How widespread is trans-generational inheritance of acquired
phenotype characteristics?
Since this issue is central and requires careful attention
to the details of the experimental evidence, I have included
abstracts from the articles cited. This form of inheritance
is now firmly established.
“Many maternal effects have
subsequently been observed, and non-genomic transmission of
disease risk has been firmly established (P. Gluckman &
Hanson, 2004; P. D. Gluckman, Hanson, & Beedle, 2007). A
study done in Scandinavia clearly shows the
transgenerational effect of food availability to human
grandparents influencing the longevity of grandchildren
(Kaati, Bygren, Pembrey, & Sjostrom, 2007; Pembrey et al.,
2006).”
Gluckman, P., & Hanson, M. (2004).
The Fetal Matrix.
Evolution, Development and Disease. Cambridge: Cambridge
University Press.
Gluckman, P. D., Hanson, M. A., & Beedle, A. S. (2007).
Non-genomic transgenerational inheritance of disease risk.
Bioessays,
29, 145-154.
http://www.ncbi.nlm.nih.gov/pubmed/17226802
That there is a heritable or familial component of
susceptibility to chronic non-communicable diseases such as
type 2 diabetes, obesity and cardiovascular disease is well
established, but there is increasing evidence that some
elements of such heritability are transmitted
non-genomically and that the processes whereby environmental
influences act during early development to shape disease
risk in later life can have effects beyond a single
generation. Such heritability may operate through epigenetic
mechanisms involving regulation of either imprinted or
non-imprinted genes but also through broader mechanisms
related to parental physiology or behaviour. We review
evidence and potential mechanisms for non-genomic
transgenerational inheritance of 'lifestyle' disease and
propose that the 'developmental origins of disease'
phenomenon is a maladaptive consequence of an ancestral
mechanism of developmental plasticity that may have had
adaptive value in the evolution of generalist species such
as Homo sapiens.
Kaati, G., Bygren, L. O., Pembrey, M. E., & Sjostrom, M.
(2007). Transgenerational response to nutrition, early life
circumstances and longevity
European Journal of Human Genetics,
15, 784-790.
http://www.ncbi.nlm.nih.gov/pubmed/17457370
Nutrition might induce, at some loci, epigenetic or other
changes that could be transmitted to the next generation
impacting on health. The slow growth period (SGP) before the
prepubertal peak in growth velocity has emerged as a
sensitive period where different food availability is
followed by different transgenerational response (TGR). The
aim of this study is to investigate to what extent the
probands own childhood circumstances are in fact the
determinants of the findings. In the analysis, data from
three random samples, comprising 271 probands and their 1626
parents and grandparents, left after exclusions because of
missing data, were utilized. The availability of food during
any given year was classified based on regional statistics.
The ancestors' SGP was set at the ages of 8-12 years and the
availability of food during these years classified as good,
intermediate or poor. The probands' childhood circumstances
were defined by the father's ownership of land, the number
of siblings and order in the sibship, the death of parents
and the parents' level of literacy. An earlier finding of a
sex-specific influence from the ancestors' nutrition during
the SGP, going from the paternal grandmother to the female
proband and from the paternal grandfather to the male
proband, was confirmed. In addition, a response from father
to son emerged when childhood social circumstances of the
son were accounted for. Early social circumstances
influenced longevity for the male proband. TGRs to
ancestors' nutrition prevailed as the main influence on
longevity.
Pembrey, M. E., Bygren, L. O., Kaati, G., Edvinsson, S.,
Northstone, K., Sjostrom, M., . . . ALSPAC_study_team.
(2006). Sex-specific, male-line transgenerational responses
in humans. European
Journal of Human Genetics,
14, 159-166.
http://www.ncbi.nlm.nih.gov/pubmed/16391557
Transgenerational effects of maternal nutrition or other
environmental 'exposures' are well recognised, but the
possibility of exposure in the male influencing development
and health in the next generation(s) is rarely considered.
However, historical associations of longevity with paternal
ancestors' food supply in the slow growth period (SGP) in
mid childhood have been reported. Using the Avon
Longitudinal Study of Parents and Children (ALSPAC), we
identified 166 fathers who reported starting smoking before
age 11 years and compared the growth of their offspring with
those with a later paternal onset of smoking, after
correcting for confounders. We analysed food supply effects
on offspring and grandchild mortality risk ratios (RR) using
303 probands and their 1818 parents and grandparents from
the 1890, 1905 and 1920 Overkalix cohorts, northern Sweden.
