Abstract
Approximately 2.6% of live births in the United States are conceived using assisted reproductive technologies (ART). While some ART, 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 in ART compared to naturally conceived mice (P = 0.017). Analysis of the dnSNV mutation spectrum identified signatures attributable to germline DNA repair activity but revealed 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. While 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.