Researchers have identified a concentrated mutation hotspot in human DNA: the roughly first 100 base pairs following transcription start sites (TSS). A new study published in Nature Communications, led by teams at the Center for Genomic Regulation (Barcelona) and Harvard Medical School, shows these TSS-proximal bases are unusually prone to post-zygotic (mosaic) mutations that arise during the rapid cell divisions after fertilization.
What the Study Found
By analysing genomic data from about 225,000 TSS regions drawn from the Genome Aggregation Database and the U.K. Biobank, and validating results with eleven family studies of mosaic variants, the authors report a roughly 35% higher mutation rate in the first ~100 base pairs after TSS compared with random expectation. The strongest enrichment appeared among rare variants, consistent with recent origin and subsequent removal by natural selection over generations.
Why It Matters
These mutations typically occur very early—during the first rapid rounds of cell division after the zygote forms—when replication errors are more likely. Such early post-zygotic changes produce mosaicism, meaning different cell lineages within the same person can carry distinct genotypes. Unlike chimerism, which usually stems from the fusion of two embryos, mosaicism originates from a single fertilized egg.
Mosaic variants are often patchy in distribution and may be clinically silent in the carrier. However, if a mutation that arose early in embryogenesis becomes present in germ cells and is transmitted to offspring, it can appear in every cell of the child and cause developmental disorders. In the study, mutations in TSS-proximal regions were observed in genes associated with cancer, brain development, and abnormal limb formation.
Implications for Research and Medicine
One practical implication is for computational models of mutation rates. If models assume a uniform baseline mutation rate across the genome, they may underestimate natural mutability at TSS regions and therefore misinterpret variant enrichment as evidence for selection or disease association. As the authors note, an accurate baseline is essential to correctly identify when a gene is truly under selection or disease pressure.
Donate Weghorn, senior author, Centre for Genomic Regulation: 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.
Takeaway
The discovery of a TSS-proximal mutation hotspot highlights a trade-off in early embryonic development: the rapid cell divisions needed to form a human body increase opportunities for replication errors. The finding offers a clearer target for studying unexplained developmental disorders, refining mutation-rate models, and investigating early contributors to cancer risk.
