Genomic imprinting

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genomic impriting is specific for mammals (eutherians and marsupials)
in vertebrates.

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Genomic imprinting

  1. 1. GENOMIC IMPRINTING Mir Mehraj M.V.Sc Scholar Animal Biotechnology
  2. 2. Introduction  The differential expression of genetic material, at either chromosomal or allelic level, depending on whether the genetic material has come from the male or female parent (Hall et al, 1990)  An epigenetic form of gene regulation that results in only the copy inherited from father or mother to function. (Jirtle and weidman et al,2007)  It is specific for mammals (eutherians and marsupials) in vertebrates. ( Killian et al , O Niel et al 2000 ,Hore et al 2007)
  3. 3.  The first description of the imprinting phenomenon was given by McGrath and Solter in 1984  Some genes are presumably modified during gametogenesis in such a way that only paternal or the maternal alleles are expressed after fertilization  Imprinting occurs by Epigenetic Mechanisms ( Delaval & Fiel et al 2004)
  4. 4.  Imprinted genes represent less than 1% of the mammalian genome.  Igf2 (Paternally expressed) is the first imprinted gene that was identified in mouse. ( De Chaira et al , Robertson et al 1991)  A gene can behave as imprinted in one tissue and be biallelically expressed in another (Solter D ., 1998)
  5. 5. Theories about Origin of GI Parent-Offspring Conflict Theory / Kinship theory  Genetic interests of parent and offspring are different, therefore the offspring would manipulate the parents to ensure survival and vice versa. (Robert L. Trivers ., 1974)  Kinship theory is an gene centered extension to the ParentalOffspring conflict theory by David Haig (genetic conflicts during pregnancy)  Paternally derived genes try to extract greater resources from the mother. In turn, the mother tries to ensure equal distribution to all her offspring
  6. 6. Ligers v/s Tiglons  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
  7. 7. Female Liger Male Tiglon
  8. 8. Ovarian time bomb Theory (OTH)  Imprinting evolved in mammals to prevent spontaneous development of unfertilized eggs and also trophoblastic disease of the ovaries (Varmuza and Mann et al, 1994)  Ovarian Teratomas (embryos without paternal genome) provide ground to this theory.
  9. 9. Mechanisms of Imprinting DNA Methylation  Attachment of methyl (-CH3) groups to the bases of DNA.  Occurs at cytosine that follows guanine at CpG dinucleotides
  10. 10. DNA METHYL TRANSFERASE There are 5 known methyl transferase enzymes Dnmt1 Dnmt2 Dnmt3a Dnmt3b Dnmt3L
  11. 11. Dnmt3a, Dnmt3b de novo methyl transferases Dnmt3b Methylation of centromeric satellite repeats Dnmt1 & Dnmt2 Maintenance of methylation Dnmt3L Interact with 3a and 3b to stimulate methyl transferase activity
  12. 12. Igf2-H19 Insulator Model  Cluster containing maternally expressed H19 and paternally expressed Igf2  This cluster resides at 11 p 15.5 in humans  Regulated by an ICR designated imprinting center 1 (IC1) in humans and ICR or Differentially Methylated Domain (DMD) in mouse  Proper imprinting of H19 and Igf2 requires that the ICR/DMD is methylated on the paternal allele and unmethylated on the maternal allele
  13. 13. Non-coding RNAs  A significant number of imprinted genes are transcribed to give a non-coding RNA.  Non-coding RNAs include antisense transcript, small nucleolar RNAs (Sno RNAs), micro RNAs, pseudo genes and other RNA of unknown function  Random X-inactivation is associated coating of X chromosome with Xist (Plath K et al., 2003)
  14. 14. Imprinted X inactivation  In the postimplantation embryo, random XCI. (Bourmil & Lee et al., 2002)  Random and imprinted XCI are controlled by X-chromosome inactivation center (XIC). ( Rougelle et al 2003)  Components of the XIC are the Xist and Tsix genes,which encode long nc RNAs , Xist & Tsix respectively.  Xist –Tisx & chromatin modification bring about X-inactivation
  15. 15. Histone modification & chromatin remodeling  Histone modifiations includes Acacetylation of lysines (HATs), Phosphorylation of serines (Kinases) and Methylation of lysines  Methylation of lysine-4 in H3 is associated with active genes and methylation of lysine-9 in H3 is associated with inactive genes  The allele-specific gene silencing in H19 is in part mediated by hypermethylation and histone deacetylation (Pedone PV et al., 1999)
