Transcript Epigenetics inheritance

Epigenetics inheritance
• It is a controversial & an unconventional finding in
recent years.
• It means that a parent's experiences, in the form
of epigenetic tags, can be passed down to future
generations.
• Some scientists argue that it is real as it explains
some strange patterns of inheritance geneticists
have been puzzling over for decades. E.g.,
X inactivation & imprinted genes.
Geneticists have long seen
this unusual phenomena
•X chromosome inactivation was proposed in
1961 as dosage compensation mechanism for one
X chromosome to undergo inactivation early in
female embryogenesis through epigenetics
mechanism
•One of the X chromosomes becomes very
shortened & condensed so that most of its genes
are not able to be ‘read’ by the cells.
•Genomic imprinting, a normal phenomenon in
which a gene is silenced depending on whether it
was inherited from father or from mother.
•So far over 50 human genes have been identified
to be imprinted when working normally (mother’s
or father’s copy is silenced)
•But what ‘marks’ a chromosome as having come
from mother or father & what triggers the
silencing?
•The answer: the DNA methylating enzymes
•Angelman syndrome, described in 1965,
caused by deletion or inactivation of genes on
the maternally inherited Ch15 while the
paternal copy, which may be of normal
sequence, is imprinted & therefore
epigenetically silenced.
•The sister syndrome, Prader –Willi Syndrome
is caused by a similar loss of paternally
inherited genes & maternal imprinting.
Transgenerational epigenetic
inheritance in mammals
F0
F1
F2
pregnant
foetus
grand children
F3
great grand children
3rd generations in man
(M Pembrey et al. 2005)
•Observational study utilising historical records of
harvests at the beginning of last century in an isolated
municipality in Sweden, Överkalix.
•Females experienced a twofold higher mortality if their
paternal grandmother had good food availability during
their Slow Growth Period (8-10 years old)
•Paternal grandfather’s food supply was only linked to
mortality rates of grandsons, while paternal
grandmother’s food supply was only linked to mortality
of granddaughters.
•A single winter of overeating as a youngster could
initiate a biological chain of events that would lead
one’s grandchildren to die decades earlier than their
peers did.
•Grandsons of Overkalix boys who had overeaten died
an average of 6 years earlier due to cardiovascular
diseases than the grandsons of those who had
endured a poor harvest. Controlling confounding
factors it ↑ 32 years!
•If food was plentiful, then diabetes mortality in the
grandchildren increased
•Women lived shorter lives on average if their paternal
grandmothers experienced famine during pregnancy
Conclusions from transgenerational response
studies (Marcus Pembrey)
• Social patterning down the generations does not
explain (away) the transgenerational responses
observed in the Överkalix or ALSPAC study
• It seems sperm carry information about ancestral
environment, probably attached to chromosomes
• There are exposure sensitive periods in early life
• The molecular basis of the transgenerational signal
is still unknown but there are possible candidates
• Transgenerational responses are not necessarily
the same as inheritance of acquired characteristics
• They are likely to involve epigenetic regulation, but
“responsive DNA” is also a possibility
Menstrual & reproductive changes of women
whose mothers were exposed in utero to
diethylstilbestrol (DES)
•Given to pregnant women to reduce risk of
miscarriage 1930s-1970s
•Women exposed prenatally developed structural
anomalies of reproductive tract, menstrual irregularity,
infertility, pregnancy loss, premature delivery, &
elevated risk of Gynae cancers especially cancers of
the vagina.
•These abnormalities have been replicated in mouse
model. DES is a transplacental chemical teratogen &
carcinogen in humans
•Daughters born to women exposed in utero
(granddaughters) showed menstrual irregularity &
delayed menstrual regularisation
•Similar studies in mice have shown the same
outcomes in female descendants.
