New mutation hotspot discovered in human genome

The regions are located at the starting point of genes, also known as transcription start sites. These are sequences where cellular machinery starts to copy DNA into RNA. The first 100 base pairs after a gene's starting point are 35% more prone to mutations compared with what you'd expect by chance, according to the study published in Nature Communications.

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.

 

The study found that many of the excess mutations appear immediately after conception, during the first few rounds of cell division in the human embryo. Also known as mosaic mutations, these changes to the DNA sequence end up in some cells but not others and are part of the reason the mutational hotspot has gone undiscovered until now.

A parent can carry disease-contributing mosaic mutations without symptoms because the change ends up in some cells or tissues only. However, they can still pass the mutation on through their eggs or sperm. The child then carries the mutation in all their cells, which could cause disease.

The researchers made the discovery by looking at transcription start sites across 150,000 human genomes from the UK Biobank and 75,000 from the Genome Aggregation Database (gnomAD). They compared the results with data that included information about mosaic mutations from eleven separate family studies.

They found that many gene starting sites across the human genome experienced excess mutations. When the researchers looked more closely, they found the most affected regions were the starting points of sets of genes linked to cancer, brain function and defective limb development.

The mutations are likely to be harmful. The study found a strong excess of mutations near start sites when looking at extremely rare variants, which are normally very recent mutations. That excess shrank when looking at older, more common variants, suggesting natural selection is filtering the mutations out.

In other words, families with mutations in gene starting sites, particularly those linked to cancer and brain function, are less likely to pass them on. Over generations, the mutations do not stick around.

Nature Communications (2025). DOI: 10.1038/s41467-025-66201-0