Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-based de novo mutation analyses

Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-based de novo mutation analyses

Abstract De novo mutations (DNMs) are drivers of genetic disorders. However, the study of DNMs is hampered by technological limitations preventing accurate quantification of ultra-rare mutations. Duplex Sequencing (DS) theoretically has < 1 error/billion base-pairs (bp). To determine the DS utili...

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Main Authors: Jonatan Axelsson, Danielle LeBlanc, Habiballah Shojaeisaadi, Matthew J Meier, Devon M. Fitzgerald, Daniela Nachmanson, Jedidiah Carlson, Alexandra Golubeva, Jake Higgins, Thomas Smith, Fang Yin Lo, Richard Pilsner, Andrew Williams, Jesse Salk, Francesco Marchetti, Carole Yauk
Format: Article
Language:English
Published: Nature Portfolio 2024-10-01
Series:Scientific Reports
Subjects:
Sperm DNA mutations
De novo mutations
Mutation frequency
Mutational spectrum
Extrachromosomal circular DNA
Duplex sequencing
Online Access:https://doi.org/10.1038/s41598-024-73587-2
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Summary:Abstract De novo mutations (DNMs) are drivers of genetic disorders. However, the study of DNMs is hampered by technological limitations preventing accurate quantification of ultra-rare mutations. Duplex Sequencing (DS) theoretically has < 1 error/billion base-pairs (bp). To determine the DS utility to quantify and characterize DNMs, we analyzed DNA from blood and spermatozoa from six healthy, 18-year-old Swedish men using the TwinStrand DS mutagenesis panel (48 kb spanning 20 genic and intergenic loci). The mean single nucleotide variant mutation frequency (MF) was 1.2 × 10− 7 per bp in blood and 2.5 × 10− 8 per bp in sperm, with the most common base substitution being C > T. Blood MF and substitution spectrum were similar to those reported in blood cells with an orthogonal method. The sperm MF was in the same order of magnitude and had a strikingly similar spectrum to DNMs from publicly available whole genome sequencing data from human pedigrees (1.2 × 10− 8 per bp). DS revealed much larger numbers of insertions and deletions in sperm over blood, driven by an abundance of putative extra-chromosomal circular DNAs. The study indicates the strong potential of DS to characterize human DNMs to inform factors that contribute to disease susceptibility and heritable genetic risks.
ISSN:2045-2322

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