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)
( Killian et al , O Niel et al 2000 ,Hore et al 2007)
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
Imprinted genes represent less than 1% of the mammalian
Igf2 (Paternally expressed) is the first imprinted gene that
was identified in mouse.
( De Chaira et al , Robertson et al
A gene can behave as imprinted in one tissue and be
biallelically expressed in another
(Solter D ., 1998)
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 .,
Kinship theory is an gene centered extension to the ParentalOffspring conflict theory by David Haig (genetic conflicts
Paternally derived genes try to extract greater resources from the
mother. In turn, the mother tries to ensure equal
distribution to all her offspring
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
Ovarian time bomb Theory
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.
Mechanisms of Imprinting
Attachment of methyl (-CH3) groups to the bases of DNA.
Occurs at cytosine that follows guanine at CpG dinucleotides
DNA METHYL TRANSFERASE
There are 5 known methyl transferase enzymes
de novo methyl
Methylation of centromeric
Dnmt1 & Dnmt2
Interact with 3a and 3b to
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
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)
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
Histone modification &
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
The allele-specific gene silencing in H19 is in part
mediated by hypermethylation and histone deacetylation
(Pedone PV et al.,
Genomic imprint cycles in
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
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
occurs during oocyte growth
Maintenance: Imprinting of the embryonic cells is maintained
Immediately after fertilization, the zygote faces a wave of global
demethylation event, first in male pronucleus, followed by
Imprint marks that were established in the gametes must resist
this demethylation process.
Remethylation of the diploid genome occurs during
These imprints are then maintained throughout the life span of
(Autran D et al.,2002)
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)
Imprinting Control Region(ICR)
Regulates the allele-specific activity of imprinted genes in the
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
Also called ‘differentially methylated region’ (DMR) and
‘differentially methylated domain’ (DMD
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.,
Reported cases of Cystic Fibrosis patients with maternal
UPID for chromosome 7
(Spence et al., 1988; Voss et al.,
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)
NUMBER OF GENES
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
Due to maternal UPD with a lack of paternal
(Nicholls et al.,
Deletion of the qll-13 region of the maternal
(Pembrey et al., 1989)
From paternal UPD .
Silver Russel Syndrome
Maternal UPD of Igf2 & H19 genes on chromosome 7.
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
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
(Angus t dsouza et al, 2004)
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)
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?