Mutation Hot Spots in Yeast Caused by Long-Range Clustering of Homopolymeric Sequences

Abstract

Evolutionary theory assumes that mutations occur randomly in the genome; however, studies performed in a variety of organisms indicate the existence ofcontext-dependent mutation biases. Sources ofmutagenesis variation across large genomic contexts (e.g., hundreds of bases) have not been identified. Here, we use high-coverage whole-genome sequencing of a conditional mismatch repair mutant line of diploid yeast to identify mutations thataccumulated after 160 generations of growth. The vast majority of the mutations accumulated asinsertion/deletions (in/dels) in homopolymeric [poly(dA:dT)] and repetitive DNA tracts. Surprisingly, the likelihood of an in/del mutation in a given poly(dA:dT) tract is increased by the presence of nearby poly(dA:dT) tracts in up to a 1,000bp region centered on the given tract. Our work suggests that specific mutation hot spots can contribute disproportionately to the genetic variation that is introduced into populations and provides long-range genomic sequence context that contributes to mutagenesis.