Scientists have discovered a new type of region in the human genome that is particularly prone to mutations, located at the starting point of genes, which is the transcription start site. The changes in these DNA fragments can be inherited by future generations, which is of great significance for people's understanding of genetics and disease occurrence. This achievement is led by the Barcelona Genome Regulation Center in Spain and published in the latest issue of Nature Communications. This discovery shows that the probability of accidental mutations occurring in the first 100 bases after the gene's starting point is 35% higher. These sequences serve as the starting point for cellular mechanisms to replicate DNA into RNA, making them one of the most functionally important regions in the genome, equally important as protein coding sequences. These sequences are highly susceptible to mutations and are one of the most functionally important regions in the entire human genome. Research has shown that many additional mutations occur during the first few rounds of cell division after conception, known as mosaic mutations, which only appear in certain cells rather than all cells. This is also part of the reason why these mutation hotspots have not been discovered for a long time. Parents may carry these mosaic mutations without symptoms because the mutations only exist in certain cells or tissues, but these mutations can still be passed on to offspring through eggs or sperm. If all cells of a child carry this mutation, it may lead to disease. The team discovered this phenomenon by analyzing the transcription start sites of 150000 human genomes and 75000 genomes in the UK Biobank, and comparing them with mosaic mutation data from 11 independent family studies. However, many genes have undergone abnormally many mutations at their starting sites, especially those related to cancer, brain function, and limb development defects, which are most severely affected. When observing older and more common mutations, this additional mutation phenomenon decreases, indicating that natural selection is filtering out these harmful mutations. In other words, families with mutations at the starting point of genes, especially those related to cancer and brain function, are less likely to pass on these mutations and gradually disappear over several generations. Currently, geneticists use mutation models to determine how many mutations are expected to occur in specific regions of the genome without special circumstances. In clinical practice, this baseline is used to determine which variants should be focused on and which should be prioritized. However, if the model is unaware of natural mutation hotspots, it may draw incorrect conclusions. For example, the model may have expected 10 mutations in a certain region, but in reality observed 50, while the correct baseline may be 80. This blind spot is the focus of this breakthrough. (New Society)