After appropriate adjustment, early paternal smoking is
associated with greater body mass index (BMI) at 9 years in
sons, but not daughters. Sex-specific effects were also
shown in the Overkalix data; paternal grandfather's food
supply was only linked to the mortality RR of grandsons,
while paternal grandmother's food supply was only associated
with the granddaughters' mortality RR. These
transgenerational effects were observed with exposure during
the SGP (both grandparents) or fetal/infant life
(grandmothers) but not during either grandparent's puberty.
We conclude that sex-specific, male-line transgenerational
responses exist in humans and hypothesise that these
transmissions are mediated by the sex chromosomes, X and Y.
Such responses add an entirely new dimension to the study of
gene-environment interactions in development and health.
Contrary to a
widespread view that such effects always die out quickly,
this form of inheritance can be just as strong as
conventional genetic inheritance.
“Their article (Nelson et al,
2012) begins by noting that many environmental agents and
genetic variants can induce heritable epigenetic changes
that affect phenotypic variation and disease risk in many
species. Moreover, these effects persist for many
generations and are as strong as conventional genetic
inheritance (Cuzin & Rassoulzadegan, 2010; Guerrero-Bosagna
& Skinner, 2012; Jirtle & Skinner, 2007; Nelson & Nadeau,
2010; Richards, 2006; Youngson & Whitelaw, 2008).”
Cuzin, F., Grandjean, V., & Rassoulzadegan, M. (2008).
Inherited variation at the epigenetic level: paramutation
from the plant to the mouse.
Curr
Opin Genet Dev,
18(2), 193-196.
http://www.ncbi.nlm.nih.gov/pubmed/18280137
In contrast with a wide definition of the 'epigenetic
variation', including all changes in gene expression that do
not result from the alteration of the gene structure, a more
restricted class had been defined, initially in plants,
under the name 'paramutation'. It corresponds to epigenetic
modifications distinct from the regulatory interactions of
the cell differentiation pathways, mitotically stable and
sexually transmitted with non-Mendelian patterns. This class
of epigenetic changes appeared for some time restricted to
the plant world, but examples progressively accumulated of
epigenetic inheritance in organisms ranging from mice to
humans. Occurrence of paramutation in the mouse and possible
mechanisms were then established in the paradigmatic case of
a mutant phenotype maintained and hereditarily transmitted
by wild-type homozygotes. Together with the recent findings
in plants indicative of a necessary step of RNA
amplification in the reference maize paramutation, the mouse
studies point to a new role of RNA, as an inducer and
hereditary determinant of epigenetic variation. Given the
known presence of a wide range of RNAs in human spermatozoa,
as well as a number of unexplained cases of familial disease
predisposition and transgenerational maintenance,
speculations can be extended to possible roles of
RNA-mediated inheritance in human biology and pathology
Guerrero-Bosagna, C., & Skinner, M. K. (2012).
Environmentally-induced epigenetic transgenerational
inheritance of phenotype and disease
Molecular and cellular
endocrinology,
354, 3-8.
http://www.ncbi.nlm.nih.gov/pubmed/22020198
Environmental epigenetics has an important role in
regulating phenotype formation or disease etiology. The
ability of environmental factors and exposures early in life
to alter somatic cell epigenomes and subsequent development
is a critical factor in how environment affects biology.
Environmental epigenetics provides a molecular mechanism to
explain long term effects of environment on the development
of altered phenotypes and “emergent” properties, which the
“genetic determinism” paradigm cannot. When environmental
factors permanently alter the germ line epigenome, then
epigenetic transgenerational inheritance of these
environmentally altered phenotypes and diseases can occur.
This environmental epigenetic transgenerational inheritance
of phenotype and disease is reviewed with a systems biology
perspective.
Jirtle, R. L., & Skinner, M. K. (2007). Environmental
epigenomics and disease susceptibility
Nature Reviews
Genetics, 8,
253-262.
http://www.ncbi.nlm.nih.gov/pubmed/17363974
Epidemiological evidence increasingly suggests that
environmental exposures early in development have a role in
susceptibility to disease in later life. In addition, some
of these environmental effects seem to be passed on through
subsequent generations. Epigenetic modifications provide a
plausible link between the environment and alterations in
gene expression that might lead to disease phenotypes. An
increasing body of evidence from animal studies supports the
role of environmental epigenetics in disease susceptibility.
