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(https://directorsblog.nih.gov/2024/07/11/sequencing-technique-detects-earliest-signs-of-genetic-mutations-underlying-cancer-aging-and-more/) Sequencing Technique Detects Earliest Signs of Genetic Mutations Underlying Cancer, Aging, and More
Jul 11th 2024, 09:00

Every day, billions of cells in your body divide, each producing two daughter cells. It’s an essential process for your tissues and organs to renew themselves and remain healthy. To do it, cells must first duplicate their DNA to ensure that each daughter cell gets an accurate copy. In this process, mistakes are inevitably made. Most DNA errors are accurately fixed and do not lead to mutations. But when small errors akin to single-letter typos aren’t corrected, they can become permanent in a cell and multiplied with each subsequent cell division. Even cells that don’t divide, such as neurons in your brain, acquire damage and mutations in their DNA with age. As a result, your tissues contain collections of cells with distinct mutations that accumulate over time.

While many of these small errors will show no obvious consequences, others can lead to cancer and other health conditions. Now, a new DNA sequencing technique, described in (https://pubmed.ncbi.nlm.nih.gov/38867045/) Nature and developed through research supported by NIH, promises to detect early DNA changes before they become permanent mutations in a cell’s genome. The method, called Hairpin Duplex Enhanced Fidelity Sequencing (HiDEF-seq), could advance our understanding of how and why mutations arise, with potentially important implications for our health. For example, the ability to identify signs that precede mutations may help predict a person’s health risks based on genetic predispositions, environmental exposures, or other factors.

The HiDEF-seq technique comes from an international team led by (https://www.evronylab.org/) Gilad Evrony at NYU Grossman School of Medicine’s Center for Human Genetics and Genomics in New York City. To understand how the method works, it helps to remember that each DNA molecule stores genetic information in the form of two complementary strands made up of four molecular “letters,” or chemical bases. Those bases are adenine (A), thymine (T), guanine (G), and cytosine (C). The sequence of about three billion As, Ts, Gs, and Cs in human DNA’s two strands generally should match up, such that As pair with Ts and Gs with Cs.

The first step in which DNA mutations arise usually involves a change in only one of the two DNA strands. Those single-strand errors only become permanent mutations in both strands when a cell’s copying machinery fails to detect the mistake before the cell divides again, or when the cell’s DNA repair machinery makes a mistake in the correction process. However, because other methods to sequence DNA can’t accurately detect changes that are in only one of the DNA strands, it hasn’t been possible for researchers to study this process in detail. This is where HiDEF-seq comes in.

The researchers wanted to develop an approach for directly sequencing single DNA molecules to detect these early-stage DNA errors. Detecting changes that are in only one of the two DNA strands requires an extremely high degree of sequencing accuracy, with less than one error per one billion bases, so the team devised a method to read DNA with higher precision than was previously possible. To put HiDEF-seq to the test, they profiled 134 samples from various human tissues, including those from people with syndromes that predisposed them to cancer due to an unusually high number of new mutations.

The research team found they could use HiDEF-seq to identify changes present in only one of the two DNA strands that were the precursors to mutational events. For example, they identified places where a C was mistakenly paired with a T instead of a G. As expected, those early changes in DNA turned up more often in people with syndromes that increase their risk of cancer than in those without. The patterns of those single-strand DNA changes also looked a lot like the patterns of double-strand DNA mutations seen in people with these syndromes, suggesting that the HiDEF-seq method was indeed seeing the precursors to mutations.

The method can also detect a common form of DNA damage called cytosine deamination, in which cytosine is converted to a different base called uracil (U), which is another source of mutations. Experiments in human sperm, which rarely pick up mutations compared to other cell types, showed a pattern of cytosine deamination that closely matched damage caused by heating healthy DNA in the lab. This led the researchers to suggest that the damage to DNA happens similarly in both situations.

The researchers have already begun to produce a catalog of the various single-strand DNA errors they’ve uncovered. They suggest that HiDEF-seq may allow new ways to monitor the everyday effects of environmental exposures or other insults on our DNA and shed light on the balance in cells between DNA damage, repair, and replication. Along the way, this new technique will enable the continued study of DNA damage and the origins of mutations in a way that hasn’t been possible before.

Reference:

Liu MH, et al. (https://www.nature.com/articles/s41586-024-07532-8) Single-strand mismatch and damage patterns revealed by single-molecule DNA sequencing. Nature. DOI: 10.1038/s41586-024-07532-8 (2024).

NIH Support: Common Fund, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Cancer Institute

Forwarded by:
Michael Reeder LCPC
Baltimore, MD

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