A Screen for Retrotransposed Imprinted Genes Reveals an Association between X Chromosome Homology and Maternal Germ-Line Methylation

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Abstract
Imprinted genes undergo epigenetic modifications during gametogenesis, which lead to transcriptional silencing of either the maternally or the paternally derived allele in the subsequent generation. Previous work has suggested an association between imprinting and the products of retrotransposition, but the nature of this link is not well defined. In the mouse, three imprinted genes have been described that originated by retrotransposition and overlap CpG islands which undergo methylation during oogenesis. Nap1l5, U2af1-rs1, and Inpp5f_v2 are likely to encode proteins and share two additional genetic properties: they are located within introns of host transcripts and are derived from parental genes on the X chromosome. Using these sequence features alone, we identified Mcts2, a novel candidate imprinted retrogene on mouse Chromosome 2. Mcts2 has been validated as imprinted by demonstrating that it is paternally expressed and undergoes promoter methylation during oogenesis. The orthologous human retrogenes NAP1L5, INPP5F_V2, and MCTS2 are also shown to be paternally expressed, thus delineating novel imprinted loci on human Chromosomes 4, 10, and 20. The striking correlation between imprinting and X chromosome provenance suggests that retrotransposed elements with homology to the X chromosome can be selectively targeted for methylation during mammalian oogenesis. The conventional view is that DNA carries all of our heritable information and our genes control development into adulthood. The discovery of epigenetics, a term coined to describe effects that are not coded for by DNA sequence, but can nonetheless affect our development and well-being, has added another layer of complexity to our understanding of genetics. One class of genes under epigenetic control are imprinted genes. Mammals inherit two copies of every gene, one from mother and one from father, and in most cases, both are active. However, for a small number of imprinted genes in mammals, only one is active, either the maternal or the paternal copy. Epigenetics amounts to a control system for switching genes on and off appropriately. We focus on a group of little-studied imprinted genes that share features that give clues to their evolutionary origins. These so-called “retrogenes” are protein-coding sequences of DNA that have undergone duplication and jumped into novel locations in the genome. Because of this, it is possible to determine where, and roughly when, many of the imprinted retrogenes originated. This provides an opportunity to study the molecular events that have generated imprinted genes during mammalian evolution.