Abstract
Resequencing efforts are uncovering the extent of genetic variation in humans and provide data to study the evolutionary processes shaping our genome. One recurring puzzle has been the abundance of complex mutations comprising multiple near-by base substitutions or insertion-deletions. We devised a generalized mutation model to study the role of template switch events in the origin of mutation clusters. Applied to the human genome, the novel model finds strong evidence for inter-strand template switch events and identifies new types of mutations that create short inversions, some flanked by a pair of inverted repeats. This new, local template switch process can create complex mutation patterns, including secondary structures, and explains apparent high frequencies of compensatory substitutions and multi-nucleotide mutations without invoking positive selection. Many of these complex mutations are polymorphic in humans but their detection with current sequencing methodologies is difficult.
