There is an increased prevalence of imprinting disorders, such as Beckwith–Wiedemann syndrome, associated with human assisted reproductive technologies (ART). Work on animal models suggests that in vitro culture may be the source of these imprinting errors. However, in this study we report that, in some cases, the errors are inherited from the father. We analyzed DNA methylation at seven autosomal imprinted loci and the XIST locus in 78 paired DNA samples. In seven out of seventeen cases where there was abnormal DNA methylation in the ART sample (41%), the identical alterations were present in the parental sperm. Furthermore, we also identified DNA sequence variations in the gene encoding DNMT3L, which were associated with the abnormal paternal DNA methylation. Both the imprinting errors and the DNA sequence variants were more prevalent in patients with oligospermia. Our data suggest that the increase in the incidence of imprinting disorders in individuals born by ART may be due, in some cases, to the use of sperm with intrinsic imprinting mutations.

An important difference between placental mammals and marsupials is the maturity of the fetus at birth. Placental mammals achieved this maturity by developing a complex and invasive placenta to support and prolong internal development. The exact genomic modifications that facilitated the evolution of this complex structure are unknown, but the emergence of genomic imprinting within mammalian lineages suggests a role for gene dosage. Here we show that a maximally altered placental structure is achieved by a single extra dose of the imprinted Phlda2 gene characterized by a dramatically reduced junctional zone and a decrease in stored glycogen. In addition, glycogen cells do not migrate into the maternal decidua in a timely fashion, but instead, Tpbpa-positive cells progressively mislocalize into the labyrinth. These defects are linked to a progressive restriction of embryonic growth from embryonic day 16.5. This work has identified a critical role for the imprinted Phlda2 gene in regulating glycogen storage in the eutherian placenta and implies that imprinting has provided a mechanism to boost nutrient supply to the fetus late in gestation, when the fetus is placing the highest demands on maternal resources, to enhance growth.