What unites these phenomena?

What unites these phenomena?
1
These cats are heterozygotes for an orange and
a black allele of an X-linked pigment gene
THE GINGHAM dog and the calico cat
Side by side on the table sat…………
2
Female bees have two alternative forms, sterile workers and fertile
queens, which develop from genetically identical larvae through
receiving different foods.
Only larvae that are fed ‘royal
jelly’ develop into queens.
3
A loss of function of the
X-linked FMR-1 gene
results in severe learning
problems, intellectual
disability (retardation)
and, for some, autism or
autism-like behaviors
All son’s have the mutant FMR-1 allele except II-4
Fragile X syndrome: remarkable variable expressivity
and incomplete penetrance
4
Plants like Arabidopsis thaliana adjust flowering time according to environmental conditions by integrating a complex array
of signal
5
The Dutch Hunger Winter & China’s Great Leaf Forward
It is well established that a pregnant woman's habits affect the health of her unborn child, but the extent
of the impact is less well known. Recent studies of tragic historical events, namely the Dutch
Hongerwinter and the Great Chinese Famine, have begun to highlight the trans-generational relationship
between food and genes.
The Dutch Hunger Winter: In the winter and spring of 1944 after a railway strike, the German
occupation limited rations such that people, including pregnant women, in the western region of The
Netherlands, including Amsterdam, received as little as 400–800 calories/d. The famine affected people
of all social classes and was followed by growing prosperity in the postwar period.
Intrauternine exposure to famine in this period is associated with diverse phenotypic outcomes such as
• an increased risk of adult schizophrenia
• an increase in body mass index among famine-exposed women [irrespective of the precise
gestational timing of the exposure]
The Great Chinese Famine, from 1958 to 1961, was caused by a combination of leader Mao Zedong's
agricultural policies during the Great Leap Forward, widespread mismanagement and severe weather.
Tens of millions of people died. Studies of Chinese born during this period link prenatal famine exposure
to an increased risk of schizophrenia — a link also found in the Dutch Hongerwinter cohort.
Children wait to be fed during the Dutch Hongerwinter of 1944–1945.
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What unites these phenomena?
7
Known or at least thought to be
the result of epigenetic events
What is epigenetics?
Science 29 October 2010: Vol. 330 no. 6004 p. 611
http://www.sciencemag.org/content/330/6004/611.short
8
An epigenetic system should be
heritable, self-perpetuating, and
reversible
Science 29 October 2010:
“An epigenetic trait is a stably heritable phenotype
resulting from changes in a chromosome without
alterations in the DNA sequence.”
Genes & Dev. 2009. 23: 781-783
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Epigenetic signals are responsible for the
establishment, maintenance, and reversal of
metastable transcriptional states that are
fundamental for the cell’s ability to “remember” past
events, such as changes in the external environment
or developmental cues.
Metastability describes the behaviour of certain physical systems that can exist in long lived states that are less
stable than the system's most stable state.
met·a·sta·ble
Of, relating to, or being an unstable and transient but relatively long-lived state of a chemical or physical system,
as of a supersaturated solution or an excited atom.
10
Epigenetic effects or changes– heritable changes in gene
expression that do not involve changes in the DNA sequence
What do we mean by gene expression?
11
12
Mechanisms involved in chromatin modifications
Nature. 2010 June 10; 465(7299): 728–735.
Five broad and interrelated mechanisms are known to affect chromatin
structure. All five have been shown to be essential contributors to the
development and cell fate determination of tissues
1. DNA methylation,
2. histone modification
3. insertion of histone variants
4. remodeling complexes
5. non-coding RNAs
13
DNMT
DNMT = DNA methyltransferase
SAM= S=adenosyl methionine
14
mechanisms of gene inactivation via DNA methylation:
http://fire.biol.wwu.edu/trent/trent/DNAsilencing.pdf
15
DNA methylation status is heritable via this mechanism:
Dnmt1 and associated proteins scan newly replicated DNA for hemimethylated sites and methylate the CpG’s on the newly synthesized
strands
16
Epigenetic mechanisms are important in many cell processes
• Progressive restriction of cell fate during embryonic development involving
changes in chromatin structure associated with loss of pluripotency, lineage
restriction and cell differentiation
• X inactivation during embryogenesis in mammalian females – one X
chromosome in each cell becomes highly condensed and transcriptionally
inactive
• Imprinted gene function in mammals -- the level of gene expression is
dependent on whether the gene copy came from mom or dad
• Phenotypic plasticity associated with variations in the environment to which
an organism is exposed
• Adult neuronal plasticity and neurogenesis --changes in chromatin marks
and transcriptional networks associated with sustained neuronal activity,
mood disorders and addiction
• Environmental effects (such as diet or stress) on phenotype may involve
epigenetic changes in gene function
• Abnormal gene expression (such as in Fragile –X syndrome or cancer
cells): epigenetic drift
17
Figure 2 | Contribution of
various chromatin-remodelling
events throughout the life
of an organism. Chromatin
modifications occurring at
different time points during
the life of an organism have
been associated with various
short to long-lasting regulatory
events that affect the
development and the function
of the brain and other tissues
NATURE|Vol 465|10 June
2010
Brain function and chromatin
plasticity
18
Genes as a Mirror of your Life rather than
your Life as a Mirror of your Genes
Epigenetic
mechanisms are
affected by several
factors and processes
including
development in utero
and in childhood,
environmental
chemicals, drugs and
pharmaceuticals,
aging, and diet
https://commonfund.nih.gov/EPIGENOMICS/figure.aspx
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• Restriction of
pluripotency
• X inactivation
.
SOLID BLACK ARROW Many epigenetic modifications become biologically
stabilized at a particular stage of development, and are maintained subsequently
throughout the lifetime of the organism
DASHED BLACK ARROW However, at certain genomic loci, epigenetic marks can
readily change over time. This ‘epigenetic drift’ is thought to depend both on
environmental and intrinsic factors. This diagram shows an example of how epigenetic
drift can lead to the loss of DNA methylation, with consequences for gene expression and
cellular and organismal phenotypes.
Nature Reviews Genetics Feb 2012
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