professor of genetics, the researchers used data from the International HapMap Project, an NIH-funded genome sequencing project that ran from 2002 to 2010.
“We have essentially developed ways to create millions of known somatic mutations synthetically,” Jin said. “We can then use this as a resource to make sure we can accurately tackle the challenge of identifying rare somatic mutations across all types of tissues.”
The flagship paper for this first set of publications, published in Cell, summarizes the results for all of the papers in the package, establishing the accuracy of the sequencing approaches. In addition to co-leading work with the Mayo Clinic on the Cell paper and leading the two Cell Genomics papers, WashU Medicine investigators are co-authors on the remaining papers in the package.
The researchers conclude that three key sequencing strategies — called bulk sequencing, single-cell sequencing and duplex sequencing — are complementary to one another and that combining them provides a comprehensive picture of mosaicism within tissues. With the accuracy of their technologies verified, the researchers are now working toward the goal of analyzing multiple tissue samples from 150 human donors of diverse ancestries and across multiple life stages.
