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The Genotype-Tissue Expression Project

Study Finds Genetic Mutations in Healthy Human Tissues

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General mutations throughout the body

The standard view of biology is that every normal cell copies its DNA instruction book with complete accuracy every time it divides. And thus, with a few exceptions like the immune system, cells in normal, healthy tissue continue to contain exactly the same genome sequence as was present in the initial single-cell embryo that gave rise to that individual. But new evidence suggests it may be time to revise that view.

By analyzing genetic information collected throughout the bodies of nearly 500 different individuals, researchers discovered that almost all had some seemingly healthy tissue that contained pockets of cells bearing particular genetic mutations. Some even harbored mutations in genes linked to cancer. The findings suggest that nearly all of us are walking around with genetic mutations within various parts of our bodies that, under certain circumstances, may have the potential to give rise to cancer or other health conditions.

Efforts such as NIH’s The Cancer Genome Atlas (TCGA) have extensively characterized the many molecular and genomic alterations underlying various types of cancer. But it has remained difficult to pinpoint the precise sequence of events that lead to cancer, and there are hints that so-called normal tissues, including blood and skin, might contain a surprising number of mutations —perhaps starting down a path that would eventually lead to trouble.

In the study published in Science, a team from the Broad Institute at MIT and Harvard, led by Gad Getz and postdoctoral fellow Keren Yizhak, along with colleagues from Massachusetts General Hospital, decided to take a closer look. They turned their attention to the NIH’s Genotype-Tissue Expression (GTEx) project.

The GTEx is a comprehensive public resource that shows how genes are expressed and controlled differently in various tissues throughout the body. To capture those important differences, GTEx researchers analyzed messenger RNA sequences within thousands of healthy tissue samples collected from people who died of causes other than cancer.

Getz, Yizhak, and colleagues wanted to use that extensive RNA data in another way: to detect mutations that had arisen in the DNA genomes of cells within those tissues. To do it, they devised a method for comparing those tissue-derived RNA samples to the matched normal DNA. They call the new method RNA-MuTect.

All told, the researchers analyzed RNA sequences from 29 tissues, including heart, stomach, pancreas, and fat, and matched DNA from 488 individuals in the GTEx database. Those analyses showed that the vast majority of people—a whopping 95 percent—had one or more tissues with pockets of cells carrying new genetic mutations.

While many of those genetic mutations are most likely harmless, some have known links to cancer. The data show that genetic mutations arise most often in the skin, esophagus, and lung tissues. This suggests that exposure to environmental elements—such as air pollution in the lung, carcinogenic dietary substances in the esophagus, or the ultraviolet radiation in sunlight that hits the skin—may play important roles in causing genetic mutations in different parts of the body.

The findings clearly show that, even within normal tissues, the DNA in the cells of our bodies isn’t perfectly identical. Rather, mutations constantly arise, and that makes our cells more of a mosaic of different mutational events. Sometimes those altered cells may have a subtle growth advantage, and thus continue dividing to form larger groups of cells with slightly changed genomic profiles. In other cases, those altered cells may remain in small numbers or perhaps even disappear.

It’s not yet clear to what extent such pockets of altered cells may put people at greater risk for developing cancer down the road. But the presence of these genetic mutations does have potentially important implications for early cancer detection. For instance, it may be difficult to distinguish mutations that are truly red flags for cancer from those that are harmless and part of a new idea of what’s “normal.”

To further explore such questions, it will be useful to study the evolution of normal mutations in healthy human tissues over time. It’s worth noting that so far, the researchers have only detected these mutations in large populations of cells. As the technology advances, it will be interesting to explore such questions at the higher resolution of single cells.

Getz’s team will continue to pursue such questions, in part via participation in the recently launched NIH Pre-Cancer Atlas. It is designed to explore and characterize pre-malignant human tumors comprehensively. While considerable progress has been made in studying cancer and other chronic diseases, it’s clear we still have much to learn about the origins and development of illness to build better tools for early detection and control.


[1] RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Yizhak K, Aguet F, Kim J, Hess JM, Kübler K, Grimsby J, Frazer R, Zhang H, Haradhvala NJ, Rosebrock D, Livitz D, Li X, Arich-Landkof E, Shoresh N, Stewart C, Segrè AV, Branton PA, Polak P, Ardlie KG, Getz G. Science. 2019 Jun 7;364(6444).


Genotype-Tissue Expression Program

The Cancer Genome Atlas (National Cancer Institute/NIH)

Pre-Cancer Atlas (National Cancer Institute/NIH)

Getz Lab (Broad Institute, Cambridge, MA)

NIH Support: Common Fund; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; National Institute of Mental Health; National Cancer Institute; National Library of Medicine; National Institute on Drug Abuse; National Institute of Neurological Diseases and Stroke

Gene Duplication: New Analysis Shows How Extra Copies Split the Work

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Word cloudThe human genome contains more than 20,000 protein-coding genes, which carry the instructions for proteins essential to the structure and function of our cells, tissues and organs. Some of these genes are very similar to each other because, as the genomes of humans and other mammals evolve, glitches in DNA replication sometimes result in extra copies of a gene being made. Those duplicates can be passed along to subsequent generations and, on very rare occasions, usually at a much later point in time, acquire additional modifications that may enable them to serve new biological functions. By starting with a protein shape that has already been fine-tuned for one function, evolution can produce a new function more rapidly than starting from scratch.

Pretty cool! But it leads to a question that’s long perplexed evolutionary biologists: Why don’t duplicate genes vanish from the gene pool almost as soon as they appear? After all, instantly doubling the amount of protein produced in an organism is usually a recipe for disaster—just think what might happen to a human baby born with twice as much insulin or clotting factor as normal. At the very least, duplicate genes should be unnecessary and therefore vulnerable to being degraded into functionless pseudogenes as new mutations arise over time

An NIH-supported team offers a possible answer to this question in a study published in the journal Science. Based on their analysis of duplicate gene pairs in the human and mouse genomes, the researchers suggest that extra genes persist in the genome because of rapid changes in gene activity. Instead of the original gene producing 100 percent of a protein in the body, the gene duo quickly divvies up the job [1]. For instance, the original gene might produce roughly 50 percent and its duplicate the other 50 percent. Most importantly, organisms find the right balance and the duplicate genes can easily survive to be passed along to their offspring, providing fodder for continued evolution.