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School of Medicine Publications and Presentations
Document Type
Article
Publication Date
8-12-2021
Abstract
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 a blind source separation technique. The analysis of a 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 the direction of transcription, suggesting a major role of DNA damage.
Recommended Citation
Seplyarskiy, V. B., Soldatov, R. A., Koch, E., McGinty, R. J., Goldmann, J. M., Hernandez, R. D., Barnes, K., Correa, A., Burchard, E. G., Ellinor, P. T., McGarvey, S. T., Mitchell, B. D., Vasan, R. S., Redline, S., Silverman, E., Weiss, S. T., Arnett, D. K., Blangero, J., Boerwinkle, E., He, J., … Sunyaev, S. (2021). Population sequencing data reveal a compendium of mutational processes in the human germ line. Science (New York, N.Y.), 373(6558), 1030–1035. https://doi.org/10.1126/science.aba7408
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License
Publication Title
Science
DOI
10.1126/science.aba7408
Academic Level
faculty
Mentor/PI Department
Office of Human Genetics
Comments
It is made available under a CC-BY-NC 4.0 International license.