How Genomic imprinting in mammals What When How Where Why What? Definition "Genomic imprinting is an epigenetic mechanism of transcriptional regulation through which expression of a subset of mammalian genes is restricted to one parental allele." (Verona et.al, 2003) timeline First report by Helen Crouse in 1960. 1. Maternal and paternal genomes do not make equivalent contributions to mammalian development. 2.( 80‟s -) Imprinting is confined to certain regions of the genome and the delineation of those regions. Within those regions, some genes may show a maternal imprint, whereas others show a paternal imprint. 3. (Now -) Identification of the molecular mechanisms of genomic imprinting. Genomic imprinting What • Some genes are expressed only from maternal or paternal allele (ie. activity of some genes depends on the gender of origin) • Prerequisites for distinguishing maternal and paternal alleles • must carry an imprint to signal the difference • must be stably inherited for many rounds of DNA replication imprint • must be erased when passing through the germline • Imprinting was identified from a number of different lines of research, including classical genetic studies, studies on X- inactivation, and the development of diploid parthenogenetic embryos. What Compelling evidence Normal embryo Oocyte + Sperm (Fertilization) = nomal embryo Uniparental embryos Parthenogenesis: when unfertilized egg develops into an embryo – Gynogenote: all genetic materials from female germline – Androgenote: all genetic material from male germline What What Importance of imprinting in development Control (P+M) Maternal Paternal What Complete hydatidform mole What Features of imprinting • primary gametic imprint acquired by one gamete in the zygote and pre-implantation embryo, subsequently maintained on one (of a pair of homologous) chromosome in all somatic cells throughout life • gametic imprint status is a major difference between male and female germ cells • Given the lack of requirement for underlying genetic factors in determining imprinting status, it MUST be epigenetically specified When? Genomic Imprinting: When Mechanisms Three steps 1.) Establishment of imprint 2) Imprint maintenance 3) Erasure Re-establishment in germ cells (reprint) Image taken from nature.com When Timing of imprint establishment M. A. Surani Nature 416, 491-493(4 April 2002) doi:10.1038/416491a When Sex specific differential timing How? How Known Molecular Mechanisms • Methylation (on gene promoters) • Anti-sense transcriptional interference • Enhancer competition • Chromosome Insulator How Imprinting is regulated by DNA methylation How How Imprinting is regulated by DNA methylation How Multiple regulators of imprinting status Hyperstimulation of ovulation can disrupt full acquistion of DNA methylation J Med Genet 2008;45:583-588 doi:10.1136/jmg.2008.057943 How Full Circle DNMT 1 Maintenance Demethylation Establishment Erasure DNMT3 De novo methylation Image taken from nature.com Where? Imprinted genes occur in clusters Where Around 80% of imprinted genes are found in clusters such as these, called imprinted domains, suggesting a level of co-ordinated control.[ Where Luedi, et. al. Genome Res. (Dec 2007) Predicts 156 imprinted genes in humans Why? Genetic Conflict Hypothesis Why •Imprinted genes can code for embryonic growth •Genes that “up regulate” embryo growth are left "on" in sperm and "turned off" in eggs •The opposite is true for genes that “down regulate” embryo growth. •More promiscuous mating =more imprinted genes Picture is from:http://critteristic.com/cats- and-kittens/two-more-sweet-little-kittens/ Why Query and controversy • Is it selectively advantageous for the father's genes to promote growth of the fetus, and thus give it a better chance of survival • advantageous for the mother's genes for the fetus to remain relatively small, to promote the mother's chances of having further offspring (or larger numbers thereof). • Differential susceptibility of two homologues (maternal and paternal) to inactivation would reduce the risk that both will simultaneously be inactivated or activated (a presumably lethal error)????? • syndromes Ligers vs. Tigons • Ligers and Tiglons are progenies that come from matings between lions and tigers – Ligers: father is a lion and mother is a tiger – Tiglons: father is a tiger and mother is a lion • Different imprinted gene between the mother and father causes difference in size and appearance in size between ligers and tiglons This information came from the Genetic Science Learning Center by the University of Utah: http://learn.genetics.utah.edu/content/epigenetics/imprinting/ Female Liger Male Tigon Picture taken from: Picture taken from: http://www.cryptomundo.com/cr http://www.metrolic.com/the- yptozoo-news/liger-attack/ survival-of-the-hybrid-species- 128467/ Summary • What: Genomic imprinting involves the specific silencing of one of a pair of genes in a parent of origin specific manner – Appropriate imprinting is a fundamental requirement of mammalian development • When: Imprinting occurs during gametogenesis following the second wave of DNA methylation erasure that occurs early in embryogenesis • Where: clusters of genes on many autosomes • How: Imprinting is regulated epigenetically by DNA methylation (and higher order modifications) • Why: Imprinting may be associated with balancing maternal and paternal „drives‟ associated with reproductive fitness.