IVF-Conceived Offspring Exhibit Altered LINE-1 Retrotransposition Dynamics Associated with Long-Term Disease Risks

BackgroundIn vitro fertilization (IVF) has revolutionized reproductive medicine; however, IVF-conceived offspring exhibit a higher risk of various long-term health issues. The underlying mechanisms remain unclear. Long Interspersed Nuclear Element-1 (L1), a mobile genetic element sensitive to environmental stress, is a potential mediator. We hypothesized that the IVF procedure acts as an embryonic stress, altering L1 retrotransposition and contributing to genomic instability associated with disease risk. MethodsWhole blood from 33 IVF and 42 naturally conceived (NC) offspring were collected for deep sequencing. We quantified L1 genomic content and mapped novel L1 insertions and deletions with Bowtie2 and MELT, and further compared their frequencies and genomic distributions between the two groups. Gene-disease association analysis was performed on genes within 500kb of differential L1 sites. ResultsThe overall L1 content was significantly higher in IVF offspring compared to NC controls (P<0.05), a finding robustly confirmed in three sibling pairs from the same parents where the IVF children had higher L1 content than their NC siblings. We identified 11 specific genomic loci with significantly different L1 insertion frequencies and 14 loci with different deletion frequencies between IVF and NC offspring. Notably, these differential sites were often located near genes significantly associated with metabolic, cardiovascular, neuropsychiatric, and neoplastic diseases, conditions previously linked to IVF conception. ConclusionOur findings demonstrate that IVF conception is associated with increased L1 content and altered genomic distribution of L1 elements in offspring. The disease-related genes near these aberrant L1 sites provide a plausible genomic link between IVF-associated embryonic stress and the increased risk of specific diseases in the IVF population. This study offers novel insights into the molecular safety of ART.