The substitution rates within different nucleotide contexts are subject to varying levels of bias. The most well known example of such bias is the excess of C to T (C > T) mutations in CpG (CG) dinucleotides. The molecular mechanisms underlying this bias are important factors in human genome evolution and cancer development. The discovery of other nucleotide contexts that have profound effects on substitution rates can improve our understanding of how mutations are acquired, and why mutation hotspots exist.