Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
VCU Massey Cancer Center, Richmond, VA, USA.
Lab Invest. 2021 Apr;101(4):503-512. doi: 10.1038/s41374-020-00498-x. Epub 2020 Oct 17.
Early human embryogenesis relies on maternal gene products accumulated during oocyte growth and maturation, until around day-3 post-fertilization when human zygotic genome activation occurs. The maternal-to-zygotic transition (MZT) is a tightly coordinated process of selective maternal transcript clearance and new zygotic transcript production. If MZT is disrupted, it will lead to developmental arrest and pregnancy loss. It is well established that microRNA (miRNA) mutations disrupt regulation of their target transcripts. We hypothesize that some cases of embryonic arrest and pregnancy loss could be explained by the mutations in the maternal genome that affect miRNA-target transcript pairs. To this end, we examined mutations within miRNAs or miRNA binding sites in the 3' untranslated regions (3'UTR) of target transcripts. Using whole-exome sequencing data from 178 women undergoing in vitro fertilization (IVF) procedures, we identified 1197 variants in miRNA genes, including 93 single nucleotide variants (SNVs) and 19 small insertions/deletions (INDELs) within the seed region of 100 miRNAs. Eight miRNA seed-region variants were significantly enriched among our patients when compared to a normal population. Within predicted 3'UTR miRNA binding sites, we identified 7393 SNVs and 1488 INDELs. Between our patients and a normal population, 52 SNVs and 30 INDELs showed significant association in the single-variant testing, whereas 51 genes showed significant association in the gene-burden analysis for genes that are expressed in preimplantation embryos. Interestingly, we found that many genes with disrupted 3'UTR miRNA binding sites follow gene expression patterns resembling MZT. In addition, some of these variants showed dramatic allele frequency difference between the patient and the normal group, offering potential utility as biomarkers for screening patients prior to IVF procedures.
早期人类胚胎发生依赖于卵母细胞生长和成熟过程中积累的母体基因产物，直到受精后第 3 天左右，即人类合子基因组激活发生之时。从母体到合子的转变（MZT）是一个选择性母体转录本清除和新的合子转录本产生的紧密协调过程。如果 MZT 受到干扰，将导致发育停滞和妊娠丢失。众所周知，miRNA（miRNA）突变会破坏对其靶转录本的调节。我们假设，一些胚胎停滞和妊娠丢失的情况可以用影响 miRNA-靶转录本对的母体基因组突变来解释。为此，我们检查了靶转录本 3'非翻译区（3'UTR）中 miRNA 或 miRNA 结合位点的突变。使用 178 名接受体外受精（IVF）程序的女性的全外显子组测序数据，我们在 miRNA 基因中鉴定出 1197 个变体，包括 100 个 miRNA 种子区域中的 93 个单核苷酸变体（SNV）和 19 个小插入/缺失（INDEL）。在与正常人群相比时，我们发现 8 个 miRNA 种子区变体在我们的患者中显著富集。在预测的 3'UTR miRNA 结合位点中，我们鉴定出 7393 个 SNV 和 1488 个 INDEL。在我们的患者和正常人群之间，52 个 SNV 和 30 个 INDEL 在单变体测试中表现出显著关联，而在单基因负担分析中，51 个在植入前胚胎中表达的基因表现出显著关联。有趣的是，我们发现许多 3'UTR miRNA 结合位点发生突变的基因表现出类似于 MZT 的基因表达模式。此外，这些变体中的一些在患者和正常组之间表现出明显的等位基因频率差异，为 IVF 程序前筛选患者提供了潜在的应用价值。
