Genomes and chromosomes in flux

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Genomes and chromosomes in flux

• 11-13-2006

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Outline

• Gene amplification
• Endoreduplication
• DNA deletion and rearrangement
• X-chromosome inactivation
• Dosage effects and compensation
• Endoreduplication
• Alteration of genomes upon hybridization

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Gene amplification

• rRNA gene amplification in Xenopus
• Normally there are 450 copies/1 C nucleus
• Leptonema 3-4x copies of rDNA
• By pachynema there are 2.34 million rRNA copies
• Chorion genes in ovarian follicle cells of
  Drosophila
• MHC locus in mammals
• Also rDNA compensation and magnification

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Gene amplification through selection

• Methotrexate resistance in mouse cell lines
• MTX binds to DHFR (dihydrofolate reductase)
• Resistant lines have modified genome
• Unstable many double minutes (acentric fragments
  that segregate randomly)
• Stable HSR homogenously stained region
• Both are composed of DHFR genes

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Gene amplification through selection

• Unit of replication is 273 kb (DHFR gene is 1kb)
• Each unit contains 3 DHFR genes and 3 ORIs
• In mosquito MTX selection leads to tetraploidy
• Modest resistance in tetraploid
• High resistances has extra chromosome that is
  almost entirely composed of DHFR genes
• Donn selected alfalfa with phosphotricin and got
  8 fold increase in glutamine synthetase

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Genome rearrangements via selection

• Candida albicans a yeast infection that is
  problematic for individuals with compromised
  immune systems
• Many strains exhibit drug resistance
• Highly studied mechanisms of increase expression
  of target or transmembrane transporters
• No meiosis in this organism

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Selmecki et al., Science 2006 Vol. 313 pp. 367 -
370
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Selection for aneuploidy in cancer cells

• Many cancerous cells are aneuploid
• Often aneuploidy is a partial cause of the
  aberrant cell division properties

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Developmentally programmed genome rearrangements

• Tetrahymena
• Endoreduplication
• Endosperm
• Trichomes
• X chromosome inactivation

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Transition from genome plasticity to chromatin

• Example of DNA elimination from Tetrahymena
• Provides link between mechanisms of genome
  plasticity and chromatin marking

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DNA elimination in tetrahymena
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Mochizuki and Grovsky 2002
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Memory of old macronucleus influences new
macronucleus What generates this memory?
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Macronucleus formation

• Example of two types of genome rearrangements
• Mechanism provides link between heterochromatin
  and genome plasticity
• Example of dynamic mechanisms of genome
  regulation

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References
Kazufumi Mochizuki and Martin A Gorovsky. Small
RNAs in genome rearrangement in Tetrahymena.
Current Opinion in Genetics Development 2004,
14181187 Sean D. Taverna, Robert S. Coyne, and
C. David Allis. Methylation of Histone H3 at
Lysine 9 Targets Programmed DNA Elimination in
Tetrahymena. Cell, Vol. 110, 701711, September
20, 2002 Yifan Liu, Kazufumi Mochizuki, and
Martin A. Gorovsky. Histone H3 lysine 9
methylation is required for DNA elimination in
developing macronuclei in Tetrahymena. PNAS
February 10, 2004 vol. 101 no. 6
16791684 Carolyn L. Jahn and Lawrence A.
Klobutcher. GENOME REMODELING IN CILIATED
PROTOZOA. Annu. Rev. Microbiol. 2002. 56489520
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X chromosome inactivation

• Barr body formation
• Forms at 16 DAP, last to replicate
• Lyons hypothesis, suggested Xi controlled
  phenotypes such as calico
• Non-random choice in some deletions
• B n-(p/2) where pploidy

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Wrap up of Gene amplification

• rDNA phenomena (amplification, compensation,
  magnification)
• Genome rearrangements via selection
• Developmentally programmed rearrangements

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Dosage compensation
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Nucleolar dominance
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