Furthermore, recent studies have demonstrated for the first
time that heritable environmentally induced epigenetic
modifications underlie reversible transgenerational
alterations in phenotype. Methods are now becoming available
to investigate the relevance of these phenomena to human
disease
Nelson VR, Heaney JD, Tesar PJ, Davidson NO & Nadeau JH
(2012). Transgenerational epigenetic effects ofApobec1 deficiency
on testicular germ cell tumor susceptibility and embryonic
viability. Proc Natl
Acad Sci U S A
109, E2766–E2773
http://www.ncbi.nlm.nih.gov/pubmed/22923694
Environmental agents and genetic variants can induce
heritable epigenetic changes that affect phenotypic
variation and disease risk in many species. These
transgenerational effects challenge conventional
understanding about the modes and mechanisms of inheritance,
but their molecular basis is poorly understood. The Deadend1
(Dnd1) gene enhances susceptibility to testicular germ cell
tumors (TGCTs) in mice, in part by interacting
epigenetically with other TGCT modifier genes in previous
generations. Sequence homology to A1cf, the RNA-binding
subunit of the ApoB editing complex, raises the possibility
that the function of Dnd1 is related to Apobec1 activity as
a cytidine deaminase. We conducted a series of experiments
with a genetically engineered deficiency of Apobec1 on the
TGCT-susceptible 129/Sv inbred background to determine
whether dosage of Apobec1 modifies susceptibility, either
alone or in combination with Dnd1, and either in a
conventional or a transgenerational manner. In the paternal
germ-lineage, Apobec1 deficiency significantly increased
susceptibility among heterozygous but not wild-type male
offspring, without subsequent transgenerational effects,
showing that increased TGCT risk resulting from partial loss
of Apobec1 function is inherited in a conventional manner.
By contrast, partial deficiency in the maternal germ-lineage
led to suppression of TGCTs in both partially and fully
deficient males and significantly reduced TGCT risk in a
transgenerational manner among wild-type offspring. These
heritable epigenetic changes persisted for multiple
generations and were fully reversed after consecutive
crosses through the alternative germ-lineage. These results
suggest that Apobec1 plays a central role in controlling
TGCT susceptibility in both a conventional and a
transgenerational manner.
Nelson, V. R., & Nadeau, J. H. (2010).
Transgenerational genetic effects.
Epigenomics,
2, 797-806.
http://www.ncbi.nlm.nih.gov/pubmed/22122083
Since Mendel, studies of phenotypic variation and disease
risk have emphasized associations between genotype and
phenotype among affected individuals in families and
populations. Although this paradigm has led to important
insights into the molecular basis for many traits and
diseases, most of the genetic variants that control the
inheritance of these conditions continue to elude detection.
Recent studies suggest an alternative mode of inheritance
where genetic variants that are present in one generation
affect phenotypes in subsequent generations, thereby
decoupling the conventional relations between genotype and
phenotype, and perhaps, contributing to ‘missing
heritability’. Under some conditions, these
transgenerational genetic effects can be as frequent and
strong as conventional inheritance, and can persist for
multiple generations. Growing evidence suggests that RNA
mediates these heritable epigenetic changes. The primary
challenge now is to identify the molecular basis for these
effects, characterize mechanisms and determine whether
transgenerational genetic effects occur in humans.
Richards, E. J. (2006). Inherited epigenetic variation -
revisiting soft inheritance
Nature Reviews Genetics, 7,
395-401.
http://www.ncbi.nlm.nih.gov/pubmed/16534512
Phenotypic variation is traditionally parsed into components
that are directed by genetic and environmental variation.
The line between these two components is blurred by
inherited epigenetic variation, which is potentially
sensitive to environmental inputs. Chromatin and DNA
methylation-based mechanisms mediate a semi-independent
epigenetic inheritance system at the interface between
genetic control and the environment. Should the existence of
inherited epigenetic variation alter our thinking about
evolutionary change?
Youngson, N. A., & Whitelaw, E. (2008). Transgenerational
epigenetic effects Annual Review of Genomics and Human Genetics,
9, 233-257.
http://www.ncbi.nlm.nih.gov/pubmed/18767965
Transgenerational epigenetic effects include all processes
that have evolved to achieve the nongenetic determination of
phenotype. There has been a long-standing interest in this
area from evolutionary biologists, who refer to it as
non-Mendelian inheritance. Transgenerational epigenetic
effects include both the physiological and behavioral
(intellectual) transfer of information across generations.
