Download Nervous System Development: Epigenesis

Epigenesis
and
Development
What is meant by “epigenesis”?
“epi” from Greek meaning “on” or “above”
“genesis” = from Greek, meaning "origin,” “creation” or
“generation“
“genetics” = “study of heredity”; a term coined in 1891 by
biologist William Bateson
“epigentics,” then, means “above genetics,” or influences in
addition to the genome, but mediated via, the genes.
or, more simply put, it refers to genes x environments interactions
Epigenesis (original meaning)
Includes environmentally-induced changes in
gene expression
But also includes interactions between
the environment and the genome
that do not alter gene expression
Defined by phenotype, not genes or environment
Early concepts of epigenesis implied that the fertilized egg
contains building materials only, somehow assembled by an
unknown directing force.
This contrasted with the then prevalent notion of
preformationism, which was a widely held belief
prior to the 1750s.
According to preformationists, a gamete (either
egg or sperm) contained a perfectly formed
embryo that simply grew (became larger)
Current ideas of development are epigenetic in
concept, but far more is now known about what
directs growth and differentiation.
Inaccurate to speak of a “genetic blueprint”
To think of the genome as a blueprint is simply
“gene-speak” preformationism
Genes code for proteins
Expression of genes,
i.e. which proteins are produced and when
is largely a result of environmental events
induction by surrounding tissues
e.g. notochord inducing neural tube
regulation of genes by internal environment
e.g. axon guidance
There is no “hard-wired” master control panel directing
development.
Sequence of local patterns in which one step in development
is a subunit of another
Each step in the developmental hierarchy is a necessary
preliminary for the next
Development is four-dimensional
Very early in development, most environmental events
controlling gene expression are internal
Later, external environments exert control over gene
expression as well
Epigenetics
Second definition used in genetics
Alterations to the DNA, other than changes to the
genes themselves (i.e. nucleotide sequence), that:
are passed on with cell division
can change normal gene expression
can be caused by (early) experience
Much more restricted meaning than the first usage
Epigenesis in this second, narrower,
mechanistic sense has long been
recognized as essential for tissue differentiation and
organogenesis
So, what is new?
The environment can also activate or silence genes,
leading to different phenotypes,
and that these modifications can be transmitted
across generations;
i.e. inheritance of acquired characteristics
but NOT Lamarkian; that is, no change in genome
Epigenomics. 2011 June ;
3(3): 267–277.
Chromatin Structure
Transcriptional Regulation
Histone Modification
Chemical modification of histone proteins in the nucleosome
Nucleosome:
DNA wound around
histone proteins
Annu. Rev. Psychol. 2010.61:439-466
Transcriptional Regulation
1. DNA Methylation
2. Histone Modification
3. Transcription Factors
Most well-studied epigenetic mechanism =
methylation of cytosine on the DNA
If methylation occurs in an active stretch of DNA,
especially a promoter region, gene expression will
likely change
Methylation of DNA, and thus gene expression,
continues after birth and be influenced by the
broader environment
Transcriptional Regulation:
DNA Methylation
Methyl group (CH3) added to DNA at CG dinucleotides
Reduces/prevents transcription
Tissue specific
Important in embryogenesis & tissue differentiation
- zygote largely unmethylated
- series of methylations leads to tissue differentiation
Possible source of trans-generational epigenetic transmission
Transcriptional Regulation:
DNA Methylation
No methylation:
Transcription
“stuff” can bind to
a promoter
C
G
C
G
C
G
C
G
T
A
T
T
A
G
T
A
C
A
A
G
M
M
M
Methylation:
Prevents binding
to a promoter
M
C
G
C
G
C
G
C
G
T
A
T
T
A
G
T
A
C
A
A
G
Transcriptional Regulation
Histone Modification
Influences “density” of DNA packaging in
chromosomes
Influences transcription
Cocaine & amphetamines (and other drugs) 
histone modification
Transcriptional Regulation
Transcription Factors
Transcription factor (regulatory protein) = protein
or protein complex that enhances or inhibits
transcription.
Alter gene expression without altering DNA itself;
i.e. expression is reversibly dependent on
presence or absence of transcription factors
Heritability
What is Heritability?
Heritability is NOT a calculation of, nor is it
even an estimate of, the degree to which a
phenotypic character is inherited.
Heritability is also NOT a measure of the
degree to which a particular character trait
is genetic or envronmental.
What is Heritability?
Heritability (H2) IS an estimate of
the total population variation of a
phenotypic character that is
attributable to genetic variation.
Thus H2 =
Vg/Vt
How is Heritability (H2) Estimated?
Variance of the population (Vt) is partitioned
into variance due to genetic variability (Vg),
that due to environmental variability (Ve)
and their interaction (Vgxe).
These sources of variability are assumed
to summate, so that:
Vt = Vg + Ve +Vgxe
It is not possible to measure Vgxe directly, and
is assumed to be negligible.
Thus, Vt = Vg + Ve.
It is difficult or impossible to eliminate Ve,
whereas Vg is easy to eliminate through the
use of inbred strains, clones, or identical
twins. Thus, Ve is estimated as the residual
variance in genetically homogeneous
populations, in which Vg = 0.
So, Vt = 0 + Ve.
Since we can easily measure Vt directly and
have an estimate of Ve from our genetically
homogeneous population, it is a simple
matter to calculate Vg in the random
population by subtraction:
Vg = Vt– Ve
Then H2 = Vg/Vt, and
VOILA!
we have our heritability estimate.
What assumptions are implicit in
this formulation of heritability?
1. that genetic and environment
effects on phenotypic variability are
additive.
2. that gene x environment interactions
are negligible.
