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Epigenetics and Beyond
ISIS Report 12/01/09
Epigenetic Inheritance
“What Genes Remember”
Epigenetic inheritance of acquired characters more powerful than inheritance of genes
The experience of one generation can modify genes passed on to the next
via a variety of mechanisms that blur the distinction between epigenetic and
genetic Dr. Mae-Wan Ho
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“Sins of the fathers, and their fathers”
The experience of young boys could affect not just their own health in later
life, but also the health of their sons and grandsons. The UK research team
led by Marcus Pembrey at the Institute of Child Health, University College
London published their findings in 2006 in the European Journal of Human
Genetics [1], accompanied by a News and Commentary piece, “Sins of the
fathers, and their fathers” [2].
Two years later, a long feature article, “What genes remember”,
in Prospect Magazine stated [3]: “Many geneticists now think that the
behaviour of our genes can be altered by experience – and even that these
changes can be passed on to future generations. This finding may transform
our understanding of inheritance and evolution.”
The significance of the finding is that it departs from well-known
and generally accepted environmental effects on the unborn foetus in mother’s
womb or other maternal effects, mediated by the many provisions in the egg
cell during embryogenesis, and after birth, in mother’s milk.
In contrast, effects passed on through the paternal line
are associated with sperm cells that contain very little apart from the father’s
genes.
Somehow, the father’s experience as a young boy appeared to have
affected his genes and the changes are transmitted to his male offspring in
what appears to be a case of Lamarckian inheritance of acquired characters
that still gets many biologists hot under the collar (see Box)..
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Lamarck, the scourge of neo-Darwinists
French naturalist Jean Baptiste de Lamarck (1744-1829) is credited with
having invented the discipline of biology and also for being the first
to propose a comprehensive theory of evolution: organisms evolve through
natural means and not through special creation. The two main mechanisms
in Lamarck’s theory of evolution were: ‘use and disuse’, use enhances
and reinforces the development of the organs or tissues while disuse results
in atrophy; and ‘inheritance of acquired characters’, transmitting to
subsequent generations the tendency to develop certain new characteristic
that the organism has acquired in its own development. Lamarck’s theory
preceded Charles Darwin’s theory of evolution by natural selection by
more than 50 years [4] (see Lamarck
the Mythical Precursor, ISIS scientific publication).
While Darwin invoked the inheritance of acquired characters as a subsidiary
mechanism to the natural selection of random variations, his modern-day
disciples, the neo-Darwinists, have strenuously opposed any taint
of Lamarckism. They insist that genetic variations – changes in base sequence
of DNA – arise by random mutations unrelated to the environment
or their survival value, which are then subject to environmental selection;
those mutants that survive, survive, while the rest die out [5] (see Why
Lamarck Won’t Go Away, ISIS scientific publication). This belief is
encapsulated in Francis Crick’s Central Dogma of molecular biology, which
decreed that genetic information flows strictly one-way from DNA to RNA
to protein (that determine the characteristics of the organism selected
by the environment), and never in reverse. In their words, the environment
can never pass information back to the genes, so acquired characters
cannot be inherited.
Since the mid-1970s, if not
before, molecular geneticists have been turning up evidence that increasingly
contradicts the Central Dogma, and by the early 1980s, the new genetics
of the ‘fluid genome’ had emerged [6] (see Living with the Fluid Genome,
ISIS publication). But apart from a few ‘heretics’, no one dared to say
a word against the Central Dogma or the neo-Darwinian theory of evolution
which depends on it.
Things have changed a lot since
the human and other genomes were sequenced, and deposited in one freely
accessible central database [7] (Death of the Central Dogma, SiS 24).
The database is not much good for business, or drug discovery [8] (The human genome sellout, ISIS
News 6), but turns out to be very good [7] “for research that exposes
the poverty of the genetic determinism ideology that has led to the creation
of the database in the first place.”
The 2004 series Life after the
Central Dogma [9] (Science
in Society 24) marked the end of genetic determinism, and documented
why the new genetics demands a thoroughly ecological approach in our public
health, environment, and social policies. Research findings since have
strongly reinforced this message to policy makers. It now appears that
the experience of individuals during critical periods of early development
can influence not just their own lives as adults, but those of their children
and children’s children.
