silence of the genes. genetics the study of inheritance
TRANSCRIPT
Silence of the Genes
Genetics
• The study of inheritance
Gregor Mendel(1823-1884)
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Mendelian Ratios
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Mutation
ATGCGAGCGAGTATGCGATCGAGT Genotype
Phenotype
Epigenetics
• Heritable changes in gene expression that do not involve changes in DNA sequence.
Epi-mutation
ATGCGAACGAGTATGCGATCGAGT Genotype
Phenotype
DNA Modifications
Histone Modifications
Proteins
Nucleosome
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DNA
histones
DNAMethylation
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histones
CH3
HistoneMethylation
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histones
CH3
Examples of Epigenetics
X-Inactivation
inactivation
male female
X Y X Xunequal expression
equal expressionX Y X X
Barr BodyQuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.
Barr Body
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Calico Cat
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X Xo O
X Xo O X Xo O
orangeallele
blackallele
black sector orange sector
Other Examples of Epigenetics
Imprinting
• Imprinted genes are expressed differently depending on whether they are inherited through the maternal or paternal parent.
Horses and Donkeys
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QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture.male
male female
female
Gynogenotes
• Embryos containing two female genomes
– do not develop normally– fail due to underdeveloped extraembryonic
placental tissue
Androgenotes
• Embryos containing two paternal genomes
– result in abnormal (often overgrown) embryo– display overdeveloped extraembryonic
placental tissue
Maternal vs. Paternal Imprinting
• Male genome wants to promote growth.
• Female genome wants to inhibit growth.
Resetting Methylation Patterns
Primordial Germ Cells
male
female
met
hyla
tion
developmental time
Battle for Maintaining DNA Methylation
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Battle to Maintain Methylationm
ethy
lati
on
developmental time
Fertilization
Female Strategy
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Genes that promote growth
Fertilization
Male Strategy
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Antisense
Genes that inhibit growth
Fertilization
Resetting Imprints is Important for Proper Development
Dolly
• First mammal to be cloned from an adult cell.
• Developed illness common in older sheep (arthritis)
• Probably due to abnormal imprinting
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Gene Silencing
HeterochromatinDensely staining condensed chromosomal regions; believed to be transcriptionally inert.
EuchromatinA chromosomal region that stains normally; thought to contain the normally functioning genes.
Heterochromatin
Paul Fransz
B. McClintock
IV
Heterochromatin
• Centromeric regions
• Telomeric regions
Position Effect Variegation
W+
W+
W+
W+
heterochromatin
spreading
suppressed
enhanced
Post-Transcriptional Gene Silencing
Anti-Sense
Sense Also Works?
Guo and Kemphues, (1995)
What is Causing Silencing?
?
dsRNAPost Transcriptional
?
Fire et al. (1998)
RNAi
?
Fire et al. (1998)
RNAi
AAA
AAA
Dicer
RISC
dsRNA
AAA
AAA
Dicer
RISC
dsRNA
RNAi
RNA Silencing
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cosuppression
quelling
RNA Silencing
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Post TranscriptionalGene Silencing
(PTGS)
RNA Silencing
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RNA Silencing
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RNA Interference(RNAi)
RNA Interference
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DNA Methylation
Mette et al. (2000)
RNAi and Transcriptional Silencing
Transcriptional Silencing
Mette et al. (2000)
Micro RNAs
Grishok et al. (2001)
dicer
RNAi Genes in S. pombe?
RNAi Genes in pombe?
• Yes!!
• Mutation of these genes results in loss of centromeric silencing.
• Loss of RNAi reveals centromeric transcripts.
• dsRNA from centromere targets transcriptional silencing.
Cen
Cen
RNAi
Small RNAs
Cen
RNAi
SilencingMachinery Small RNAs
Cen
RNAi
SilencingMachinery
Small RNAs
Cen
RNAi
• Is important for initiation and maintenance of heterochromatin at the centromere.
• Could be involved in other silencing phenomena
Where else may RNAi be functioning to silence genes?
X Chromosome Inactivation(RNAi?)
Xist
Tsix
Heard et al (2001)
Xist
Tsix
Heard et al (2001)
RNAi
SilencingMachinery
X Chromosome Inactivation(RNAi?)
Xist
Tsix
Heard et al (2001)
RNAi
SilencingMachinery
X Chromosome Inactivation(RNAi?)
Imprinting(RNAi?)
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Antisense
RNAi
SilencingMachinery
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Imprinting(RNAi?)
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Antisense
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Imprinting(RNAi?)
RNAi
SilencingMachinery
HeterochromatinDensely staining condensed chromosomal regions; are not necessarily transcriptionally inert. RNAi is important for its initiation and maintenance.
EuchromatinChromosomal regions that do not densely stain; thought to contain functioning genes that maybe transcriptionally active.