Heterosis, defined as the superior performance of F1 hybrids over their parents, has been used for centuries to increase yield in plants and animals. However, the biological basis of heterosis is poorly understood, as it does not follow standard genetic models. Based on theoretical prediction that genomic imprinting may mimic overdominance and heterosis, we investigated whether imprinting effects could explain heterosis. We used purebred and reciprocal cross Bos taurus taurus (Angus, A) and Bos taurus indicus (Brahman, B) cattle that display one of the strongest known heterotic phenotypes in mammals. We intercepted concepti at mid-gestation, when the fetus enters accelerated growth but does not yet display heterosis in weight, to map drivers of heterosis in placenta as the major organ regulating prenatal growth that predicts postnatal performance. Our analyses at the gross morphological, histomorphological and molecular level revealed nine maternal, three paternal and nine polar over/underdominance patterns consistent with genomic imprinting effects but only two with additive genetic effects. Strikingly, placental polar overdominance patterns at midgestation mirrored polar overdominance in birth weight. We found that increased nutrient supply via maternal A genome effects on placental phenotype, combined with increased nutrient transfer capacity via polar overdominance effects of paternal B genome on umbilical cord phenotype, provide the basis for heterosis in birth weight of B×A hybrids. Polar overdominance in expression of imprinted IGF2R in Placenta fetalis of B×A hybrids, and correlation of transcript abundance with number of feto-maternal syncytia in placenta, are consistent with an active signaling role of IGF2R in placenta and a further indicator of superior placental performance as the driver of heterosis. In conclusion, we have shown that phenotypic expression patterns consistent with imprinting effects on placental and umbilical cord parameters and in agreement with the conflict of interest theory of genomic imprinting drive mammalian heterosis in utero.

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