Previously overlooked regions at the start of human genes have been shown to accumulate mutations far more often then would be expected by chance,revealing a major source of inherited and mosaic variants
Researchers from the Centre for Genomic Regulation,in Barcelona,have identified previously unrecognised regions of the human genome that are especially vulnerable to mutation with the potential to influence future generations. The study has focused on short stretches of DNA at the start of genes and has shown that these regions are far more prone to change than the rest of the genome. The findings have meaningful implications for basic genetics, disease research and clinical variant interpretation.
The work has centred on transcription start sites, the positions in the genome where the cellular machinery initiates transcription to copy DNA into RNA. The team has shown that the first 100 base pairs downstream of a gene’s transcription start site are about 35% more likely to accumulate mutations than would be expected by chance.”These sequences are extremely prone to mutations and rank alongside protein-coding sequences as among the most functionally significant regions in the entire human genome,” said dr Donate Weghorn, corresponding author of the study and a researcher at the Centre for Genomic Regulation.
Because transcription start sites play a central part in the control of gene activity, the accumulation of mutations in these regions has the potential to alter when, where and how strongly genes switch on.
The team has found that many of the excess mutations arise very early in progress, during the first few rounds of cell division immediately after conception. These variants, known as mosaic mutations, arise when a mutation appears in the DNA of a cell that then gives rise to only a subset of the tissues in the body.
Consequently, some cells carry the altered sequence while others retain the original one. This mosaic pattern has made the hotspot tough to detect, because conventional genetic studies often assume that every cell in an individual carries exactly the same genome.
A parent can carry disease-contributing mosaic mutations without symptoms if the alteration lies in a subset of cells or in tissue types that do not affect health directly. Though, such mutations can still pass into eggs or sperm. When that occurs,a child can inherit the variant in every cell of the body,which can raise the likelihood of disease. The work has thus highlighted a route by which apparently unaffected parents can transmit high-impact mutations to their offspring.
To uncover the hotspot, the researchers examined transcription start sites across more than 150,000 human genomes in the UK Biobank resource, together with about 75,000 genomes from the Genome Aggregation Database (gnomAD) of Broad Institute of MIT and Harvard, in Cambridge, Massachusetts. These large population data sets provided a detailed picture of how often mutations occur at specific positions in the genome. The team then compared these signals with data on mosaic mutations derived from eleven separate family-based sequencing studies which are able to distinguish variants present only in some cells.
The analysis has shown that transcription start sites throughout the human genome carry an excess of mutations relative to the surrounding DNA sequence. When the researchers examined these regions in more detail, they observed that the most affected start sites cluster in groups of genes involved in cancer biology, brain function and the development of limbs. The pattern has suggested that regulatory mutations in these hotspots could contribute to a wide range of diseases, from neurodevelopmental conditions to congenital limb defects and hereditary cancers.
The study has also provided evidence that many of these mutations are harmful. When the researchers focused on extremely rare variants, which usually correspond to mutations that have occurred very recently in evolutionary time, they observed a strong excess of changes near t