3. that Ve is the same for inbred and
outbred strains.
Then H2 = Vg/Vt
E
G
Vt = 8
Ve = 8
Vg = 0
H2 = Vg/Vt = 0
Then H2 = Vg/Vt
E
G
Vt = 64
Ve = 8
Vg = Vt-Ve = 56
H2 = Vg/Vt = 87.5
Vt = 64
Vg = 8
H2 = Vg/Vt = 12.5
Then H2 = Vg/Vt
E
G
Vt = 8
Ve = 0
Vg = 8
H2 = Vg/Vt = 1
Then H2 = Vg/Vt
E
G
Vt = 64
Ve = 8
Vg = Vt-Ve = 56
H2 = Vg/Vt = 87.5
Vt = 64
Vg = 8
H2 = Vg/Vt = 12.5
Then H2 = Vg/Vt
E
G
Vt = 16
Ve = 8
Vg = 8
H2 = Vg/Vt = .5
Then H2 = Vg/Vt
E
G
Vt = 64
Ve = 8
Vg = Vt-Ve = 56
H2 = Vg/Vt = 87.5
Vt = 64
Vg = 8
H2 = Vg/Vt = 12.5
Heritability quotients depend as much on
environmental variation as they do on presumed
genetic variation.
Suppose, for example, that one were to estimate the
heritability of I.Q., which has been a favorite of many
psychologists and educators.
How would selection of sample alter H2?
e.g. would you exclude drug-using parents
would your estimate vary according to
range of
incomes; i.e. would you exclude the
very poor
who are undernourished or
malnourished?
As conceptually flawed as they are, heritability
estimates are also limited in that they apply only to
the population represented in the sample and
cannot be generalized to other populations
Twin Studies
Twin Studies
What independent variables are included?
Genetic
Monozygotic vs digyzotic vs siblings vs unrelated
Environmental
Reared together vs reared apart
Twin Studies
What dependent variable is measured?
Concordance
All-or-none, e.g. disease diagnosis.
If one member of the pair has the trait, what is the probability
that the other shares that trait?
Correlation
If a graded trait, e.g. height
Is there a difference in the correlation of the trait in pairs
in the different groups?
What are the problems
with twin studies?
i.e., what questionable
assumptions are made?
Epigenesis
Epigenetic Transmission
Whole Chromosome Regulation
(X chromosome inactivation or Lyonization)
Regulation during Protein Synthesis
Transcriptional Regulation
Methylation
Histone Modification
Transcription Factors
“Editing” Regulation
Alternative RNA splicing
Pre-translational Regulation
“interfering” RNA
Regulation after Protein Synthesis
Many mechanisms
“Editing” Gene Regulation
Alternative RNA Splicing
Different exons are spliced together to give different polypeptide blueprints
Variation between species
Possibly why number of human genes is so small
RNA transcript before editing:
exon 1
intron 1
exon 1
exon 2
exon 2
exon 3
mRNA after editing:
Polypeptide 1
intron 2
exon 4
exon 3
intron 3
exon 1
exon 4
exon 2
intron 4
exon 3
mRNA after editing:
Polypeptide 2
exons are nucleotide sequences that are present in RNA products
introns are nucleotide sequences that are edited out during RNA splicing
exon 5
exon 5
RNA Interference
A short sequence of single-stranded interfering
RNA (“iRNA”) and a complex of proteins and
enzymes (“silencing stuff”) binds with mRNA
and cleaves it.
Acts as a “dimmer switch,” reducing translation.
See http://www.nature.com/focus/rnai/animations/animation/animation.htm
for animated explanation.
RNA Interference:
iRNA =
+
Interfering Stuff =
Forms interfering complex
Binds to mRNA
Cleaves mRNA
mRNA
See http://www.nature.com/focus/rnai/animations/animation/animation.htm for animated
explanation.
Protein Activation/Deactivation
Phosphorylation (add a phosphate group)
Acetylation (add an acetyl group)
Alkylation (add an ethyl, methyl group)
Ubiquitination (adding the protein ubiquitin
to an existing protein instructs cellular
machinery to degrade/destroy the protein)
Epigenetic Transmission
Two types of genetic transmission
Blueprint transmission (sequence transmission)
Transmission of information via the nucleotide
sequence (A, C, G, T)
Regulatory transmission (epigenetic transmission)
Transmission of information via gene regulation
Transmission of genetics above the sequence
of nucleotides
e.g., gene methylation and histone modification
Genomic Imprinting
The expression (active vs inactive) of a gene
depends on which parent transmits the gene.
some turned off when inherited from the father
turned on when inherited from the mother
Others turned on when inherited from father
turned off when inherited from mother
Mechanisms
methylation
phosphorylation of histones
example of epigenetic transmission
Epigenomics. 2011 June ; 3(3): 267–277.
Epigenomics. 2011 June ; 3(3): 267–277.
Epigenetic Transmission
Behavioral Example: Denenberg & Rosenberg (1967)
Rats either handled or not handled in infancy
Early handling reduces anxiety throughout life
Offspring of handled rats less anxious
Offspring of offspring (“grandchildren”) less anxious
When anxiety is operationally defined as more active in an open
field environment
Finally, for the philosophically inclined…
Do humans have free will?
Do other animals have free will? I.e., can we make choices or are
they illusory products of physiological activity of the brain that we
do not adequately understand at present? Are they directed by
some greater unknown force or higher power (God)?
If humans have free will, then they can willfully alter their
epigenome.
furthermore, willful actions that alter the genome of one
generation may then impact future generations; that is,
evolution via epigenesis may be driven by free, willful decisions
in humans? in other animals?