Although in most cases the underlying molecular mechanisms
are not understood, modifications of the chromosomes that
pass to the next generation through gametes are sometimes
involved, which is called transgenerational epigenetic
inheritance. There is a trend for those outside the field of
molecular biology to assume that most cases of
transgenerational epigenetic effects are the result of
transgenerational epigenetic inheritance, in part because of
a misunderstanding of the terms. Unfortunately, this is
likely to be far from the truth.
RNA transmitted changes independent of DNA have been
followed in planarians for 100 generations:
Rechavi O, Minevish G & Hobert O (2011).
Transgenerational inheritance of an acquired small RNA-based
antiviral response in C. elegans.
Cell
147, 1248–1256.
http://www.cell.com/retrieve/pii/S0092867411013419#Summary
Induced expression of the Flock House virus in the soma of
C. elegans results in the RNAi-dependent production of
virus-derived, small-interfering RNAs (viRNAs), which in
turn silence the viral genome. We show here that the
viRNA-mediated viral silencing effect is transmitted in a
non-Mendelian manner to many ensuing generations. We show
that the viral silencing agents, viRNAs, are
transgenerationally transmitted in a template-independent
manner and work in trans to silence viral genomes present in
animals that are deficient in producing their own viRNAs.
These results provide evidence for the transgenerational
inheritance of an acquired trait, induced by the exposure of
animals to a specific, biologically relevant physiological
challenge. The ability to inherit such extragenic
information may provide adaptive benefits to an animal.
Transgenerational epigenetic effects in the brain are
reviewed in
Bohacek J, Gapp K, Saab BJ & Mansuy IM. (2013).
Transgenerational Epigenetic Effects on Brain Functions.
Biological Psychiatry
73, 313-320.
http://www.biologicalpsychiatryjournal.com/article/S0006-3223(12)00729-9/abstract
Psychiatric diseases are multifaceted disorders with complex
etiology, recognized to have strong heritable components.
Despite intense research efforts, genetic loci that
substantially account for disease heritability have not yet
been identified. Over the last several years, epigenetic
processes have emerged as important factors for many brain
diseases, and the discovery of epigenetic processes in germ
cells has raised the possibility that they may contribute to
disease heritability and disease risk. This review examines
epigenetic mechanisms in complex diseases and summarizes the
most illustrative examples of transgenerational epigenetic
inheritance in mammals and their relevance for brain
function. Environmental factors that can affect molecular
processes and behavior in exposed individuals and their
offspring, and their potential epigenetic underpinnings, are
described. Possible routes and mechanisms of
transgenerational transmission are proposed, and the major
questions and challenges raised by this emerging field of
research are considered.
Transgenerational epigenetic effects underly the inheritance
of sensitivity to odors in mice:
Dias BG & Ressler KJ. (2013). Parental olfactory experience
influences behavior and neural structure in subsequent
generations. Nature
Neuroscience,
doi:10.1038/nn.3594
Using olfactory molecular specificity, we examined the
inheritance of parental traumatic exposure, a phenomenon
that has been frequently observed, but not understood. We
subjected F0 mice to odor fear conditioning before
conception and found that subsequently conceived F1 and F2
generations had an increased behavioral sensitivity to the
F0-conditioned odor, but not to other odors. When an odor
(acetophenone) that activates a known odorant receptor
(Olfr151) was used to condition F0 mice, the behavioral
sensitivity of the F1 and F2 generations to acetophenone was
complemented by an enhanced neuroanatomical representation
of the Olfr151 pathway. Bisulfite sequencing of sperm DNA
from conditioned F0 males and F1 naive offspring revealed
CpG hypomethylation in the Olfr151 gene. In addition, in
vitro fertilization, F2 inheritance and cross-fostering
revealed that these transgenerational effects are inherited
via parental gametes. Our findings provide a framework for
addressing how environmental information may be inherited
transgenerationally at behavioral, neuroanatomical and
epigenetic levels.
For examples of epigenetic inheritance in plants see
Pennisi, E (2013) Evolution Heresy? Epigenetics Underlies
Heritable Plant Traits
Science 341 6 September
http://www.sciencemag.org/content/341/6150/1055.summary
“For some evolutionary biologists, just hearing the term
epigenetics raises hackles. They balk at suggestions that
something other than changes in DNA sequences—such as the
chemical addition of methyl groups to DNA or other so-called
epigenetic modifications— has a role in evolution. All of
which guarantees that a provocative study presented at an
evolutionary biology meeting …. last month will get close
scrutiny. It found that heritable changes in plant flowering
time and other traits were the result of epigenetics alone,
unaided by any sequence changes.”
