Researchers show that horizontal gene transfer may occur in mammals through DNA fragments from dying cells

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Summary

For decades, scientists have known that bacteria can exchange genetic material in a process called horizontal gene transfer. Research by Professor Mittra’s group suggests that horizontal transfer also happens in mammals via fragments of DNA known as cell-free chromatin particles that are released from dying cells. Once inside new host cells, the chromatin particles acquire novel functions and act as autonomous “satellite” genomes. This discovery may redefine mammalian genomics and evolution.

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For decades, scientists have known that bacteria can exchange genetic material, in a process called horizontal gene transfer. This allows bacteria to rapidly evolve new traits, such as antibiotic resistance. A groundbreaking study, led by Professor Indraneel Mittra at the Advanced Centre for Treatment, Research & Education in Cancer, Mumbai, shows that this process may also happen in mammals – through fragments of DNA known as cell-free chromatin particles. These fragments are released from the billions of cells that die in the body every day and can be taken up by living cells to form complex genetic structures with novel functions. This discovery challenges the way we think about genomics and evolution.

In their study, Professor Mittra’s team extracted cell-free chromatin particles from human serum and introduced them into mouse cells grown in the lab. These particles were readily absorbed by the cells, where they indiscriminately fused together into large and complex genetic formations called concatemers. Remarkably, these concatemers began to behave like autonomous genomes, performing many of the functions that are normally attributed to the nuclear genome. These “satellite genomes” began replicating themselves, assembling their own protein-making machinery and independently making novel proteins. The team discovered that these concatemers also carry special genetic elements known as LINE-1 and Alu, which are ‘jumping genes’. Such elements have the ability to move around within a genome, and can reshape a cell’s genetic blueprint over time. Once inside the mouse cells, these human derived elements multiplied and amplified and rearranged themselves, potentially altering the host cell’s DNA in unpredictable ways.

“Our findings support a model where a cell simultaneously harbors two genome forms: one that is inherited, called hereditary genome, and numerous others that are acquired, the satellite genomes,” explains Prof. Mittra. “The blurring of the line between these two genome forms potentially offers a new mechanism for rapid genomic innovation and diversity opening new research avenues in biology and medicine.”

In another surprising discovery, the researchers found that cell-free chromatin particles – and the resulting concatemers – are mostly made up of non-coding DNA, long thought to be “junk”. Non-coding DNA comprises up to 99% of the human genome and is not typically known to perform any of the above activities. For example, non-coding DNA doesn’t normally produce proteins, although it has long been suspected to play other important roles. This finding suggests that non-coding DNA has hidden biological functions which remain dormant but are activated following cellular death to become detectable within the concatemers.

Professor Mittra’s findings have profound implications for how we understand genome modification and evolution. We currently think of genetic change happening slowly, through mutations that are passed down from parents to offspring. However, if cells can absorb and rearrange genetic fragments from the numerous dying cells through “within-self” horizontal gene transfer, a more dynamic process could be at play.

This research may also provide a new approach to cancer treatment. Cancer cells are known to contain extra bits of DNA floating outside their normal chromosomes. These fragments, known as extrachromosomal DNA, can drive cancer growth and help tumours become resistant to treatment. The team’s study suggests that these DNA fragments may be concatemers comprised of cell-free chromatin particles acquired from surrounding dying cells that can hijack the cell’s genetic machinery. If this is the case, then deactivating the cell-free chromatin particles before they enter new host cells could open up new approaches to cancer treatment.

Professor Mittra’s team has opened a new chapter in mammalian genomics. Their research challenges the long-held assumption that our DNA is a fixed, inherited code. Instead, their work suggests that DNA is dynamic, constantly changing as our cells exchange and rearrange external genetic material. This discovery could transform not only how we think about evolution but also how we approach medicine, particularly in fields like cancer research, ageing and regenerative medicine.

Link to the published paper in the journal eLife:
https://elifesciences.org/articles/103771

Funding information
This study was supported by the Department of Atomic Energy, Government of India, through its grant CTCTMC to the Tata Memorial Centre awarded to Indraneel Mittra.

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About Professor Indraneel Mittra
Professor Indraneel Mittra is Dr. Ernest Borges Chair in Translational Research and Professor Emeritus in the Department of Surgical Oncology at the Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Mumbai.