Genomic imprinting in mammals

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 Xinactivation, 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:
Mechanisms

Three steps
1.) Establishment
of imprint
2)
Imprint
maintenance
3)
Erasure
Re-establishment
in germ cells (reprint)
Image taken from
When
Timing of imprint establishment
M. A. Surani
Nature 416, 491-493(4 April 2002)
doi:10.1038/416491a
When
Sex specific differential timing
When
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
DNMT3
De novo
methylation
Image taken from
nature.com
Erasure
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/catsand-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
Picture taken from:
http://www.cryptomundo.com/cr
yptozoo-news/liger-attack/
Male Tigon
Picture taken from:
http://www.metrolic.com/thesurvival-of-the-hybrid-species128467/
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