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Genome-wide DNA methylation and imprinted gene analysis in babies conceived by ART Gooding, Luke David

Abstract

Assisted reproductive technologies (ARTs) are associated with a number of adverse pregnancy, neonatal, and long-term outcomes. One plausible explanation is that ART procedures may be causing alterations in epigenetic mechanisms, including the regulation of imprinted genes, that persist during development. Therefore, I investigated gene expression of the imprinted genes PLAGL1, CDKN1C, KCNQ1OT1, and H19 in cord blood from 24 IVF, 18 ICSI, 9 IUI, and 26 naturally conceived babies as well as genome-wide DNA methylation using Illumina’s EPIC methylation array in cord blood from 10 IVF, 9 ICSI, and 10 naturally conceived babies. All the samples were procured from healthy newborn singletons. No differences in the gene expression of the imprinted genes were observed across conception modes. The genome-wide DNA methylation analysis revealed an overall stability of DNA methylation following ART; however, a small number of CpG sites exhibited hypervariability in the ICSI (47 CpG sites) and the IVF (4 CpG sites) groups. Furthermore, the mCSEA method for detecting DMRs revealed 101 promoter associated DMRs in the ICSI group and 101 promoter associated DMRs in the IVF group. 35 DMRs overlapped between the ICSI and IVF groups, suggesting some regions may be susceptible to DNA methylation alterations following ART. Four imprinted gene DMRs were also found to overlap DMRs between conception modes. Overall this analysis revealed that a small number of genomic regions may be impacted by ART. These regions may be significant as genes associated with neurodevelopmental disorders, intrauterine programming of adult onset obesity, and male infertility were observed to be altered in both the IVF and ICSI groups. Although validation of these regions is required, this analysis provides support for ART impacting DNA methylation that persists to birth in genes related to adverse outcomes and mediating transmission of DNA methylation alterations from infertile parents to babies.

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Attribution-NonCommercial-NoDerivatives 4.0 International