• Small number of genes are marked on their parental allele
• Only one parental allele is expressed
• 1980: pronuclear transplantation experiments demonstrated that mammalian development requires contribution from both parents
  • Maternal uniparental embryos were exclusively embryonic tissues
  • Paternal uniparental embryos developed into extra-embryonic structures only
• Engineering of offspring dome through combination of nuclei from nongrowing and fully grown oocytes with mutations in 2 different imprinted loci
  • Resulting bimaternal offspring had normal imprinted gene expression
• Some methods used to identify imprinted genes:
  • Molecular characterization
  • Gene targeting experiments
  • Genome wide studies – more popular once sequencing of the whole genome possible
• Igf2r: insulin-like growth factor type 2 receptor, first of 3 imprinted genes reported in 1991
• H19 gene encodes a ncRNA, maternal-specific expression (identified via SNPs)
• To date, ~100 imprinted genes have been found in mammals
• ICRs: imprinting control regions, shows parent-of-origin specific epigenetic modifications that are set up in the germline
• Many imprinted genes are dosage sensitive, with over/under expression resulting in consequences
  • e.g. prenatal growth control, brain function, postnatal energy homeostasis
• Conditions that result from faulty imprinting:

1. Prader-Willi syndrome: loss of expression of SNRPN implicated, but contribution unknown
2. Angelman syndrome: caused by the absence of UBE3A transcript expressed from maternal chromosome
3. Beckwith-Wiedemann syndrome:
4. Silver-Russell syndrome:

• Placenta and the brain are sites of widespread imprinted gene expression
• Absence of Igf2r causes impaired nutrient transport to the fetus
• Peg10, Rtl1 are imprinted genes required for placental development, originated from retrotransposons
• In the brain, imprinted genes are implicated in metabolic axes, behaviour, learning, maternal care
• G5a: gene expressed from the maternally inherited chromosome in the hypothalamus, controls melanocortin-mediated energy expenditure
• Peg1, Peg3 paternally expressed imprinted genes, strongly transcribed in brain, KO leads to decreased maternal care

Properties of the Imprinting Mechanism

4 important properties of the genomic imprinting process:

1. The mark must be able to influence transcription
2. It must be heritable in somatic lineages
3. The mark is likely to be placed on the chromosomes when the paternal and maternal chromosomes are located in different nuclei
4. Must be a mechanism of erasure so that paternally inherited chromosomes in the female germline can establish a new mark and vice versa