A long-overlooked weak point in your DNA has just been revealed

The vulnerable regions sit at the beginning of genes, known as transcription start sites. These are the points where the cell begins copying DNA into RNA. According to a study published on November 26 in Nature Communications, the first 100 base pairs after this starting point experience mutations at a rate 35% higher than expected by chance.

"These sequences are extremely prone to mutations and rank among the most functionally important regions in the entire human genome, together with protein-coding sequences," explains Dr. Donate Weghorn, corresponding author of the study and researcher at the Centre for Genomic Regulation in Barcelona.

Early Development and Mosaic Mutations

The research team discovered that many of these extra mutations arise soon after conception during the earliest rounds of cell division in the embryo. These alterations, known as mosaic mutations, appear in only some cells rather than throughout the entire body. Because of this uneven distribution, the hotspot remained undetected for a long time.

A parent may carry mosaic mutations that contribute to disease without showing symptoms, since only a portion of their tissues contain the change. Despite the lack of symptoms, they can still pass these mutations through eggs or sperm. A child who inherits one of these mosaic mutations will have it present in every cell, which can lead to health problems.

Large-Scale Genome Analysis Reveals Mutation Patterns

To make this discovery, researchers examined transcription start sites across 150,000 genomes from the UK Biobank and 75,000 genomes from the Genome Aggregation Database (gnomAD). They then compared their findings with data from eleven family studies that provided detailed information about mosaic mutations.

Their analysis showed that many gene start sites across the genome accumulate more mutations than expected. When they looked more closely, they found that the highest concentration of these excess mutations occurred in the starting regions of genes involved in cancer, brain function and abnormal limb development.

The study suggests these mutations are likely harmful. The team observed a strong concentration of mutations near start sites when examining extremely rare variants, which tend to represent recent changes. That excess became smaller in older, more common variants, indicating that natural selection gradually removes these mutations. Families carrying such mutations, especially in genes linked to brain function or cancer, are less likely to pass them on. Over multiple generations, these mutations tend to disappear.

Why Mutational Models Need Adjustment

Avoiding false conclusions and finding missed clues

The findings highlight a potential source of error in mutational models. These tools estimate how many mutations should appear in a given part of the genome if nothing unusual is happening. Clinicians use that baseline to determine which mutations deserve further attention.

Because transcription start sites naturally accumulate more mutations than previously recognized, the expected baseline for these regions is higher than current models assume. This means geneticists will need to update their tools to avoid misinterpreting results.

"If a model doesn't know this region is naturally mutation-rich, it might expect, say, 10 mutations but observe 50. If the correct baseline is 80, then 50 means fewer than expected and is a sign harmful changes are being removed by natural selection. You would completely miss the importance of that gene," explains Dr. Weghorn.

These insights also affect genetic studies that search only for mutations that appear in a child but not in either parent. While this approach works for mutations present in every cell, it fails to capture mosaic mutations, which appear in a mix of tissues. As a result, some important contributors to disease may be overlooked.

"There is a blind spot in these studies. To get around this, one could look at the co-occurrence patterns of mutations to help detect the presence of mosaic mutations. Or look at the data again and revisit discarded mutations that occur near the transcription starts of genes most strongly affected by the hotspot," says Dr. Weghorn.

Why Gene Start Sites Are So Mutation-Prone

A new source of mutations

The study describes the transcription process as fast and chaotic. The cell's molecular machinery often pauses and resumes activity near the starting point, and sometimes begins copying in both directions. At the same time, temporary structures can form that leave segments of DNA exposed to potential damage.

According to the authors, these moments of instability make transcription start sites especially vulnerable during the rapid cell divisions that occur shortly after conception. Although cells can usually repair these issues, the pressure to grow quickly leads to some mutations being left behind like small scars on the genome.

The findings reveal an important missing element in the understanding of how mutations form. Known causes such as replication errors or ultraviolet damage have been documented for decades. "Finding a new source of mutations, particularly those affecting the human germline, doesn't happen often," concludes Dr. Weghorn.