•Possible transgenerational effects were proposed
to include reproductive tract tumours, similar to
those seen in their prenatally exposed mothers
•Infertility may also be more frequent in the
daughters of the prenatally exposed women &
•DES exposure may exacerbate age-related
infertility, a possibility compatible with findings in
men who were exposed to DES in utero
3rd & 4th
Generations Inheritance in
Rats
•An experimental study from Emory in USA
found that lab rats conditioned to fear a certain
smell will pass that fear on to their children.
•Mouse pups — and even the offspring's
offspring — can inherit a fearful association of a
certain smell with pain, even if they have not
experienced the pain themselves & without the
need for genetic mutations
•Skinner et al.from Washington State University
showed that various environmental toxins can
cause transgenerational inheritance in lab rats.
•Exposure to an environmental toxin during
embryonic development can cause an animal &
almost all of its descendents, to develop adultonset illnesses (cancer & kidney disease).
•The effect persisted through 4 generations, with
about 85% of the offspring in each generation
developing conditions such as breast tumors,
prostate disease, kidney disease, immune
system abnormalities & premature aging.
•Vinclozolin, a fungicide commonly used in
vineyards & methoxychlor, a pesticide replaced
DDT – ‘endocrine disruptors’, interfere with normal
functioning of reproductive hormones. Injected at a
time that is equivalent to 6–18 w. human gestation
•Pregnant rats produced male offspring with low
sperm counts & low fertility, but were still able to
produce offspring. When these were mated with
unexposed females their male offspring had the
same problems.
•The effect persisted through to F3 generation
tested, with more than 90 percent of the male
offspring in each generation affected.
•A study from Los Angeles Biomedical
Research Institute, showed that if pregnant rats
are exposed to nicotine, not only will their
offspring develop the asthma induced by this
drug, so will the offsprings of those offsprings
Maternal high-fat diet effects on
3rdgeneration female body size via the
paternal lineage
•A research group reported that maternal high-fat
diet exposure in mice resulted in ↑ body size &
↓insulin sensitivity that persisted across 2
generations via both maternal & paternal lineages.
•They found that only the F3 females displayed ↑
body size & this effect was only passed on via the
paternal lineage.
•This finding supports a stable germline-based
transgenerational mode of inheritance;
• They hypothesized that imprinted genes may be
involved in this epigenetic programming.
•They detected a potential dynamic pattern of
paternally expressed genes from the paternal
lineage that was not noted in the maternal
lineage.
•These findings suggest that the environmental
influence on developmental regulation of growth &
body size may be the result of broad programming
events at imprinted loci, thereby providing sex
specificity to both the transmission & inheritance
of traits related to disease predisposition.
Bacterial Antibiotic
Resistance &
Epigenetics
Inheritance
The evolution of antibiotic resistance in bacteria
is partly based on epigenetic inheritance
• A study from Cincinnati USA investigated the
evolution of resistant E. coli when exposed to low
concentrations of antibiotics
• The extreme instability of the observed low level
antibiotic resistance clones argues strongly that it
does not involve DNA mutation events.
• Once a gene expression pattern is established
there are epigenetic memory mechanisms capable
of preserving the gene expression state for
multiple generations.
• Inherited memory can be mediated by DNA
methylation, or by inherited chromatin modifications,
or through the genetic regulatory network.
• A subpopulation of bacteria within a person is
allowed to survive low doses of antibiotic, from
inappropriate antibiotic administration, or from a food
source, or through a protected microenvironment
within the body.
• Cells with low-level resistance generated through
epigenetics inheritance could then produce sufficient
numbers for a sufficient period of time to accumulate
more stable DNA mutations through natural
selection that confer a higher level of antibiotic
resistance.
• Authors concluded
• There are many other examples of epigenetic
inheritance between generations that have been
reported in metazoans as well
Paramutation in plants
FAB-7 DNA element in fruit flies
RNA-mediated epigenetic inheritance in the
mouse .
• It is reasonable to suppose that such mechanisms
generating heritable phenotypic variation could
provide the substrate for the action of natural
selection