Genomic imprinting

Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed in a parent-of-origin-specific manner. Forms of genomic imprinting have been demonstrated in fungi, plants and animals. As of 2014, there are about 150 imprinted genes known in the mouse and about half that in humans. Genomic imprinting is an epigenetic phenomenon that causes genes to be expressed in a parent-of-origin-specific manner. Forms of genomic imprinting have been demonstrated in fungi, plants and animals. As of 2014, there are about 150 imprinted genes known in the mouse and about half that in humans. Genomic imprinting is an inheritance process independent of the classical Mendelian inheritance. It is an epigenetic process that involves DNA methylation and histone methylation without altering the genetic sequence. These epigenetic marks are established ('imprinted') in the germline (sperm or egg cells) of the parents and are maintained through mitotic cell divisions in the somatic cells of an organism. Appropriate imprinting of certain genes is important for normal development. Human diseases involving genomic imprinting include Angelman syndrome, Prader–Willi syndrome and male infertility. In diploid organisms (like humans), the somatic cells possess two copies of the genome, one inherited from the father and one from the mother. Each autosomal gene is therefore represented by two copies, or alleles, with one copy inherited from each parent at fertilization. For the vast majority of autosomal genes, expression occurs from both alleles simultaneously. In mammals, however, a small proportion (<1%) of genes are imprinted, meaning that gene expression occurs from only one allele (some recent studies have questioned this assertion, claiming that the number of regions of parent-of-origin methylation in, for example, the human genome, is much larger than previously thought). The expressed allele is dependent upon its parental origin. For example, the gene encoding insulin-like growth factor 2 (IGF2/Igf2) is only expressed from the allele inherited from the father. The term 'imprinting' was first used to describe events in the insect Pseudococcus nipae. In Pseudococcids (mealybugs) (Hemiptera, Coccoidea) both the male and female develop from a fertilised egg. In females, all chromosomes remain euchromatic and functional. In embryos destined to become males, one haploid set of chromosomes becomes heterochromatinised after the sixth cleavage division and remains so in most tissues; males are thus functionally haploid. That imprinting might be a feature of mammalian development was suggested in breeding experiments in mice carrying reciprocal chromosomal translocations. Nucleus transplantation experiments in mouse zygotes in the early 1980s confirmed that normal development requires the contribution of both the maternal and paternal genomes. The vast majority of mouse embryos derived from parthenogenesis (called parthenogenones, with two maternal or egg genomes) and androgenesis (called androgenones, with two paternal or sperm genomes) die at or before the blastocyst/implantation stage. In the rare instances that they develop to postimplantation stages, gynogenetic embryos show better embryonic development relative to placental development, while for androgenones, the reverse is true. Nevertheless, for the latter, only a few have been described (in a 1984 paper). No naturally occurring cases of parthenogenesis exist in mammals because of imprinted genes. However, in 2004, experimental manipulation by Japanese researchers of a paternal methylation imprint controlling the Igf2 gene led to the birth of a mouse (named Kaguya) with two maternal sets of chromosomes, though it is not a true parthenogenone since cells from two different female mice were used. The researchers were able to succeed by using one egg from an immature parent, thus reducing maternal imprinting, and modifying it to express the gene Igf2, which is normally only expressed by the paternal copy of the gene. Parthenogenetic/gynogenetic embryos have twice the normal expression level of maternally derived genes, and lack expression of paternally expressed genes, while the reverse is true for androgenetic embryos. It is now known that there are at least 80 imprinted genes in humans and mice, many of which are involved in embryonic and placental growth and development. Hybrid offspring of two species may exhibit unusual growth due to the novel combination of imprinted genes. Various methods have been used to identify imprinted genes. In swine, Bischoff et al. 2009 compared transcriptional profiles using short-oligonucleotide microarrays to survey differentially expressed genes between parthenotes (2 maternal genomes) and control fetuses (1 maternal, 1 paternal genome). An intriguing study surveying the transcriptome of murine brain tissues revealed over 1300 imprinted gene loci (approximately 10-fold more than previously reported) by RNA-sequencing from F1 hybrids resulting from reciprocal crosses. The result however has been challenged by others who claimed that this is an overestimation by an order of magnitude due to flawed statistical analysis.