Colomé-Tatché M, Cortijo S, Wardenaar R, Morgado L, Lahouze
B, Sarazin A, Etcheverry M, Martin A, Feng S,
Duvernois-Berthet E, Labadie K, Wincker P, Jacobsen SE,
Jansen RC, Colot V, Johannes F (2012). Features of the
Arabidopsis recombination landscape resulting from the
combined loss of sequence variation and DNA methylation.
Proc. Natl. Acad. Sci.
USA doi:10.1073/pnas.1212955109. Research
reported by Frank Johannes (Groningen)
http://www.johanneslab.org/
Schmitz, R.J. et al (2011) Transgenerational Epigenetic
Instability is a source of Novel Methylation Variants.
Science,
334, 369-373. “We
examined spontaneously occurring variation in DNA
methylation in Arabidopsis thaliana plants propagated by single-seed descent for 30
generations……
transgenerational epigenetic variation in DNA methylation
may generate new allelic states that alter transcription,
providing a mechanism for phenotypic diversity in the
absence of genetic mutation.” “Regardless of their origin,
the majority of epialleles identified in this study are
meiotically stable and heritable across many generations in
this population.”
http://www.sciencemag.org/content/334/6054/369.abstract
http://genome.cshlp.org/content/early/2013/08/29/gr.152538.112.full.pdf+html
The big question now
is how large a role these forms of inheritance have played
in the evolutionary process. But that is a question that
applies to all the
proposed mechanisms of evolutionary change and also to the
ways in which they must have interacted. Articles relevant
to that question include:
Hua, Z. (2013) Epigenomic programming contributes to the
genomic drift evolution of the F-Box protein superfamily in
Arabidopsis.
PNAS,
110, 16927–16932. “Comparisons within expanding sequence databases
have revealed a dynamic interplay among genomic and
epigenomic forces in driving plant evolution. Such forces
are especially obvious within the F-Box (FBX) superfamily,
one of the largest and most polymorphic gene families in
land plants, where its frequent lineage-specific expansions
and contractions provide an excellent model to assess how
genetic variation impacted gene function before and after
speciation.” “…reversible epigenomic modifications helped
shape FBX gene evolution by transcriptionally suppressing
the adverse effects of gene dosage imbalance and harmful FBX
alleles that arise during genomic drift, while
simultaneously allowing innovations to emerge through
epigenomic reprogramming.”
http://www.ncbi.nlm.nih.gov/pubmed/24082131
Takuno, S & Gaut B.S. (2013) Gene body methylation is
conserved between plant orthologs and is of evolutionary
consequence. PNAS, 110, 1797-1802.
“Gene body methylation was strongly conserved between
orthologs of the two species and affected a biased subset of
long, slowly evolving genes. Because gene body methylation
is conserved over evolutionary time, it shapes important
features of plant genome evolution, such as the bimodality
of G+C content among grass genes.”
http://www.ncbi.nlm.nih.gov/pubmed/23319627
The following article
is a useful critique of the inheritability of stress-induced
chromatin changes in plants, and lays out some criteria to
be used in further work.
Pecinka, A. & Scheid, O.M. (2012)
Stress-Induced Chromatin Changes: A Critical View on
Their Heritability.
Plant Cell Physiol
53, 801-808. “We
propose a set of criteria that should be applied to
substantiate the data for stress-induced, chromatin-encoded
new traits. Well-controlled stress treatments, thorough
phenotyping and application of refined genome-wide
epigenetic analysis tools should be helpful in moving from
interesting observations towards robust evidence.” “plants
are good candidates for a further, unprepossessed search.
Constant refinement of chromatin analysis tools and growing
genetic information, also for non-model species, together
with the criteria listed here, will help answer whether it
is time for a renaissance of Lamarck’s ideas.”
http://pcp.oxfordjournals.org/content/53/5/801.full
This is also a valuable review:
O’Malley R.C. & Ecker, J.R. (2012) Epiallelic Variation in
Arabidopsis thaliana. Cold
Spring Harbour Symp Quant Biol.
77, 135-145.
“Genotype is the primary determinate of phenotype. During
the past two decades, however, there has been an emergent
recognition of the epigenotype, a separate layer of heredity
distinct from the primary DNA sequence that can have
profound effects on phenotype.” “We discuss examples of
epialleles that have been created in the laboratory and
others that have been identified in natural populations,
because these two models provide complementary information
regarding the genetic pathways, mechanisms of transmission,
and biological and evolutionary context for the role of the
epigenotype in phenotypic variation.”
http://symposium.cshlp.org/content/77/135.full
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