Genetic mosaicism more common than thought
"It is simply astounding how much previously undiscovered heterogeneity there is in our genomes"
Blood stem cells from healthy people show chromosomal changes, as researchers from the Max Delbrück Center and the European molecular biology Laboratory report. This suggests that genetic mosaics could contribute to age-related diseases.
In a study led by Professor Jan Korbel, senior scientist and head of data science at the European Molecular Biology Laboratory (EMBL), and Dr. Ashley Sanders, group leader at the Max Delbrück Center's Berlin Institute for Medical Systems Biology (MDC-BIMSB), researchers found that about one in 40 human bone marrow cells exhibit massive chromosomal alterations - for example, in copy number variations and chromosomal rearrangements - without an obvious disease or abnormality. In addition, cell samples from people over the age of 60 tended to show a higher number of cells with such genome changes. This points to a previously unknown mechanism that may contribute to age-related diseases. The study was published in the journal "Nature Genetics".
"The study underlines that we are all mosaics," says Korbel. "Even supposedly normal cells carry all kinds of genetic mutations. Ultimately, this means that there are more genetic differences between individual cells in our bodies than between us humans."
Detection of subtle genome details in individual cells
Both Korbel and Sanders are investigating how genetic structural changes - deletions, duplications, inversions and translocations of large sections of the human genome - contribute to the development of diseases. With regard to cancer, it is known that genetic mutations can cause cells to grow uncontrollably and form a tumor, explains Sanders. "We are using similar approaches to understand how non-cancerous diseases develop," she adds.
The discovery was made possible by a single-cell sequencing technology known as Strand-Seq. This is a special DNA sequencing technique that can reveal minute details of genomes in single cells that are difficult to detect with other methods. Sanders is a pioneer of this technology. As part of her doctoral thesis, she was involved in the development of the Strand-Seq method, which she later refined with colleagues as a post-doc in Korbel's lab.
Strand-Seq allows researchers to detect structural changes in individual cells with greater precision and resolution than any other sequencing technology, says Sanders. The technology has led to a completely new understanding of genetic mutations and is now widely used to describe genomes and translate findings into clinical research. "We are just realizing that not every cell in our body has exactly the same DNA - contrary to what the textbooks say," she says.
Genetic mosaicism is widespread
This study is the first time that Strand-Seq technology has been used to investigate mutations in the DNA of healthy people. The researchers examined biological samples from different age groups - from newborns to 92-year-olds - and found mutations in blood stem cells located in the bone marrow in 84 percent of the study participants. This indicates that strong genetic mutations are very common.
"It is simply astounding how much previously undiscovered heterogeneity there is in our genomes," says Ashley Sanders. "What this means for the definition of 'normal' human aging and how it may affect the types of diseases we suffer from are extremely important questions for the field."
The study also found that people over the age of 60 whose bone marrow cells carry genetic changes also tend to have higher numbers of them. Stocks of certain genetic variants, known as subclones, occur more frequently than others. The frequent presence of these subclones indicates a possible connection with ageing.
But whether the mechanisms that keep the proliferation of subclones in check fail with increasing age, or whether the proliferation of subclones itself contributes to age-related diseases, is not known, says Korbel. "Our future single-cell studies should give us clearer insights into how these mutations, which have so far gone unnoticed, affect our health and possibly contribute to how we age."
Note: This article has been translated using a computer system without human intervention. LUMITOS offers these automatic translations to present a wider range of current news. Since this article has been translated with automatic translation, it is possible that it contains errors in vocabulary, syntax or grammar. The original article in German can be found here.
Original publication
Karen Grimes, Hyobin Jeong, Amanda Amoah, Nuo Xu, Julian Niemann, Benjamin Raeder, Patrick Hasenfeld, Catherine Stober, Tobias Rausch, Eva Benito, Johann-Christoph Jann, Daniel Nowak, Ramiz Emini, Markus Hoenicka, Andreas Liebold, Anthony Ho, Shimin Shuai, Hartmut Geiger, Ashley D. Sanders, Jan O. Korbel; "Cell-type-specific consequences of mosaic structural variants in hematopoietic stem and progenitor cells"; Nature Genetics, 2024-5-28
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