Genomic imprinting results in preferential expression of the paternal, or maternal allele of certain genes. We have performed a genome-wide characterization of imprinting in the mouse embryonic and adult brain. This approach uncovered parent-of-origin allelic effects in over 1300 loci. We identified parental bias in the expression of individual genes and of specific transcript isoforms, with differences between brain regions. Many imprinted genes are expressed in neural systems associated with feeding and motivated behaviors, and parental biases preferentially target genetic pathways governing metabolism and cell adhesion. We observed a preferential maternal contribution to gene expression in the developing brain and a major paternal contribution in the adult brain. Thus, parental expression bias emerges as a major mode of epigenetic regulation in the brain.Parent-of-origin effects influence gene expression and trait inheritance in offspring. Genomic imprinting is a form of epigenetic regulation that results in the preferential expression of the paternally or maternally inherited allele of certain genes (1). Currently, fewer than 100 imprinted genes have been identified, and the evolutionary pressures that underlie imprinting are debated (2,3). Clinical and experimental data suggest roles for imprinting in regulating brain development and function (4). In humans, Prader-Willi Syndrome (PWS) and Angelman Syndrome (AS) result from a deletion of the paternal or maternal copy of 15q11-13, respectively. PWS is associated with hyperphagia, stubbornness and compulsive traits (5), whereas AS is associated with absent speech, happy affect and inappropriate laughter (6). Further, studies of parthenogenetic (PG)-and androgenetic (AG)-chimeras in the mouse have suggested preferential maternal contribution to the development of the cortex, but preferential paternal contribution to the hypothalamus (7,8). Such biased roles have yet to be clearly demonstrated. Moreover, despite tantalizing reports, our understanding of the neural systems governed by imprinted genes, and of the scope and features of imprinted loci expressed in the brain is very limited.6 Address correspondance to Dr. Catherine Dulac: dulac@fas.harvard.edu or Dr. Christopher Gregg: cgregg@mcb.harvard.edu. 7 These authors contributed equally to this study. HHMI Author Manuscript HHMI Author Manuscript HHMI Author ManuscriptImprinting refers to functional differences between the maternal and paternal chromosomes or alleles (9), and is also used more strictly to define complete allele-specific silencing (10). Known imprinted genes have been shown to display all-or-none and biased allelic expression according to the gene and tissue considered (11,12). We report here a genomewide analysis of parental allelic effects involving complete silencing or parental biases in gene expression in the murine embryonic day 15 (E15) brain, and in the adult male and female cortex (medial prefrontal cortex (mPFC)) and hypothalamus (preoptic area (POA)). Together with a compa...

A well known, epidemiologically reproducible risk factor for human carcinomas is the long-term consumption of "red meat" of mammalian origin. Although multiple theories have attempted to explain this human-specific association, none have been conclusively proven. We used an improved method to survey common foods for free and glycosidically bound forms of the nonhuman sialic acid N-glycolylneuraminic acid (Neu5Gc), showing that it is highly and selectively enriched in red meat. The bound form of Neu5Gc is bioavailable, undergoing metabolic incorporation into human tissues, despite being a foreign antigen. Interactions of this antigen with circulating anti-Neu5Gc antibodies could potentially incite inflammation. Indeed, when human-like Neu5Gc-deficient mice were fed bioavailable Neu5Gc and challenged with anti-Neu5Gc antibodies, they developed evidence of systemic inflammation. Such mice are already prone to develop occasional tumors of the liver, an organ that can incorporate dietary Neu5Gc. Neu5Gc-deficient mice immunized against Neu5Gc and fed bioavailable Neu5Gc developed a much higher incidence of hepatocellular carcinomas, with evidence of Neu5Gc accumulation. Taken together, our data provide an unusual mechanistic explanation for the epidemiological association between red meat consumption and carcinoma risk. This mechanism might also contribute to other chronic inflammatory processes epidemiologically associated with red meat consumption.

Genetically modified organisms (GMOs) are increasingly deployed at large scales and in open environments. Genetic biocontainment strategies are needed to prevent unintended proliferation of GMOs in natural ecosystems. Existing biocontainment methods are insufficient either because they impose evolutionary pressure on the organism to eject the safeguard, because they can be circumvented by environmentally available compounds, or because they can be overcome by horizontal gene transfer (HGT). Here we computationally redesign essential enzymes in the first organism possessing an altered genetic code to confer metabolic dependence on nonstandard amino acids for survival. The resulting GMOs cannot metabolically circumvent their biocontainment mechanisms using environmentally available compounds, and they exhibit unprecedented resistance to evolutionary escape via mutagenesis and HGT. This work provides a foundation for safer GMOs that are isolated from natural ecosystems by reliance on synthetic metabolites.

Genomic imprinting results in preferential gene expression from paternally versus maternally inherited chromosomes. We used a genome-wide approach to uncover sex-specific parent-of-origin allelic effects in the adult mouse brain. Our study identified preferential selection of the maternally inherited X chromosome in glutamatergic neurons of the female cortex. Moreover, analysis of the cortex and hypothalamus identified 347 autosomal genes with sex-specific imprinting features. In the hypothalamus, sex-specific imprinted genes were mostly found in females, which suggests parental influence over the hypothalamic function of daughters. We show that interleukin-18, a gene linked to diseases with sex-specific prevalence, is subject to complex, regional, and sex-specific parental effects in the brain. Parent-of-origin effects thus provide new avenues for investigation of sexual dimorphism in brain function and disease.