2023-04-25 02:00:00
Mutations catalogued: Using tissue samples from almost 1,000 people, researchers have created a comprehensive atlas of the mutations that accumulate over the course of our lives. The results provide insights into processes of aging and disease development, especially in relation to cancer. The findings could open up new avenues of diagnostics and treatment, including the ability to reverse harmful mutations, the team reports in Science.
Each of our cells carries our unique DNA blueprint. Since we were conceived, this genetic material has been copied again and again and passed on from cell division to cell division. However, copying errors or external influences can result in mutations in the DNA. Most of these changes are cleared by cellular repair mechanisms or the affected cells die rapidly. But every now and then such errors persist and are henceforth passed on to daughter cells.
cause of age-related diseases
“The accumulation of DNA damage is considered to be one of the main causes of age-related diseases,” explain Nicole Rockweiler from Washington University and her team. “Oncology has shown that it is possible to detect such mutations years before the harmful effects become clinically evident, and thus start treatment early.”
For most diseases apart from cancer, however, it is still unclear to what extent there is a direct causal connection to so-called postzygotic mutations, i.e. mutations that have accumulated over the course of our lives. However, further insights could also pave the way for early detection measures. In earlier studies, postzygotic mutations were usually only examined for single, easily accessible tissue types such as blood and skin.
54 tissue types from 948 people
Rockweiler and her team have now compiled the most comprehensive atlas of DNA mutations in human tissues to date. To do this, they examined tissue samples from 948 people who had donated their bodies to research after their death. The analyzes cover 54 tissue and cell types and catalog which mutations occur in the respective cells over the course of life.
The result: “We found that some tissues, such as the esophagus and liver, have many mutations, while other tissues, such as the brain, develop fewer mutations,” says Rockweiler. “This is obvious because the esophagus and liver are exposed to many environmental toxins that can promote errors in the transmission of genetic information. The brain, on the other hand, is made up mostly of non-replicating cells, so mutations are less likely.”
The team also found an increased number of mutations in the skin cells that were heavily exposed to UV radiation and other environmental influences. “What was unexpected was that men had lower mutation rates than women in all three skin types examined,” the researchers report.
Accumulated errors
In addition, the research team reconstructed which mutations occurred at which point in the life of the individual. Accordingly, most of the mutations accumulated with age – partly due to environmental influences, partly due to unfavorable coincidences. Around half of the variations could be explained by factors such as age, gender, tissue type and ancestry. For example, European Americans had more sun-related mutations in their skin than African and Asian Americans.
In addition to these mutations acquired throughout life, each affecting individual tissue types, Rockweiler and her team found numerous mutations that appeared in multiple tissue types. The research team assumes that these mutations arose during development in the womb, even before the affected tissue types diverged.
“When you look at the mutations that are happening in such an important part of our lives, it’s amazing that we can end up doing pretty well at the end of our evolution,” Rockweiler said.
Undo harmful mutations?
According to the team of authors, the influence of the various mutations on individual health depends heavily on the respective tissue, the mutation and individual characteristics. “In order to fully understand the consequences of genetic variants, it is important to develop methods for interpreting the effects on the body over the life course,” the team says.
A better understanding of the mechanisms could also help to develop new therapies in the future. “When it comes to genetic changes as the basis of disease, there are a variety of technologies today that allow us to make changes to the genome,” said Rockweiler’s colleague Donald Conrad. “It might be possible to change the mutations we have acquired through bad luck or bad habits and restore them to their original state.” (Science, 2023, doi: 10.1126/science.abn7113)
Quelle: Oregon Health & Science University
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