Modest increase in the de novo single-nucleotide mutation rate in house mice born by assisted reproduction.
Document Type
Article
Publication Date
1-5-2026
Original Citation
Blanco-Berdugo L,
Garretson A,
Dumont B.
Modest increase in the de novo single-nucleotide mutation rate in house mice born by assisted reproduction. Genome Res. 2026;36(1):50–60.
Keywords
JMG, Animals, Mice, Reproductive Techniques, Assisted, Female, Mice, Inbred C57BL, Mutation Rate, Male, Polymorphism, Single Nucleotide, Fertilization in Vitro, Genomic Instability
JAX Source
Genome Res. 2026;36(1):50–60.
ISSN
1549-5469
PMID
41233158
DOI
https://doi.org/10.1101/gr.281180.125
Grant
This work was supported by start-up funds from The Jackson Laboratory and a MIRA from The National Institute of General Medical Sciences to B.L.D. (R35 GM133415)
Abstract
Approximately 2.6% of live births in the United States are conceived using assisted reproductive technologies (ARTs). Although some ARTs, including in vitro fertilization (IVF) and intracytoplasmic sperm injection, are known to alter the epigenetic landscape of early embryonic development, their impact on DNA sequence stability is unclear. Here, we leverage the strengths of the laboratory mouse model system to investigate whether a standard ART series (ovarian hyperstimulation, gamete isolation, IVF, embryo culture, and embryo transfer) affects genome stability. Age-matched cohorts of 12 ART-derived and 16 naturally conceived C57BL/6J inbred mice were reared in a controlled setting and whole-genome-sequenced to ∼50× coverage. Using a rigorous pipeline for de novo single-nucleotide variant (dnSNV) discovery, we observe a ∼30% (95% CI: 4.5%–56%) increase in the dnSNV rate with ART compared with naturally conceived mice (P = 0.017). Analysis of the dnSNV mutation spectrum identifies signatures attributable to germline DNA repair activity but reveals no differentially enriched signatures between cohorts. We observe no enrichment of dnSNVs in specific genomic contexts, suggesting that the observed rate increase in ART-derived mice is a general genome-wide phenomenon. Together, our findings show that ART is moderately mutagenic in house mice and motivate future work to define the procedure(s) associated with this increased mutational vulnerability. Although we caution that our findings cannot be immediately translated to humans, they nonetheless emphasize a pressing need for investigations on the potential mutagenicity of ART in our species.