Population sequencing data reveal a compendium of mutational processes in human germline

Authors

Vladimir B. Seplyarskiy
Ruslan A. Soldatov
Evan Koch
Ryan J. McGinty
Jakob M. Goldmann
Ryan D. Hernandez
Kathleen Barnes
Adolfo Correa
Esteban G. Burchard
John Blangero, The University of Texas Rio Grande Valley

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.

Comments

It is made available under a CC-BY-NC 4.0 International license.

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