Strand-seq, a single-cell sequencing technique, has been used to survey the mosaic structural variant (mSV) landscape of normal blood stem cells. This work, which was led by scientists based at the European Molecular Biology Laboratory (EMBL) and the Max Delbrück Center, detected de novo mSVs in 1 of every 43 hematopoietic stem and progenitor cells (HSPCs). Such mSVs, the scientists found, may emerge regardless of age, and without necessarily causing any apparent disease or abnormality. Nonetheless, the scientists also observed that people over the age of 60 tended to have higher numbers of cells harboring mSVs. This observation suggests that a previously unidentified mechanism may contribute to aging-related diseases.
The study appeared in Nature Genetics, in a paper titled, “Cell-type-specific consequences of mosaic structural variants in hematopoietic stem and progenitor cells.”
“Utilizing Strand-seq, we sequenced 1,133 single-cell genomes from 19 human donors of increasing age,” the article’s authors wrote. “While mSVs are continuously acquired throughout life, expanded subclones in our cohort are confined to individuals >60. Cells already harboring mSVs are more likely to acquire additional somatic structural variants, including megabase-scale segmental aneuploidies.”
The scientists also conducted high-resolution cell-typing for eight hematopoietic stem and progenitor cells. “Clonally expanded mSVs disrupt normal cellular function by dysregulating diverse cellular pathways, and enriching for myeloid progenitors,” they reported. “Our findings underscore the contribution of mSVs to the cellular and molecular phenotypes associated with the aging hematopoietic system, and establish a foundation for deciphering the molecular links between mSVs, aging, and disease susceptibility in normal tissues.”
More generally, the study highlights that all people are mosaics. “Even so-called normal cells carry all sorts of genetic mutations,” said Jan Korbel, PhD, one of the study’s senior authors and a senior scientist in the EMBL’s Genome Biology Unit. “Ultimately, this means that there are more genetic differences between individual cells in our bodies than between different human beings.”
Kobel and the study’s other senior author, Ashley Sanders, PhD, group leader at the Max Delbrück Center, study how genetic structural variations—deletions, duplications, inversions, and translocations of large sections of the human genome—contribute to the development of disease. In the cancer field, it is well known that genetic mutations can cause cells to grow out of control and lead to the formation of a tumor. Kobel and Sanders, however, also focus on how noncancerous diseases develop.
In their work, they employ Strand-seq, a unique DNA sequencing technique that can reveal subtle details of genomes in single cells that are too difficult to detect with other methods. Sanders is a pioneer in the development of this technology. As part of her doctoral research, she helped develop the Strand-seq protocol, which she later honed with colleagues while working as a postdoctoral fellow in Korbel’s lab.
Strand-seq enables researchers to detect structural variants in individual cells with better precision and resolution than any other sequencing technology allows, Sanders said. The technology has ushered in an entirely new understanding of genetic mutations and is now being widely used to characterize genomes and to help translate findings into clinical research.
“We are just recognizing that contrary to what we learned in textbooks, every cell in our body doesn’t have the exact same DNA,” she said.
The study represents the first time anyone has used Strand-seq technology to study mutations in the DNA of healthy people. The researchers included biological samples from a range of age groups—from newborn to 92 years old—and found mutations in blood stem cells, which are located in the bone marrow, in 84% of the study participants, indicating that large genetic mutations are very common.
“It’s just amazing how much heterogeneity there is in our genomes that has gone undetected so far,” Sanders said. “What this means in terms of how we define normal human aging and how this can impact the types of diseases we get is really an important question for the field.”
The study also found that in people over the age of 60, bone marrow cells carrying genetic alterations tended to be more abundant, with populations of specific genetic variants, or subclones, more common than others. The frequent presence of these subclones suggests a possible connection to aging.
But whether the mechanisms that keep subclones from proliferating in check break down as we age, or whether the expansion of subclones itself contributes to diseases of aging is not known. “In the future,” Korbel said, “our single-cell studies should give us clearer insights into how these mutations that previously went unnoticed affect our health and potentially contribute to how we age.”
