Preferential occurrence of 1-2 microindels.

Microindels are unique, infrequent mutations that result in inserted and deleted sequences of different sizes (between one and 50 nucleotides) at the same nucleotide position. Little is known about the mutational mechanisms that are responsible for these mutations. From our database of 6,016 independent somatic mutational events in the lacI gene in Big Blue mice, we assembled the 30 microindels (0.5%) for analysis. Microindels with one nucleotide inserted and two nucleotides deleted (1-2 microindels) accounted for seven (23%) of the microindels observed, with the remaining microindels distributed among 21 other combinations of insertion and deletion sizes. A preferential occurrence of 1-2 microindels (20%) was also observed in human germline transmitted mutations in the Human Gene Mutation Database (HGMD). An examination of the sequence flanking the mouse 1-2 microindels did not reveal obvious site specificity or associated secondary structure. A detailed examination of 1-2 microindels did not reveal the features typical of pure microinsertion and microdeletion events, but rather suggested a unique mutational mechanism. The 1 bp insertion in 1-2 microinsertions, and pure 1 bp insertions show distinct features. The mechanism for 1-2 microindels is not obviously a simple combination of pure microinsertion and microdeletion events. The dramatic enhancement of 1-2 microindels requires explanation. We speculate that certain error-prone polymerases may be responsible for the preferential occurrence of 1-2 microindels in both somatic tissues and germ cells. It is estimated that a human adult carries roughly 400 billion somatic 1-2 microindels with the potential to predispose to cancer.