  16. 16. Genomic imprint cycles in Embryo  Erasure: Old imprint is totally erased at an early time-point in the PGCs of the developing foetus between 10.5 and 12.5 days post-coitus in mice (Hajkova et al.,2000)  Establishment : Male: Postnatally within diploid gonocytes prior to meiosis Female: PGCs are arrested in diplotene stage (13.5 days of embryonic life) and not methylated until birth and Methylation occurs during oocyte growth  Maintenance: Imprinting of the embryonic cells is maintained throughout life
  17. 17.  Immediately after fertilization, the zygote faces a wave of global demethylation event, first in male pronucleus, followed by maternal pronucleus.  Imprint marks that were established in the gametes must resist this demethylation process.  Remethylation of the diploid genome occurs during gastrulation.  These imprints are then maintained throughout the life span of the Individual (Autran D et al.,2002)
  18. 18. Female:  In the oocytes, methyl transferases belonging to Dnmt3 family are required to set maternal specific methylation patterns for imprinted genes in mice  Dnmt3a, Dnmt3b and Dnmt3L seem to be operational here  Dnmt3L lacks a methyl transferase activity probably provides sequence specificity for the other de novo methyl transferases, Dnmt3a and Dnmt3b, by directing them to the DNA region requiring normal methylation patterns. (Hata k et al., 2001)
  19. 19. Imprinting Control Region(ICR)  Regulates the allele-specific activity of imprinted genes in the cluster.  ICRs usually carry a germline derived methylation imprint.  Common feature they share is that they have a relatively high level of CpG dinucleotides and have simple sequence repeats in the vicinity  Also called ‘differentially methylated region’ (DMR) and ‘differentially methylated domain’ (DMD
  20. 20. Uniparental disomy (UPD)
  21. 21.  Uniparental disomy (UPD) has been described for chromosomes 5, 6, 7, 9, 11, 13, 14, 15, 16, 21, 22 and the XY pair (Petersen et al., 1992; Engel, 1993; Brzustowicz et al., 1994)  Reported cases of Cystic Fibrosis patients with maternal UPID for chromosome 7 (Spence et al., 1988; Voss et al., 1989)  Reported a child with SMA (Spinal muscular atrophy ) who inherited 2 copies of chromosome 5 from his father and none from his mother (Allitto et al., 1993; Brzustowicz et al., 1994)
  22. 22. Imprinted Genes SPECIES NUMBER OF GENES Human 305 Mouse 179 Pig 81 Cattle 28 Sheep 20 Birds 18 Horse 3 Dog 1 Cat 1 Rabbit 1 Primates 2
  23. 23. Genomic Imprinting in Diseases • Prader-Willi Syndrome  First described by Prader et al ., 1956  1 in 14,000  Can be due to • Deletion of the qll-13 region of the paternal chromosome 15 (Cassidy, 1992) • Due to maternal UPD with a lack of paternal chromosome 15 (Nicholls et al., 1989)
  24. 24. Angelman syndrome  Deletion of the qll-13 region of the maternal chromosome 15 (Pembrey et al., 1989)  From paternal UPD . al., 1991) (Malcolm et Silver Russel Syndrome  Maternal UPD of Igf2 & H19 genes on chromosome 7.
  25. 25. Beckwith-Wiedemann syndrome Is a fetal overgrowth syndrome associated with Wilm’s tumor, rhabdomyosarcoma etc. Paternal disomy of chromosome 11p15.5 Imprinted genes IGF2 and H19 Over expression of IGF2 and lack of H1
  26. 26. Cancer  Igf2 loss of imprinting leads to wilm`s tumor. ( Jirtle et al ,1999)  Igf2 loss of imprinting a potential biomarker for colo rectal cancer predisposition . (Cruz et al: M Cui et al , 2004 )  Hepatocellular carcinomas show Igf2R loss of imprinting. (Angus t dsouza et al, 2004)
  27. 27. GI and Environment  You are what your mother ate.  Dietary supplementation of mice with extra folic acid, vitamin B12 ,choline alter the phenotype of their offspring via increased DNA methylation. (Robert waterland et al,2007)  So a possible role of diet in genomic imprinting. ( Jirtle et al , 2008)
  28. 28. CONCLUSIONS  Genomic imprinting is an epigenetic modification.  It can be both of an advantage or disadvantage.  It can provide answers to some intractable questions surrounding gene regulation  Some questions still remain unanswered:  Do we really need imprinting?  Can we do away with imprinted genes?
  29. 29. •Thank You

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