Patchy, incomplete, and heterogeneous X-inactivation in the human placenta

The placenta is formed after the first few weeks of pregnancy and is the genotype of the fetus. It acts as an immune modulator in the uterine environment to sustain a successful pregnancy. One of the X chromosomes in XX females is silenced by a process called X-inactivation. Prior research suggests that incorrect dosage on the X chromosome could lead to poor development of the placenta and ultimately result in complications in pregnancy. Previous studies of X-inactivation in the placenta were either in non-human placentas, or were limited to only a few SNPs and genes in human placentas. Thus, it is not clear whether within human placenta, X-inactivation is completely homogeneous, patchy, or mosaic. Further, X-inactivation is not complete in humans; as many as one-third of the genes on the X chromosome escape X-inactivation, but variability in genes that escape X-inactivation in the placenta has not been investigated. We sequenced RNA from 60 placenta samples from 30 full-term, uncomplicated pregnancies with female offspring. We can confidently rule out X-inactivation being completely mosaic in the human placenta. Rather, we find strong evidence that X-inactivation in the human placenta is patchy, with large potential clonal expansions of either silenced maternal or paternal X-chromosomes, with provocative suggestions of bias towards silencing the paternal X. We also find variation in the degree of silencing, where a high portion of variants (between 26.8-75.3% in any sample) are silenced incompletely. Finally, we find evidence for variability in genes that escape X-inactivation within and among placenta samples.