WashU Medicine Researchers Verify New Methods to Detect Rare Somatic Mosaicism DNA Changes

Washington University Researchers Verify Genetic Tools for Rare DNA Changes

Washington University School of Medicine researchers have confirmed the accuracy of genetic tools designed to identify rare DNA changes that build up across a person’s life, News-Medical reported. Investigators leading the work verified that combining three distinct sequencing methods provides a reliable picture of genetic mosaicism within human tissues, marking a step forward in understanding how these cellular variations influence aging and disease.

For decades, standard genetic research focused heavily on inherited variants passed from parents to offspring through reproductive cells, which appear identically in every cell throughout the body. However, human biology involves a much more intricate genome. Over time, individual cells accumulate unique alterations known as somatic mutations or somatic variants. While many of these changes remain neutral and harmless, scientists link specific somatic variations directly to age-related illnesses and elevated cancer risks.

Three Sequencing Strategies Target Somatic Mosaicism

Because somatic variants appear only in isolated groups of cells rather than the entire body, measuring them has historically presented a major technological hurdle. To overcome this, researchers within the Somatic Mosaicism across Human Tissues (SMaHT) Network evaluated the performance of three core sequencing approaches: bulk sequencing, single-cell sequencing, and duplex sequencing. According to the findings published across a package of papers in Cell Press journals, these three strategies function as complementary methods rather than competing ones. Combining them yields a comprehensive assessment of mosaicism across diverse tissue types.

The network operates with support from the National Institutes of Health’s Common Fund. Washington University School of Medicine serves as the national coordinating center for the initiative, led by principal investigator Ting Wang, PhD, who holds the post of the Loewentheil Distinguished Professor of Medicine and heads the James S. McDonnell Department of Genetics. WashU Medicine also functions as the largest of five data production centers in the network, contributing over 25 percent of all data generated since the project launched in 2023.

Ting Wang, PhD, principal investigator, stated that there is a broad understanding that individuals are a genetic mosaic, but it is necessary to define the spectrum of normal somatic variation. Once that reference spectrum of normal is defined, researchers can start to investigate what may lead to disease with the goal of finding ways to mitigate it.

Wang explained that genomic sequencing technology has only recently reached the resolution required to track how somatic variants distribute throughout the body. The primary goal of this initial publication phase focused strictly on verifying that computational tools can identify rare DNA changes with high statistical sensitivity and specificity.

Genomic Resources Validate Computational Pipeline Accuracy

To establish the accuracy of these computational pipelines, the research teams turned to large-scale genomic resources. In one study published in Cell Genomics, investigators led by Wang utilized sequencing data from the Human Pangenome Reference Consortium, a project also coordinated nationally by WashU Medicine to expand the diversity of reference human genomes. While researchers traditionally rely on pangenome data to track inherited traits, this study demonstrates that the dataset can uncover somatic DNA variation within any tissue.

In a second Cell Genomics study led by Sheng Chih (Peter) Jin, PhD, an assistant professor of genetics at WashU Medicine, the team utilized data sourced from the International HapMap Project, which ran from 2002 to 2010.

"We have essentially developed ways to create millions of known somatic mutations synthetically," Jin said, explaining how the team built a resource to rigorously test their detection capabilities across multiple tissue types.

The flagship findings appear in Cell, summarizing the coordinated results and establishing the baseline accuracy for the sequencing techniques.

With the accuracy of their technological framework now verified, the network is preparing for the next phase of the project. Investigators plan to analyze multiple tissue samples collected from 150 human donors representing diverse ancestries and across multiple life stages.