A genome-wide mutation analysis method enabling high-throughput identification of chemical mutagen signatures

Area of Science:

• Genomics and Mutagenesis
• Cancer Research
• Microbial Genetics

Background:

• Trinucleotide mutational signatures from cancer genomes offer insights into mutagen roles in cancer development.
• A simple genome-wide method for analyzing mutagen-induced alterations is lacking, hindering the identification of mutagen exposure signatures and their cancer associations.

Purpose of the Study:

• To introduce a novel approach for analyzing chemically induced mutations in bacterial cells.
• To facilitate the identification of trinucleotide signatures of mutagen exposure and their relationship with human cancers.

Main Methods:

• Utilized paired-end overlapping next-generation sequencing for genome-wide analysis of base substitutions.
• Analyzed DNA from Salmonella typhimurium strain TA100 exposed to alkylating agents: ethylnitrosourea (ENU), methylnitrosourea (MNU), and ethyl methanesulfonate (EMS).
• Examined mutation patterns within the 96 possible trinucleotide contexts.

Main Results:

• Observed increased G:C > A:T mutation frequency in all exposed samples.
• Detected increased A:T base pair substitution frequencies specifically in ENU-exposed samples.
• Identified a distinct trinucleotide mutation pattern (NpCpY consensus sequence) similar to alkylating agent signatures in human cancer.

Conclusions:

• The novel sequencing approach effectively facilitates the analysis of chemically induced mutations in bacteria.
• This method aids in understanding chemical mutagenicity mechanisms and identifying potential causal mutagens in human cancers.
• The findings highlight the utility of bacterial models for deciphering cancer-associated mutational signatures.