%0 Journal Article %J Science %D 2021 %T Population sequencing data reveal a compendium of mutational processes in the human germ line. %A Seplyarskiy, Vladimir B %A Soldatov, Ruslan A %A Koch, Evan %A McGinty, Ryan J %A Goldmann, Jakob M %A Hernandez, Ryan D %A Barnes, Kathleen %A Correa, Adolfo %A Burchard, Esteban G %A Ellinor, Patrick T %A McGarvey, Stephen T %A Mitchell, Braxton D %A Vasan, Ramachandran S %A Redline, Susan %A Silverman, Edwin %A Weiss, Scott T %A Arnett, Donna K %A Blangero, John %A Boerwinkle, Eric %A He, Jiang %A Montgomery, Courtney %A Rao, D C %A Rotter, Jerome I %A Taylor, Kent D %A Brody, Jennifer A %A Chen, Yii-Der Ida %A de Las Fuentes, Lisa %A Hwu, Chii-Min %A Rich, Stephen S %A Manichaikul, Ani W %A Mychaleckyj, Josyf C %A Palmer, Nicholette D %A Smith, Jennifer A %A Kardia, Sharon L R %A Peyser, Patricia A %A Bielak, Lawrence F %A O'Connor, Timothy D %A Emery, Leslie S %A Gilissen, Christian %A Wong, Wendy S W %A Kharchenko, Peter V %A Sunyaev, Shamil %K Algorithms %K CpG Islands %K DNA Damage %K DNA Demethylation %K DNA Mutational Analysis %K DNA Replication %K Genetic Variation %K Genome, Human %K Germ Cells %K Germ-Line Mutation %K Humans %K Long Interspersed Nucleotide Elements %K Mutagenesis %K Oocytes %K Transcription, Genetic %X

Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.

%B Science %V 373 %P 1030-1035 %8 2021 08 27 %G eng %N 6558 %1 https://www.ncbi.nlm.nih.gov/pubmed/34385354?dopt=Abstract %R 10.1126/science.aba7408 %0 Journal Article %J Nat Genet %D 2019 %T Error-prone bypass of DNA lesions during lagging-strand replication is a common source of germline and cancer mutations. %A Seplyarskiy, Vladimir B %A Akkuratov, Evgeny E %A Akkuratova, Natalia %A Andrianova, Maria A %A Nikolaev, Sergey I %A Bazykin, Georgii A %A Adameyko, Igor %A Sunyaev, Shamil R %K Cells, Cultured %K DNA %K DNA Damage %K DNA Repair %K DNA Replication %K Germ-Line Mutation %K Humans %K Mutagenesis %K Neoplasms %K Polymorphism, Single Nucleotide %K Transcription, Genetic %X

Studies in experimental systems have identified a multitude of mutational mechanisms including DNA replication infidelity and DNA damage followed by inefficient repair or replicative bypass. However, the relative contributions of these mechanisms to human germline mutation remain unknown. Here, we show that error-prone damage bypass on the lagging strand plays a major role in human mutagenesis. Transcription-coupled DNA repair removes lesions on the transcribed strand; lesions on the non-transcribed strand are preferentially converted into mutations. In human polymorphism we detect a striking similarity between mutation types predominant on the non-transcribed strand and on the strand lagging during replication. Moreover, damage-induced mutations in cancers accumulate asymmetrically with respect to the direction of replication, suggesting that DNA lesions are resolved asymmetrically. We experimentally demonstrate that replication delay greatly attenuates the mutagenic effect of ultraviolet irradiation, confirming that replication converts DNA damage into mutations. We estimate that at least 10% of human mutations arise due to DNA damage.

%B Nat Genet %V 51 %P 36-41 %8 2019 01 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/30510240?dopt=Abstract %R 10.1038/s41588-018-0285-7