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 pregnant F1 foetus F2 grand children F3 great grand children

3 rd 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

3 rd & 4 th 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 adult- onset 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 3 rd generation 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