Effects of susceptibility variants may depend on from which parent they are inherited. While many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Combining genealogy with long range phasing, we demonstrate that for 38,167 Icelanders genotyped using SNP chips, the parental origin of most alleles can be determined. We then focused on SNPs that associate with diseases and are within 500kb of known imprinted genes. Seven independent SNP associations were examined. Five, one each with breast cancer and basal cell carcinoma, and three with type 2 diabetes (T2D), exhibit parental-origin specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, a novel variant rs2334499 at 11p15 was seen to associate with T2D where the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site.

We have isolated a novel mouse gene (Gtl2) from the site of a gene trap integration (Gtl2lacZ) that gave rise to developmentally regulated lacZ expression, and a dominant parental‐origin–dependent phenotype. Heterozygous Gtl2lacZ mice that inherited the transgene from the father showed a proportionate dwarfism phenotype, whereas the penetrance and expressivity of the phenotype was strongly reduced in Gtl2lacZ mice that inherited the transgene from the mother. Gtl2 expression is highly similar to the β‐galactosidase staining pattern, and is down‐regulated but not abolished in mice carrying the Gtl2lacZ insertion. In early postimplantation embryos, Gtl2 is expressed in the visceral yolk sac and embryonic ectoderm. During subsequent development and organogenesis, Gtl2 transcripts are abundant in the paraxial mesoderm closely correlated with myogenic differentiation, in parts of the central nervous system, and in the epithelial ducts of developing excretory organs. The Gtl2 gene gives rise to various differentially spliced transcripts, which contain multiple small open reading frames (ORF). However, none of the ATG codons of these ORFs is in the context of a strong Kozak consensus sequence for initiation of translation, suggesting that Gtl2 might function as an RNA. Nuclear Gtl2 RNA was detected in a temporally and spatially regulated manner, and partially processed Gtl2 transcripts were readily detected in Northern blot hybridizations of polyadenylated RNA, suggesting that primary Gtl2 transcripts are differently processed in various cell types during development. Gtl2 transcript levels are present in parthenogenic embryos but may be reduced, consistent with the pattern of inheritance of the Gtl2lacZ phenotype. Dev. Dyn. 1998;212:214–228. © 1998 Wiley‐Liss, Inc.

X chromosome dosage compensation in female eutherian mammals is regulated by the noncoding Xist RNA and is associated with the differential acquisition of active and repressive histone modifications, resulting in repression of most genes on one of the two X chromosome homologs. Marsupial mammals exhibit dosage compensation; however, they lack Xist, and the mechanisms conferring epigenetic control of X chromosome dosage compensation remain elusive. Oviparous mammals, the monotremes, have multiple X chromosomes, and it is not clear whether they undergo dosage compensation and whether there is epigenetic dimorphism between homologous pairs in female monotremes. Here, using antibodies against DNA methylation, eight different histone modifications, and HP1, we conduct immunofluorescence on somatic cells of the female Australian marsupial possum Trichosurus vulpecula, the female platypus Ornithorhynchus anatinus, and control mouse cells. The two marsupial X's were different for all epigenetic features tested. In particular, unlike in the mouse, both repressive modifications, H3K9me3 and H4K20Me3, are enriched on one of the X chromosomes, and this is associated with the presence of HP1 and hypomethylation of DNA. Using sequential labeling, we determine that this DNA hypomethylated X correlates with histone marks of inactivity. These results suggest that female marsupials use a repressive histone-mediated inactivation mechanism and that this may represent an ancestral dosage compensation process that differs from eutherians that require Xist transcription and DNA methylation. In comparison to the marsupial, the monotreme exhibited no epigenetic differences between homologous X chromosomes, suggesting the absence of a dosage compensation process comparable to that in therians.DNA methylation | histone modifications | X chromosome inactivation I n mammals, X inactivation has evolved to solve the difference in X chromosome gene dosage between homogametic female mammals and heterogametic male mammals. Inactivation of one of the two female X chromosomes provides an equal dose in eutherian mammals and marsupials. In the mouse, X-chromosome inactivation (XCI) is imprinted in early development and is then reprogrammed at the blastocyst stage to become random, where, in response to expression of Xist RNA from the future inactive X (Xi), repressive histone modifications, histone variants, and DNA methylation are acquired (1, 2). This results in transcriptional repression of most X-linked genes. In particular, the eutherian Xi is late in replicating and is distinguished from the active X by a specific set of covalent histone modifications. The Xi is hypoacetylated on the NH 2 -terminal lysines of nearly all histones (3, 4) and lacks H3K4me2 and H3K4me3 but carries H3K9me2, H3K9me3, and H3K27me3 (1). In addition, Xi chromatin is enriched in the histone variants macroH2A1 and macroH2A2 (5). In human and bovine models, H3K27me3 and H3K9me3 are spatially distributed in nonoverlapping regions (6, 7). These stable histone modifications ...

issue of Current Biology, contained an error. In the sentence "Using the same procedure, we readily detected Drosha cleavage products corresponding to 3# extremity of the mir434, mir435, and mir431 stem loops," mir435 should have been mir433. The authors regret the error.

The mechanism behind transgenerational epigenetic inheritance is unclear, particularly through the maternal grandparental line. We previously showed that disruption of folate metabolism in mice by the Mtrr hypomorphic mutation results in transgenerational epigenetic inheritance of congenital malformations. Either maternal grandparent can initiate this phenomenon, which persists for at least four wildtype generations. Here, we use genome-wide approaches to reveal genetic stability in the Mtrr model and genome-wide differential DNA methylation in the germline of Mtrr mutant maternal grandfathers. We observe that, while epigenetic reprogramming occurs, wildtype grandprogeny and great grandprogeny exhibit transcriptional changes that correlate with germline methylation defects. One region encompasses the Hira gene, which is misexpressed in embryos for at least three wildtype generations in a manner that distinguishes Hira transcript expression as a biomarker of maternal phenotypic inheritance.