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The Avon Study
The UK Avon Longitudinal Study of Parents and Children (ALSPAC) is
a long-term health research project involving more than 14 000 mothers enrolled
during pregnancy in 1991 and 1992. Analysing data from the study, researchers
showed that the sons of fathers who smoked before puberty had a significantly
greater body mass index (measure of obesity) at 9 years of age: 18.15 compared
with 17.23 in sons of fathers that never smoked [1]. But there was no effect
on the body mass index of the daughters.
Faced with this intriguing finding, the research
team turned to old records of people born in1890, 1905, and 1920 from Overkalix,
an isolated community in Northern Sweden,
where previously, they had reported an association of ancestral food supply
with longevity and death from cardiovascular disease and diabetes.
Re-analyzing the records showed that the paternal
grandfathers’ food supply during mid childhood was indeed linked to the risk
of death in grandsons, but not in grand-daughters. Poor availability
of food was associated with reduced risk of death in grandsons by 35
percent while good availability of food was associated with increased
risk of death by 67 percent compared with controls.
In contrast, the nutritional status of the paternal
grandmother had no influence on the grandsons, but affected the granddaughter
in a similar way. Good food availability increased the risk of death for grand-daughters
by 113 percent, while poor food availability decreased the risk of death by
49 percent.
A previous study on the same ALSPAC database
had found an association between high birth weight in grand children and type
2 diabetes in maternal grandparents; but not in paternal grandparent [10].
Epigenetic inheritance
The results of the ALSPAC studies imply that experience during
a crucial period of life could influence more than one generation in a sex-specific
way.
Although the mechanisms involved in humans are not yet known, this kind of
trans-generational effects is being taken more seriously because similar effects
- now described as ‘epigenetic inheritance’ - have been documented in a substantial
number of animal studies. For example, how an adult rat responds to stress was
found to depend on whether its mother cared for it adequately as a pup, which
marks certain genes for the rest of its life [11] (Caring Mothers Reduce Response to Stress
for Life, SiS 24), and we shall update that fascinating story [12]
(Caring
Mothers Strike Fatal Flow against Genetic Determinism, SiS 41). Another
series of studies show that a single exposure of rats during embryogenesis to
the fungicide vincozolin is sufficient to cause a range of serious diseases
and abnormalities in the adults that are transmitted to three further generations
[13] (see Epigenetic
Toxicology, SiS 41).
Epigenetic change is usually defined as that which does not involve
changing DNA sequences, or “the structural adaptation of chromosomal regions
so as to register signal or perpetuate altered activity states” [14], but
such definition are rapidly becoming obsolete.
In reality, epigenetic modifications encompass a great variety of mechanisms
acting not just at transcription but at post-transcription and translation of
genetic messages, and indeed, even rewrites genomic DNA itself [15, 16] (see
Epigenetic
Inheritance through Sperm Cells, and Rewriting
the Genetic Text in Brain Development and Evolution, SiS 41). Epigenetic
mechanisms include various enzyme-catalyzed chemical modifications of genomic
DNA (methylation of cytosine residues in CpG dinucleotides) and histone chromatin
proteins (methylation, acetylation, phosphorylation, ubiquitinylation, etc.),
which recruits other proteins such as transcription factors and repressors,
that together, determine the activity state of specific genes or sets of genes
[17, 18]. Also included are changes to the genetic messages transcribed [19,
20]. RNA editing systematically alters base sequences, such as changing adenosine
(A) to inosine (I), which is read as guanosine (G), resulting in an entirely
new message. Alternative splicing creates different proteins; and RNA interference
determines which messages are cleaved, or blocked from translation. Transcription
factors promoting the expression of certain genes may be involved at the same
time in repressing neighbouring genes [19]. Finally, epigenetic mechanisms include
reverse transcription of altered transcripts [15, 16], which has the effect
of rewriting the genetic messages encoded in genomic DNA, and hence distinctly
blurring the boundaries between epigenetic and genetic.
Epigenetic modifications occur in cell differentiation, so that
different genes are expressed, different messages are altered, say in brain
cells as opposed to skin cells, and they are inherited by the daughter cells
in cell division. Most epigenetic changes are ‘erased’ in the germ cells that
produce the next generation (DNA methylation is studied in greatest detail
in this respect), but some modifications survive, and are passed on to the
next generation. We shall be dealing with different examples in other articles
in this series.
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