X chromosome inactivation in the human placenta is patchy and distinct from adult tissues

In humans, one of the X chromosomes in genetic females is inactivated by a process called X chromosome inactivation (XCI). Variation in XCI across the placenta may contribute to observed sex differences and variability in pregnancy outcomes. However, XCI has predominantly been studied in human adult tissues. Here, we sequenced and analyzed DNA and RNA from two locations from 30 full-term pregnancies. Implementing an allele-specific approach to examine XCI, we report evidence that XCI in the human placenta is patchy, with large patches of either maternal or paternal X chromosomes inactivated. Further, using similar measurements, we show that this is in contrast to adult tissues, which generally exhibit mosaic X inactivation, where bulk samples exhibit both maternal and paternal X chromosome expression. Further, by comparing skewed samples in placenta and adult tissues, we identify genes that are uniquely inactivated or expressed in the placenta compared with adult tissues, highlighting the need for tissue-specific maps of XCI.