To the editor:

A recent study elucidates the interplay of selective forces that result in increased X-chromosome linkage of genes expressed predominantly in sex-limited tissues such as the testis and ovary1. The study also reports increased X linkage of genes that are highly expressed in the placenta. In the report and accompanying commentary, the bias of placentally expressed genes is ascribed to the placenta being a 'female' tissue1,2. Although the placenta develops jointly from maternal and fetal tissues, however, anatomical and molecular genetic studies indicate that an explanted placenta is composed predominantly of fetal trophoblast. Therefore, most DNA sequences in placental cDNA collections are likely to be fetal, rather than maternal, in origin3,4. This is evident from scrutiny of the placental cDNA collections used by Khil et al.1, which shows that known trophoblast-specific genes are well represented.

Although the explanation for the placental bias proposed by Khil et al.1 therefore requires clarification, we suggest that their finding is nevertheless consistent with Rice's proposal that increased X linkage is a feature of sexually antagonistic genes5. The fetal component of the placenta is a key site of imprinted-gene expression6. It has been proposed that imprinting evolved as a form of sexual antagonism acting on the parental alleles at loci expressed in offspring that influence the level of maternal investment7. Paternal alleles are predicted to favor increased maternal investment in offspring, and maternal alleles to favor reduced investment. Consistent with this theory, experimental overexpression of maternally inherited alleles or underexpression of paternally inherited alleles causes reduced growth of fetal and placental tissues6. In mammals, the paternally inherited X chromosome is epigenetically inactivated in most of the fetal extraembryonic tissues that contribute to the placenta of female embryos. Therefore, placentally expressed genes that undergo X inactivation are effectively imprinted, with maternal expression, and, under the parental conflict theory, are predicted to favor reduced maternal investment. Consistent with this theory, mouse embryos carrying supernumerary X chromosomes of maternal origin have reduced placental growth8,9.

In spite of the expectation that imprinting should evolve at any locus mediating maternal investment in offspring, imprinted genes are scarce; this fact may be explained by the existence of mechanistic barriers to the evolution of parental allele–specific expression10. But the presence, in placental tissues of fetal origin, of the paternally silenced X chromosome provides a preadapted mechanism for the evolution of maternal-specific gene expression which, from a joint consideration of Rice5 and the parental conflict theory7, predicts increased X linkage of placentally expressed genes that reduce placental growth and maternal investment. It is, therefore, unnecessary to ascribe 'femaleness' to the placenta in order to explain the findings of Khil et al.1, because sexual antagonism is played out, at one remove, in the fetal trophoblast between maternally and paternally inherited alleles.