Extensive load of somatic CNVs in the human placenta

Abstract

Placenta is a temporary, but indispensable organ in mammalian pregnancy. From its basic nature, it exhibits highly invasive tumour-like properties facilitating effective implantation through trophoblast cell proliferation and migration, and a critical role in pregnancy success. We hypothesized that similarly to cancer, somatic genomic rearrangements are promoted in the support of placental function. Here we present the first profiling of copy number variations (CNVs) in human placental genomes, showing an extensive load of somatic CNVs, especially duplications and suggesting that this phenomenon may be critical for normal gestation. Placental somatic CNVs were significantly enriched in genes involved in cell adhesion, immunity, embryonic development and cell cycle. Overrepresentation of imprinted genes in somatic duplications suggests that amplified gene copies may represent an alternative mechanism to support parent-of-origin specific gene expression. Placentas from pregnancy complications exhibited significantly altered CNV profile compared to normal gestations, indicative to the clinical implications of the study.

RNA sequencing of chorionic villi from recurrent pregnancy loss patients reveals impaired function of basic nuclear and cellular machinery

“…This is a key feature in implantation process and normally functioning trophoblastic cells, and is represented in the most extreme form in multinuclear syncytiotrophoblast layer in the human placenta and in trophoblastic giant cells in mouse37. Consistent with the critical role of endocycle process in the normal placental development and function, our recent study identified an extensive load of somatic structural variants in the human placental genome and the highest fraction of genomic rearrangements was detected in normal pregnancies38. Endoreplication is essential for normal early development in many eukaryotic organisms39 and the role of E2F transcription factors in the involved processes appears to be evolutionarily conserved among mammals and insects40.…”

Copy number variation profile in the placental and parental genomes of recurrent pregnancy loss families

“…We have previously shown that the high load of CNVs in the human placental genome arises mainly from somatic duplications9. Notably, the seminal study also demonstrated that placentas from late pregnancy complications such as preeclampsia, gestational diabetes and fetal growth disturbances exhibit significantly lower number of CNVs.…”

“…For 50 placental samples profiled for their CNV content in the current and previous study9, also RNA-Seq dataset has been generated2021. In order to assess the functional effect of CNVs on the expression of the involved genes (termed as ‘CNV genes’; n = 2,273 across all samples), we compared their transcript levels with the remaining Ensembl genes, not disrupted by CNVs in any placental samples (‘non CNV genes’; n = 45,156).…”

“…As a major outcome, we reported an extensive load of somatic CNVs, especially duplications in the placental genome9. As the highest number of placental CNVs was detected for healthy term pregnancies, we suggested that this phenomenon might be critical for normal gestation.…”

“…Our previous study revealed a load of somatic CNVs, especially duplications, in the placental genomes of successful pregnancies9. CNVs enriched for genes involved in immune regulation, cell adhesion, embryonic development and cell cycle may modulate the expression of relevant genes at specific time points to guarantee normal progression and maintenance of pregnancy.…”