Prsentation PowerPoint

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Replication associated strand asymmetries in
mammalian genomesIn silico detection of
replication origins
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Samuel Nicolay Benjamin Audit Edward Brodie of
Brodie Alain Arneodo (ENS-Lyon)
Maxime Huvet Marie Touchon Yves
d'Aubenton-Carafa Claude Thermes (CGM, Gif sur
Yvette)
Supports CNRS, ACI IMPBio, ANR
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 SECOND PARITY RULE   
Long genome sequence fragments tend to show on
the same strand fA fT and fG fC
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LARGE SCALE PROPERTIES OF GENOMIC MUTATIONS
at equilibrium
Second Parity rule (PR2) fA fT and fG fC
(at large scales)
(Chargaff, 1962 Sueoka, Lobry, 1995)
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What mechanisms cause composition asymmetries ?
REPLICATION asymmetry of mutation/repair
processes between leading and lagging strands
lagging strand
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3
5
leading strand
3
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Composition asymmetry in procaryotes
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What mechanisms cause composition asymmetries ?
TRANSCRIPTION asymmetry of mutation/repair
processes between transcribed and non-transcribed
strands
non-transcribed strand
RNA POLYMERASE
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3
3
5
3
transcribed strand
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Skew profiles associated to transcription and
replication in Eubacteria
S STA SGC
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Bacillus subtilis
S
Mbp
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STRAND ASYMMETRIES IN EUKARYOTES ? 1. Strand
asymmetries associated to transcription in the
human genome
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Strand asymmetries associated to transcription in
human genes
Introns (126 000)
12 000 genes (no exons, no repeats)
Downward jumps (3)
Upward jumps (5)
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2. Strand asymmetries associated to replication
in the human genome
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Skew profiles around human replication origins
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Superimposition of replication and transcription
biases
ORI
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Conservation of skew profiles in mammalian
genomes
human
mouse
rat
dog
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3. In silico detection of replication origins in
the human genome
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Detection of upward jumps associated to
replication

• Main problem
• necessity to avoid the jumps due only to
  transcription

• Scale of analysis
• larger than typical size of genes
• smaller than typical size of replicons
• ? necessity of multi-scale analysis

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Multi scale jump detection using the wavelet
transform
S
S
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Multi scale jump detection using the wavelet
transform
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Asymmetry of the human genome
Histograms of jump amplitude
upward
downward

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 Factory roof  skew profiles
x (Mb)
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 Factory roofs  around experimentally
determined replication origins
MCM4
TOP1
S
S
x (kb)
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Conservation of potential origins in mammalian
genomes
human
mouse
dog
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Model of eucaryotic replicon
Replication terminaison sites distributed
between fixed adjacent origins
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Detection of factory roofs using the wavelet
transform
factory roof wavelets

• 759  factory roofs spanning 
• 40 of the human genome

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ASYMMETRY OF HUMAN GENOME
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EUCARYOTIC REPLICON MODEL
replicative skew profile
superposition of transcription and replication
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Comparison with replication timing data
Replication timing
Woodfine et al., Cell Cycle (2005)
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GENE ORGANISATION IN HUMAN CHROMOSOMES
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Organisation of transcription around predicted
replication origins
Co-orientation of transcription and replication
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Model of mammalian chromatin organization
Open chromatin
ORI
ORI
Genomic DNA
S
Replication origins are situated at the center
of open chromatin regions
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• Conclusions
• Existence of replication-coupled strand
  asymmetries in human genome
• Replication origins correspond to large
  transitions of skew profiles
• These transitions are conserved in mammalian
  genomes
• Detection of more than one thousand putative
  origins active in germ-line cells
•  Factory roof  profiles regularly
  distributed termination sites
• Essential rome of replication in organisation
  of gene order and expression