Washington University School of Medicine in St. Louis is leading a national effort to study the small DNA changes that accumulate over time and create genetic differences between tissues in the same person. Known as somatic mosaicism, these changes affect cell function and contribute to aging and disease, especially cancer risk, yet are rare and hard to measure. Three new papers, led by WashU Medicine scientists and published in Cell Press journals, describe methods for measuring and interpreting this variation across tissue types.
The work is part of the Somatic Mosaicism across Human Tissues (SMaHT) Network. WashU Medicine is the network’s national organizing center and largest data producer, both under principal investigator Ting Wang.
A genome is often assumed to be identical in every cell, but DNA actually varies as tissues build up distinct changes over time. Research has mostly focused on inherited variants, passed from parents through sperm and eggs, because they appear in every cell and are easier to find. This work instead targets somatic mutations, which arise during life and affect only some cells. “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.”
Wang said sequencing technology has only recently advanced enough to study how somatic variants are distributed, and the first paper and second paper set out to confirm the team’s tools can identify such rare changes accurately. The first paper, published in Cell Genomics, used data from the Human Pangenome Reference Consortium—another WashU Medicine-coordinated effort to diversify the reference human genome—and was first to show the approach can find somatic variation in any tissue.
The second paper, also in Cell Genomics and led by Sheng Chih (Peter) Jin, used data from the NIH-funded International HapMap Project, run 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 third paper, the package’s flagship study published in Cell, brings together the results and confirms the sequencing approaches’ accuracy.
Across all three papers, the team found that bulk, single-cell, and duplex sequencing complement each other and together give the fullest picture of mosaicism within tissues. With accuracy confirmed, researchers are now preparing to analyze samples from 150 donors of diverse ancestries and life stages.
The work is part of the Somatic Mosaicism across Human Tissues (SMaHT) Network. WashU Medicine is the network’s national organizing center and largest data producer, both under principal investigator Ting Wang.
A genome is often assumed to be identical in every cell, but DNA actually varies as tissues build up distinct changes over time. Research has mostly focused on inherited variants, passed from parents through sperm and eggs, because they appear in every cell and are easier to find. This work instead targets somatic mutations, which arise during life and affect only some cells. “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.”
Wang said sequencing technology has only recently advanced enough to study how somatic variants are distributed, and the first paper and second paper set out to confirm the team’s tools can identify such rare changes accurately. The first paper, published in Cell Genomics, used data from the Human Pangenome Reference Consortium—another WashU Medicine-coordinated effort to diversify the reference human genome—and was first to show the approach can find somatic variation in any tissue.
The second paper, also in Cell Genomics and led by Sheng Chih (Peter) Jin, used data from the NIH-funded International HapMap Project, run 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 third paper, the package’s flagship study published in Cell, brings together the results and confirms the sequencing approaches’ accuracy.
Across all three papers, the team found that bulk, single-cell, and duplex sequencing complement each other and together give the fullest picture of mosaicism within tissues. With accuracy confirmed, researchers are now preparing to analyze samples from 150 donors of diverse ancestries and life stages.