Researchers headed by a team at Oregon Health & Science University (OHSU) have created what they claim to be the largest atlas of post-zygotic mutations (PZMs) in healthy human tissue. They generated the atlas using 54 tissue and cell types compiled after death from 948 individuals who donated their bodies for the National Institute of Health’s Genotype-Tissue Expression (GTEx) project. With hundreds of donors, the assembled guide is the most complete ever created, and could lead to better diagnosis and treatment of disease associated with “bad luck or bad habits.”

The new resource is the largest in terms of the combined number of tissues and number of donors sampled, and could help unlock new avenues for treating as well as diagnosing genetic disease, and provide insights that improve our understanding of the genetic basis of cancer and a myriad of other diseases caused by cellular malfunction, including aging.

“If you’re talking about genetic changes being the basis of disease, there are a wide variety of technologies now that allow us to make changes to the genome,” said Don Conrad, PhD, associate professor in the OHSU School of Medicine who directs the division of genetics at the Oregon National Primate Research Center. “It may be possible to change those mutations we’ve acquired due to bad luck or bad habits and change them back to what they were before.”

Conrad is senior author of the team’s published paper in Science, which is titled, “The origins and functional effects of postzygotic mutations throughout the human life span,” in which the authors noted, “In this work, we present one of the most comprehensive and diverse surveys of PZM variation in normal individuals, which should prove a valuable resource for understanding the causes and consequences of PZMs across the body.”

“The effects of age ravage all tissues of the body, but the pace and consequences of age-related decay vary among tissues and people,” the authors wrote. “The accumulation of DNA damage is thought to be a primary agent of age-related disease ….”

Every person begins as a single cell at the moment of conception, carrying a DNA blueprint within the nucleus of that first fertilized cell. Using those original DNA instructions, the cell divides and replicates into vast groups of cells that form distinct tissues carrying out unique functions in the body. At any one time, the average person is comprised of about 30 trillion cells, and in the course of a lifetime, that same person produces quadrillions of cells.

Over time, an individual cell is damaged again and again. In some cases, they repair themselves thousands of times a day. “Every once in a while, the cell makes a mistake during DNA repair, or misses one—and that’s a change that gets propagated on,” Conrad said. “Our work gives us a window to the extent that those changes occur in different organs and tissues, and during different periods of our lives.” This situation, known as somatic mosaicism, is a result of cells mutating from the original DNA blueprint.

The authors explained that postzygotic mutations begin to accrue in the human genome immediately after fertilization. And it is this accumulation of DNA damage that is thought to represent a major cause of age-related disease. “… surveys of PZMs in normal tissues [for example, blood, brain, and skin] and across the body have found PZMs to be pervasive across the genome and individuals,” they wrote.  However, they continued “… how and when PZMs affect development and lifetime health remain unclear … beyond cancer, there are few conditions where PZMs are known to have a causal role.”

Until now, genetic research investigating mutations that occur has generally been conducted in biopsies of cancerous tissue such as skin melanomas and lung tumors, or in easily accessible tissues such as blood. The new atlas instead opens a field of inquiry into mutations that occur over the course of a lifetime.

To generate the new atlas, researchers developed a computational method using bulk RNA sequencing to characterize the mutations in a massive catalog of tissue samples throughout the body. “… we developed a suite of methods called Lachesis to identify single-nucleotide PZMs from bulk RNA sequencing (RNA-seq) data and predict when the mutations occurred during development and aging … We ran the algorithm on the final major release of the GTEx project—a collection of RNA-seq data from 17,382 samples derived from 948 donors across 54 diverse tissues and cell types—to generate one of the most comprehensive databases of PZMs in normal tissues.”

They were able to trace the point at which mutations occurred by mapping them to a “developmental tree,” indexing them across tissues and among many people. “We used this atlas and the rich metadata on GTEx donors to characterize sources of variation in PZM burden among individuals and unveil the spatial, temporal, and functional variation of PZMs in normal development and aging.”

They found many mutations arose systematically and somewhat predictably as people age, although roughly 10% of mutations appeared to be the result of something intrinsic to an individual, be it genes or environment.

And while most detectable mutations occurred later in life, many occurred before birth. “Through phylogenetic reconstruction of PZMs, we found that their type and predicted functional impact vary during prenatal development, across tissues, and through the germ cell life cycle,” the team noted. Added first author Nicole Rockweiler, PhD, previously part of Conrad’s lab at OHSU and Washington University in St. Louis, and now a postdoctoral associate at the Broad Institute of Massachusetts Institute of Technology and Harvard University, “Going from a single cell to a child is a remarkable process. When you add on layers of mutations happening at such an important part of our lives, it’s amazing that we can come out pretty well at the end of our gestation.”

In their paper, the authors concluded, “In this work, we present one of the most comprehensive and diverse surveys of PZM variation in normal individuals, which should prove a valuable resource for understanding the causes and consequences of PZMs across the body … They further pointed out that methods for interpreting the effects across the body and life span will be needed to fully understand the consequences of genetic variants.”

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