Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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

Axelsson, Jonatan LU ; LeBlanc, Danielle ; Shojaeisaadi, Habiballah ; Meier, Matthew J ; Fitzgerald, Devon M ; Nachmanson, Daniela ; Carlson, Jedidiah ; Golubeva, Alexandra ; Higgins, Jake and Smith, Thomas , et al. (2024) In Scientific Reports 14(1). p.23134-23134
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Male, Spermatozoa/metabolism, Adolescent, Mutation, Mutation Rate, DNA Mutational Analysis/methods, Polymorphism, Single Nucleotide, High-Throughput Nucleotide Sequencing, Sweden, Sequence Analysis, DNA/methods
in
Scientific Reports
volume
14
issue
1
pages
23134 - 23134
publisher
Nature Publishing Group
external identifiers
  • pmid:39379474
  • scopus:85206020085
ISSN
2045-2322
DOI
10.1038/s41598-024-73587-2
language
English
LU publication?
yes
additional info
© 2024. The Author(s).
id
d00b3062-e5f5-4e56-8f47-17ef1c9ef7a9
date added to LUP
2024-10-24 08:28:34
date last changed
2024-12-20 10:42:21
@article{d00b3062-e5f5-4e56-8f47-17ef1c9ef7a9,
  abstract     = {{<p>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 &lt; 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 &gt; 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.</p>}},
  author       = {{Axelsson, Jonatan and LeBlanc, Danielle and Shojaeisaadi, Habiballah and Meier, Matthew J and Fitzgerald, Devon M and Nachmanson, Daniela and Carlson, Jedidiah and Golubeva, Alexandra and Higgins, Jake and Smith, Thomas and Lo, Fang Yin and Pilsner, Richard and Williams, Andrew and Salk, Jesse and Marchetti, Francesco and Yauk, Carole}},
  issn         = {{2045-2322}},
  keywords     = {{Humans; Male; Spermatozoa/metabolism; Adolescent; Mutation; Mutation Rate; DNA Mutational Analysis/methods; Polymorphism, Single Nucleotide; High-Throughput Nucleotide Sequencing; Sweden; Sequence Analysis, DNA/methods}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{1}},
  pages        = {{23134--23134}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Frequency and spectrum of mutations in human sperm measured using duplex sequencing correlate with trio-based de novo mutation analyses}},
  url          = {{http://dx.doi.org/10.1038/s41598-024-73587-2}},
  doi          = {{10.1038/s41598-024-73587-2}},
  volume       = {{14}},
  year         = {{2024}},
}