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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Nature Portfolio
2024-10-01
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| Online Access: | https://doi.org/10.1038/s41598-024-73587-2 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jonatan Axelsson |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-642eb87b6f244a7fb80c1b98bc0a8549 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-642eb87b6f244a7fb80c1b98bc0a85492024-12-22T12:26:03ZengNature PortfolioScientific Reports2045-23222024-10-0114111510.1038/s41598-024-73587-2Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-based de novo mutation analysesJonatan Axelsson0Danielle LeBlanc1Habiballah Shojaeisaadi2Matthew J Meier3Devon M. Fitzgerald4Daniela Nachmanson5Jedidiah Carlson6Alexandra Golubeva7Jake Higgins8Thomas Smith9Fang Yin Lo10Richard Pilsner11Andrew Williams12Jesse Salk13Francesco Marchetti14Carole Yauk15Department of Biology, University of OttawaEnvironmental Health Science and Research Bureau, Health CanadaEnvironmental Health Science and Research Bureau, Health CanadaEnvironmental Health Science and Research Bureau, Health CanadaTwinStrand Biosciences, Inc.TwinStrand Biosciences, Inc.TwinStrand Biosciences, Inc.TwinStrand Biosciences, Inc.TwinStrand Biosciences, Inc.TwinStrand Biosciences, Inc.TwinStrand Biosciences, Inc.Department of Obstetrics & Gynecology, Wayne State UniversityEnvironmental Health Science and Research Bureau, Health CanadaTwinStrand Biosciences, Inc.Environmental Health Science and Research Bureau, Health CanadaDepartment of Biology, University of OttawaAbstract 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.https://doi.org/10.1038/s41598-024-73587-2Sperm DNA mutationsDe novo mutationsMutation frequencyMutational spectrumExtrachromosomal circular DNADuplex sequencing |
| spellingShingle | 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 Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-based de novo mutation analyses Scientific Reports Sperm DNA mutations De novo mutations Mutation frequency Mutational spectrum Extrachromosomal circular DNA Duplex sequencing |
| title | Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-based de novo mutation analyses |
| title_full | Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-based de novo mutation analyses |
| title_fullStr | Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-based de novo mutation analyses |
| title_full_unstemmed | Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-based de novo mutation analyses |
| title_short | Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-based de novo mutation analyses |
| title_sort | frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio based de novo mutation analyses |
| topic | Sperm DNA mutations De novo mutations Mutation frequency Mutational spectrum Extrachromosomal circular DNA Duplex sequencing |
| url | https://doi.org/10.1038/s41598-024-73587-2 |
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