Hotspots of Human Mutation

Mutation of the human genome results in three classes of genomic variation: single nucleotide variants; short insertions or deletions; and large structural variants (SVs). Some mutations occur during normal processes, such as meiotic recombination or B cell development, and others result from DNA replication or aberrant repair of breaks in sequence-specific contexts. Regardless of mechanism, mutations are subject to selection, and some hotspots can manifest in disease. Here, we discuss genomic regions prone to mutation, mechanisms contributing to mutation susceptibility, and the processes leading to their accumulation in normal and somatic genomes. With further, more accurate human genome sequencing, additional mutation hotspots, mechanistic details of their formation, and the relevance of hotspots to evolution and disease are likely to be discovered. Genetic mutations are influenced by sequence context, structure, and genomic features.Mechanisms responsible for many mutational hotspots have been identified.Hotspots are largely related to loci prone to mutation during replication or DNA repair.Selection leads to recurrent mutations in somatic tissues that can be exploited for therapeutic purposes.