DNA damage bypass is a major source of clustered mutations

Sunyaev Lab, HMS Biomedical Informatics; Division of Genetics, BWH
DNA damage bypass is a major source of clustered mutations

The superb accuracy of transmission of genetic information between generations is one of the most fascinating properties of life. Infrequent errors in this transmission lead to mutations that are the source of genetic variation which fuels evolution and causes genetic disease. Most mutations generate individual single nucleotide substitutions but some are complex events such as substitution clusters. Mutation clusters contain more information than individual mutations and serve as a powerful tool to investigate mutational mechanisms using statistical methods. The analysis of more than 1 500 000 clustered mutations reveals three underling mutagenic processes. We attribute two of these processes to the translesion synthesis bypassing DNA damage.

Kharchenko Lab, HMS Biomedical Informatics
Population sequencing data reveal a compendium of mutational processes in human germline

Mechanistic processes underlying human germline mutations remain largely unknown. Variation in mutation rate and spectra along the genome is informative about the biological mechanisms. We statistically decompose this variation into separate processes using independent component analysis of mutational spectra. The analysis of large-scale whole genome sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. Seven of these processes lend themselves to a biological interpretation. One process is driven by bulky DNA lesions that resolve asymmetrically with respect to transcription and replication. Two processes independently track direction of replication fork and replication timing. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions. We also demonstrate that a recently discovered mutagenic process specific to oocytes can be localized solely from population sequencing data. This process is spread across all chromosomes and is highly asymmetric with respect to direction of transcription suggesting a major role of DNA damage.