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Epigenesisand
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 ingene 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 beliefprior to the 1750s.
According to preformationists, a gamete (eitheregg or sperm) contained a perfectly formedembryo that simply grew (became larger)
Current ideas of development are epigenetic inconcept, but far more is now known about whatdirects 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 whenis largely a result of environmental events
induction by surrounding tissuese.g. notochord inducing neural tube
regulation of genes by internal environmente.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 divisioncan change normal gene expressioncan 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 characteristicsbut NOT Lamarkian; that is, no change in genome
Epigenomics. 2011 June ; 3(3): 267–277.
Chromatin Structure
Chemical modification of histone proteins in the nucleosome
Nucleosome:DNA wound aroundhistone proteins
Transcriptional Regulation
Histone Modification
Annu. Rev. Psychol. 2010.61:439-466
Transcriptional Regulation
1. DNA Methylation2. Histone Modification3. 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
T
G
C
CGCGCGCG
T
T
T
A
A
A
G
A
A
Transcriptional Regulation:DNA Methylation
No methylation:Transcription “stuff” can bind to a promoter
Methylation:Prevents binding to a promoter T
G
C
CGCGCGCG
T
T
T
A
A
A
G
A
A
M
M
M
M
Influences “density” of DNA packaging in chromosomes
Influences transcription
Cocaine & amphetamines (and other drugs) histone modification
Transcriptional Regulation
Histone Modification
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
Transcriptional Regulation
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 ofthe total population variation of a phenotypic character that isattributable 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 assumedto 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 environmenteffects on phenotypic variability areadditive.2. that gene x environment interactions
are negligible.3. that Ve is the same for inbred and outbred strains.
G Vt = 8Ve = 8Vg = 0H2 = Vg/Vt = 0
Then H2 = Vg/Vt
E
EG Vt = 64
Ve = 8Vg = Vt-Ve = 56H2 = Vg/Vt = 87.5
Vt = 64Vg = 8H2 = Vg/Vt = 12.5
Then H2 = Vg/Vt
G Vt = 8Ve = 0Vg = 8H2 = Vg/Vt = 1
Then H2 = Vg/Vt
E
EG Vt = 64
Ve = 8Vg = Vt-Ve = 56H2 = Vg/Vt = 87.5
Vt = 64Vg = 8H2 = Vg/Vt = 12.5
Then H2 = Vg/Vt
G Vt = 16Ve = 8Vg = 8H2 = Vg/Vt = .5
Then H2 = Vg/Vt
E
EG Vt = 64
Ve = 8Vg = Vt-Ve = 56H2 = Vg/Vt = 87.5
Vt = 64Vg = 8H2 = Vg/Vt = 12.5
Then H2 = Vg/Vt
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?
GeneticMonozygotic vs digyzotic vs siblings vs unrelated
EnvironmentalReared together vs reared apart
Twin Studies
What dependent variable is measured?
ConcordanceAll-or-none, e.g. disease diagnosis.
If one member of the pair has the trait, what is the probabilitythat the other shares that trait?
CorrelationIf a graded trait, e.g. height
Is there a difference in the correlation of the trait in pairsin the different groups?
What are the problemswith twin studies?
i.e., what questionable assumptions are made?
EpigenesisEpigenetic Transmission
Transcriptional Regulation
Pre-translational Regulation
Whole Chromosome Regulation
“interfering” RNA
Methylation
Transcription FactorsHistone Modification
Regulation during Protein Synthesis
“Editing” RegulationAlternative RNA splicing
(X chromosome inactivation or Lyonization)
Regulation after Protein SynthesisMany mechanisms
exon 1 intron 1 exon 2 exon 5exon 4exon 3 intron 3intron 2 intron 4RNA transcript before editing:
exon 1 exon 2 exon 4exon 3 exon 1 exon 2 exon 3 exon 5
mRNA after editing: mRNA after editing:
Alternative RNA Splicing
Polypeptide 1 Polypeptide 2
“Editing” Gene Regulation
Different exons are spliced together to give different polypeptide blueprints
Variation between speciesPossibly why number of human genes is so small
exons are nucleotide sequences that are present in RNA productsintrons are nucleotide sequences that are edited out during RNA splicing
See http://www.nature.com/focus/rnai/animations/animation/animation.htm for animated explanation.
RNA InterferenceA short sequence of single-stranded interferingRNA (“iRNA”) and a complex of proteins andenzymes (“silencing stuff”) binds with mRNAand cleaves it.Acts as a “dimmer switch,” reducing translation.
iRNA = Interfering Stuff = +
Forms interfering complex
mRNA
Binds to mRNA
Cleaves mRNA
See http://www.nature.com/focus/rnai/animations/animation/animation.htm for animated explanation.
RNA Interference:
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)
Two types of genetic transmissionBlueprint transmission (sequence transmission)
Regulatory transmission (epigenetic transmission)
Transmission of information via the nucleotide sequence (A, C, G, T)
Transmission of information via gene regulationTransmission of genetics above the sequence
of nucleotidese.g., gene methylation and histone modification
Epigenetic Transmission
The expression (active vs inactive) of a gene depends on which parent transmits the gene.
some turned off when inherited from the fatherturned on when inherited from the mother
Others turned on when inherited from fatherturned off when inherited from mother
Mechanismsmethylationphosphorylation of histones
example of epigenetic transmission
Genomic Imprinting
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 infancyEarly handling reduces anxiety throughout life
Offspring of handled rats less anxiousOffspring 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?