Study strengths and limitations
The authors did not have access to information about chorionicity of the monozygotic twin pairs. Consequently, they were unable to correlate chorionicity with the degree of noted genetic difference between the monozygotic twin pairs. Additionally, although the authors were thoughtful in their utilization of offspring and spouses to infer germline genomic content, the study had a limited number of tissues sampled, which could reduce the applicability. However, the sample size, clinically accessible tissue sampling, and thoughtful analysis used in this study make it an interesting and relevant contribution to reproductive medicine and evolutionary biology.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
We all accumulate changes to our DNA throughout life. The study by Jonsson and colleagues illustrates that for many, this accumulation of genetic changes starts very early in gestation. In the early zygote, the authors observed roughly 1 mutation per cell division prior to the point of twinning. In the realm of prenatal diagnosis, one should consider that monochorionic twins with different phenotypes (that is, an ultrasonography anomaly in 1 of the twin pair) could represent a genetic change rather than an environmental difference. This genetic change may not be shared by the other twin despite originating from the same primordial cell line. The genetic changes that the authors investigated were detected on genome sequencing, which is much more comprehensive than the exome sequencing that is increasingly utilized in rare disease diagnosis. The clinical utility of this observation in prenatal diagnosis has yet to be proven, but this study provides preliminary data that 15% of monozygotic twins have genetic differences and may warrant individualized testing.
We all accumulate changes to our DNA throughout life. The study by Jonsson and colleagues illustrates that for many, this accumulation of genetic changes starts very early in gestation. In the early zygote, the authors observed roughly 1 mutation per cell division prior to the point of twinning. In the realm of prenatal diagnosis, one should consider that monochorionic twins with different phenotypes (that is, an ultrasonography anomaly in 1 of the twin pair) could represent a genetic change rather than an environmental difference. This genetic change may not be shared by the other twin despite originating from the same primordial cell line. The genetic changes that the authors investigated were detected on genome sequencing, which is much more comprehensive than the exome sequencing that is increasingly utilized in rare disease diagnosis. The clinical utility of this observation in prenatal diagnosis has yet to be proven, but this study provides preliminary data that 15% of monozygotic twins have genetic differences and may warrant individualized testing.
The genetic landscape of the placenta
Coorens TH, Oliver TR, Sanghvi R, et al. Inherent mosaicism and extensive mutation of human placentas. Nature. Published online March 10, 2021. doi:10.1038/ s41586-021-03345-1.
Confined placental mosaicism (CPM) is a phenomenon in which the genetics of the placenta are different from those of the fetus. Historically, this phenomenon has been described in 1% to 2% of pregnancies based on karyotype data obtained from chorionic villus sampling. Some studies have demonstrated adverse pregnancy outcomes in the setting of CPM, thought to be secondary to aneuploid cells in the placenta leading to insufficiency or dysfunction.
Although our sophistication and level of detail in prenatal genetic testing has rapidly expanded to include information about copy number variants and singlenucleotide changes, their contribution to CPM has been understudied. Coorens and colleagues recently published a landmark study that describes a surprisingly high rate of mosaicism for these smaller genetic changes.
A cohort study of placentas
The authors performed whole genome sequencing on placental samples obtained from 37 term pregnancies. Umbilical cord tissue and maternal blood also were collected and served as controls for fetal and maternal genetic profiles, respectively.
In a subgroup of 5 placentas, lasercapture microscopy was used to separate placental cells of different origins, including trophoblastic cells, mesenchymal core cells, and cells originating from the inner cell mass. To investigate variation within different geographic regions of a single placenta, these cell lines were derived multiple times from each quadrant of the 5 placentas.
Placental biopsies revealed “bottlenecks” of genetic differentiation
Genome sequencing was used uniquely in this study to help delineate the phylogeny of placental cells by tracking somatic mutations both in different geographic locations of each placenta and between different cells of origin within 1 placenta.
The authors concluded that bottlenecks of differentiation in placental development led to unique genetic signatures in every bulk placental sample studied. Their findings led them to describe the placenta as a “patchwork” of independent genetic units resulting from clonal expansion at different stages of embryonic development.
Early insights into human placental cells
This study provides fascinating insight into the surprisingly high rates of copy number variants and single-gene changes that exist, in mosaic form, within human placentas. The authors distinguish the placenta from other human organs (such as the colon, endometrium, liver, and skin) in which many fewer genetic changes exist. In fact, they suggest parallels between the “mutational signature” of the placenta with rapidly dividing neoplastic cells.
As one of the first investigations into the variation and complexity of genetic changes within the placenta, this study was not designed to draw conclusions regarding the clinical impact of the numerous genetic changes described. Further studies will elucidate the potential contribution of genetically mosaic placentas to common adverse obstetric outcomes. ●
WHAT THIS EVIDENCE MEANS FOR PRACTICE
With a new appreciation for the smaller genetic alterations that exist within placental tissue, it appears that the rate of CPM has been vastly underestimated. We know that aneuploid placental cells increase the risk of adverse pregnancy outcomes and we may learn more about the contribution of copy number variants and single-nucleotide changes to preeclampsia, growth restriction, and pregnancy loss. Furthermore, as the applications of cell-free fetal DNA (cffDNA) in genetic screening continue to expand, we must exercise caution in assuming that copy number variants or single-nucleotide changes detected by cffDNA reflect those of the developing fetus.
With a new appreciation for the smaller genetic alterations that exist within placental tissue, it appears that the rate of CPM has been vastly underestimated. We know that aneuploid placental cells increase the risk of adverse pregnancy outcomes and we may learn more about the contribution of copy number variants and single-nucleotide changes to preeclampsia, growth restriction, and pregnancy loss. Furthermore, as the applications of cell-free fetal DNA (cffDNA) in genetic screening continue to expand, we must exercise caution in assuming that copy number variants or single-nucleotide changes detected by cffDNA reflect those of the developing fetus.