Genomic Analysis Reveals Tumor-Like Nature of Human Placenta

Fetus at week 35, illustration
Fetus at week 35, computer illustration.

An in-depth investigation into the genetics of the placenta reveals its tumor-like nature and shows how it may help normalize genetic mutations in the fetus that would otherwise have resulted in miscarriage.

The research team, led by the University of Cambridge and the Wellcome Sanger Institute, think that as the fetus divides away from the placenta, it uses it as a place to deposit genetic defects that would otherwise cause health problems.

It has been known for some time that the tissue that forms the placenta is genetically unusual compared to other organs in the body, but not to what extent. This study, which is published in the journal Nature, is the first to carry out whole-genome sequencing of multiple placental samples — 86 bulk placental samples and 106 microdissections from different parts of the placenta. They also tested parental samples and samples from the fetuses for comparison purposes.

Unlike any other type of healthy tissue in the body, all the placentas the researchers tested were highly mutated and often contained copy number changes in a similar fashion to cancerous tissue. Based on their findings, the researchers believe that this mosaic state is actually normal for placental tissue and not the rare exception.

“Chunks of normal tissue elsewhere in the body are composed of millions of cells that come from different cell lineages. This design probably protects the tissue from genetic errors of individual linages,” Sam Behjati, M.D., Ph.D., a group leader at the Sanger who co-led the research, told Clinical Omics.

“The placenta, by contrast, is a patchwork of chunks of placental tissue derived from just one lineage, just like tumors.”

The specific reasons behind this high level of mutation and genetic diversity in the placenta is not completely understood, but one reason for it may be to help protect the fetus during development.

For example, in one case the researchers observed some cells containing three copies of chromosome 10 in the placenta, two copies from the mother and one from the father. However, in the rest of the placenta and the fetus, all the cells contained two copies of chromosome 10 (both from the mother) suggesting the original copy number error started in the embryo but was later corrected.

“It was fascinating to observe how such a serious genetic flaw as a chromosomal copy number error was ironed out by the baby but not by the placenta,” commented Gordon Smith, M.D., Ph.D., a professor and head of the Department of Obstetrics and Gynaecology at the University of Cambridge, who co-led the study.

“This error would have been present in the fertilized egg. Yet derivative cell populations, and most importantly those that went on to form the child, had the correct number of copies of chromosome 10, whereas parts of the placenta failed to make this correction. The placenta also provided a clue that the baby had inherited both copies of the chromosome from one parent, which can itself be associated with problems.”

Maris Laan, Ph.D., was not involved in this study, but is a professor of human genetics at the University of Tartu in Estonia and has a special interest in placental genetics.

Commenting on the purpose of the placenta’s genetic fluidity, she told Clinical Omics: “It is still not clear whether these somatic genetic changes are simply a side product of rapid cellular proliferation during early embryogenesis or whether these changes are actually necessary and promoted to support trophoblast development, more efficient invasion of the uterus and proper placental formation in support of the fetal development.”

During the first 3 months of pregnancy, the placenta has to develop very fast in order to support the growth of the embryo, so the ability to grow in a similar way to a tumor may help the tissue to fulfill this purpose.

Although the placenta’s unusual genetics can help the fetus to survive and reach full term, some of these genetic changes can be detrimental to both mother and baby.

“The maternal body has certain adaptations in her immune system during pregnancy to be able to tolerate ‘a stranger’ in her body. One cost of these adaptations may be that not all fetal genomic abnormalities are recognized and the fetus discarded,” notes Laan.

Mutations in the placenta can also increase the risk for maternal conditions during pregnancy. For example, a placental genetic variant near the FLT1 gene can increase the risk for pre-eclampsia, which can be fatal for both mother and baby.

“The current study… further highlights the unique profile of the placental genome and it opens up the research to understand, how these somatic changes modulate pregnancy success, programming of the fetal development and long-term health of the fetus and the mother,” says Laan.

More research is needed to provide solutions to maternal or fetal health problems associated with placental development, but the Cambridge research provides much needed data for future work in this under investigated area.

“Our study… provides a definitive blueprint for addressing the question about placental genetic abnormalities and pregnancy outcomes,” says Behjati. “Ultimately, if we find the genetic causes of the complications of pregnancy, we might be able to devise treatments to help improve the health of the mother and the unborn child.”

Laan agrees and draws attention to the difficulties of working in this field. “Worldwide, it has been challenging to draw the attention of stake-holders and grant agencies to the importance of funding placental research. Somehow, the placenta and its genome research does not fit under any schemes and most researchers… neglect its importance.”

She explains that not many scientists work in this area, as the nature of the tissue itself makes it ethically more challenging and more complicated to design and carry out genetic research compared to other areas.

“Although there has been extensive biobanking efforts during the past 10-15 years, there are only a limited number of clinically well described placental sample collections worldwide. Longitudinal studies are needed on how the genetics and epigenetics of placenta will affect the health and disease risk across life-span of both, the mother and the child.”

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