Genetics, Epigenetics and Dynamic Molecular Memory. The Basics: Genetics – The G,A,T,Cs of inheritance. Mutations or changes in genotype may result in changes in phenotype. Epigenetics – Heritable chromatin remodeling.
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Dynamic Molecular Memory
Genetics – The G,A,T,Cs of inheritance.
Mutations or changes in genotype may result in changes in phenotype.
Epigenetics – Heritable chromatin remodeling.
Covalent modification of DNA or chromatin proteins can be passed on.
Dynamic molecular memory – Stable switching
of gene expression; which mimics a
mutation in an individual.
Relatively stable covalent modification of DNA or chromatin proteins.
Study of one generation
to the next.
Concerns the chemical nature of genes. Central Dogma:
Changes in the genetic makeup of a population over time and across geographical space.
Simple, but often confusing…
Outbred = animals with diverse genetic make-up, containing multiple alleles [various lab rats]
Inbred Strain = all animals equal to identical twins (isogenic) [C57BL/6, DBA, most lab mice]
- homozygous at ALL alleles
Recombinant Inbred Strain = inbred offspring from crosses of two inbred strains [BxD]
- genetic mix of two strains, but completely homozygous at ALL alleles
Congenic strain = region on one chromosome introgressed onto different background strain
Consomic strain = one whole chromosome is introgressed from one strain to another
Knock out, Knock in = a single gene is removed, completely added or simply changed -
however, keep in mind that since two strains are used, linked genes fix
Transgenic strain = a gene is added in “trans”; i.e. it can insert anywhere in the genome
Line = Selectively bred line of animals…similar to what we consider a “breed”
[Set of genome-wide congenic strains]
Constitutive Heterochromatin: chromatin that usually remains condensed in all cells
Facultative Heterochromatin: regions that are condensed in some cells, and not in others
Euchromatin: open, or less condensed DNA regions
X-inactivation results in Barr bodies
with different X chromosomes shut off
in each cell. Since this is done early in
development, a patch effect is seen.
access of transcriptional machinery to bind DNA:
Euchromatin is not simply
Nucleosome = Octet of 2x
(H2A, H2B, H3 and H4)
Chromosomal regions such as
teleomeres that are tethered to
the periphery are silenced…but
recent studies suggest that localization specific silencing is more complex.
Analysis of Bergeson lab microarray data suggests regional cis-control:
Epigenetics: A change in phenotype that is heritable but does not involve DNA mutation. (Gottschling. Epigenetics, 2007)
The Avy allele: map of the A locus and range of phenotypes in isogenic Avy mice:a, Avy has an IAP (subtype II, striped box) inserted in the pseudoexon 1A of the locus, with the direction of transcription from the LTRs (arrowhead) opposite to that of the A promoters. Hair-cycle−specific non-coding exons (open boxes), coding exons (filled boxes) and an interrupted inverted repeat (grey bar arrow) are indicated. The locus is not shown to scale (100 kb separates the insertion site and hair-cycle−specific promoters). Transcription originating in a cryptic promoter (arrowhead) in the 3' LTR of the IAP in the Avy allele results in constitutive expression of agouti in multiple tissues1, 2, 4, 25. b, Isogenic C57BL/6 Avy/a mice show a continuum of phenotypes ranging from completely yellow, through degrees of yellow/agouti mottling, to completely agouti (termed pseudoagouti because the mice are isogenic with fully yellow mice and not genetically agouti). The extent of the yellow coat colour correlates closely with adult body weight. Yellow mice have pancellular agouti expression driven by the inserted IAP. Mottled mice are mosaics of cells that have or lack ectopic expression driven by the IAP. Pseudoagouti mice lack expression from the cryptic promoter, so that A is regulated by its hair-cycle promoters, and these mice have the wild-type coat colour and normal body weight1, 2, 3.
Morgan et al., Nature Genetics, 1999.
Chromatin Mobility within the Nuclear Architecture affects Gene Expression
Organization of the nucleus:
DNMT1 – Maintenance of methylation
DNMT2 – has weak activity with unknown function
DNMT3A – de novo methylation
DNMT3B – de novo methylation
Understood to be “active” removal, but mechanism
remains to be elucidated. (Histone demethylases have
Miller and Sweatt, Neuron, 2007
Fear conditioning increases
DNA methylation enzymes.
Proposed molecular mechanism of long-term memory
Genotype Specific Change in Drinking Associated with Decrease in Dnmt3b:
Bergeson and Blednov: preliminary data
Evidence Age-Specific Epigenetic Regulation by Binge Alcohol Drinking: