Integrative transcriptome meta-analysis reveals widespread sex-biased gene expression at the human fetal-maternal interface

Abstract

As males and females share highly similar genomes, the regulation of many sexually dimorphic traits is constrained to occur through sex-biased gene regulation. There is strong evidence that human males and females differ in terms of growth and development in utero and that these divergent growth strategies appear to place males at increased risk when in sub-optimal conditions. Since the placenta is the interface of maternal-fetal exchange throughout pregnancy, these developmental differences are most likely orchestrated by differential placental function. To date, progress in this field has been hampered by a lack of genome-wide information on sex differences in placental gene expression. Therefore, our motivation in this study was to characterize sex-biased gene expression in the human placenta. We obtained gene expression data for >300 non-pathological placenta samples from 11 microarray datasets and applied mapping-based array probe re-annotation and inverse-variance meta-analysis methods which showed that >140 genes (false discovery rate (FDR) <0.05) are differentially expressed between male and female placentae. A majority of these genes (>60%) are autosomal, many of which are involved in high-level regulatory processes such as gene transcription, cell growth and proliferation and hormonal function. Of particular interest, we detected higher female expression from all seven genes in the LHB-CGB cluster, which includes genes involved in placental development, the maintenance of pregnancy and maternal immune tolerance of the conceptus. These results demonstrate that sex-biased gene expression in the normal human placenta occurs across the genome and includes genes that are central to growth, development and the maintenance of pregnancy.