Patterns and Mutational Signatures of Tandem Base Substitutions Causing Human Inherited Disease

Tandem base substitutions (TBSs) are multiple mutations that comprise two or more contiguous nucleotide substitutions without any net gain or loss of bases. They have recently become recognized as a distinct category of human genomic variant. However, their role in causing human inherited disease so far has not been studied methodically. Here, using data from the Human Gene Mutation Database (http://www.hgmd.org), we identified 477 events to be TBSs (doublets, 448; triplets, 16; and quadruplets to octuplets, 13). A comprehensive sequence pattern and context analysis implied the likely fundamental importance of translesion synthesis (TLS) DNA polymerases in generating these diverse TBSs but revealed that TLS polymerases may operate differently in generating TBSs of 3 bases (bypass of endogenous DNA lesions) than those of 4 bases (serial replication slippage). Moreover, GC was found to be the most frequently affected dinucleotide with GC/GC>AA/TT being the most frequent double TBS. Comparison with cancer genome mutational spectra allowed us to conclude that human germline TBSs arise predominantly through the action of endogenous mechanisms of mutagenesis rather than through exposure to exogenous mutagens. Finally, the rates of double and triple TBSs were estimated to be 0.2-1.2x10(-10) and 0.8-4.8x10(-12) per base per generation, respectively.