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Transcript of Http://cs273a.stanford.edu [Bejerano Spr06/07] 1 TTh 11:00-12:15 in Clark S361 Profs: Serafim...
http://cs273a.stanford.edu [Bejerano Spr06/07] 1
TTh 11:00-12:15 in Clark S361
Profs: Serafim Batzoglou, Gill Bejerano
TAs: George Asimenos, Cory McLean
http://cs273a.stanford.edu [Bejerano Spr06/07] 2
Lecture 14
Co-option: Case study to Survey
Course Project
http://cs273a.stanford.edu [Bejerano Spr06/07] 3
Genomic Distribution of Ultraconserved Elements
•exonic•non•possibly
http://cs273a.stanford.edu [Bejerano Spr06/07] 4
Looks Like A Novel Coelacanth Repeat
http://cs273a.stanford.edu [Bejerano Spr06/07] 5
Uniquely Abundant in Coelacanth
?
x
Upto 80%id between Coelacanth instances
and some human instances, inc uc.338.
100 diverged copies in a Gigabase
60 highly similar copies in a Megabase
http://cs273a.stanford.edu [Bejerano Spr06/07] 6
Repeats / obile Elements ("selfish DNA")
HumanGenome:
3*109 letters1.5%
knownfunction >50%
junk
http://cs273a.stanford.edu [Bejerano Spr06/07] 7
The LF SINE (for Lobefin Fish / “Living Fossil”)
Reconstructionout back
target siteduplications
not similar to any known repeat
http://cs273a.stanford.edu [Bejerano Spr06/07] 8
>360My Old and Going Strong
?
x
B
D
Upto 80%id between Coelacanth SINE
and some human instances, inc uc.338.
http://cs273a.stanford.edu [Bejerano Spr06/07] 9
Cis-reg & Ultra elements from obile Elements
[Yass is a small town in New South Wales, Australia.]
Co-option event, probably due to favorable genomic context
All other copies are destined to decay over time at a neutral rate
[Bejerano et al., Nature 2006]
http://cs273a.stanford.edu [Bejerano Spr06/07] 10
Exapted Into Which Cellular Roles?
?
xHuman instances cluster together, found <1Mb from 35 TFs (P<3*10-6).
No evidence for Transcription (Tx) as small RNAs,
no orientation preference in introns, not in antisense Tx.
http://cs273a.stanford.edu [Bejerano Spr06/07] 11
Instance 500kb Downstream of ISL1
ISL1 is a neuro-developmental gene, also expressed in testis.
Three previously known enhancers are conserved across vertebrates.
1Mb
http://cs273a.stanford.edu [Bejerano Spr06/07] 12
Repeat made Regulatory Region
Reporter GeneMinimal PromoterConservedElement
in situ
transgenic
http://cs273a.stanford.edu [Bejerano Spr06/07] 13
Co-option into Different Roles
repeat
proteincoding
generegulating
http://cs273a.stanford.edu [Bejerano Spr06/07] 14
Age old Hypothesis: Repeat to Rewire!
[Britten & Davidson, 1971]
[Davidson & Erwin, 2006]
http://cs273a.stanford.edu [Bejerano Spr06/07] 15
Elsewhere…
[Thornburg et al., Gene, 2006]
Screened repeat copies found in
all annotated human promoters
for many TF binding site matrices
Found many enrichments:…
…
http://cs273a.stanford.edu [Bejerano Spr06/07] 16
The Co-Optionome
transposition
event
functionalelements
quantify co-option
LF-SINE, DeuSINE, MER121, …
?
x
[Lowe, Bejerano & Haussler, PNAS, 2007]
?
http://cs273a.stanford.edu [Bejerano Spr06/07] 17
Computationally Driven Biology Simplified
casestudy
hypothesis
set
gene
raliz
esurvey
analy
ze
CSBIO
candidates
experiment
http://cs273a.stanford.edu [Bejerano Spr06/07] 18
How to Generalize?
?
x
http://cs273a.stanford.edu [Bejerano Spr06/07] 19
In Search of the Co Optionome
conserved repetitive
50%5% 20%1.5%
>100Mya
highly conserved non-coding
(think functional, regulatory)
>100Mya
mobile element
instances
[%age
of H.G]
10,000 elements!
1Mb, 0.04% H.G
50-489bp, avg 100bp
http://cs273a.stanford.edu [Bejerano Spr06/07] 20
Specimen
Alus
ZFPM2: Zinc Finger TF,
Regulator of GATA TFs.
http://cs273a.stanford.edu [Bejerano Spr06/07] 21
Co-options are from all Repeat Classes
1Mb
http://cs273a.stanford.edu [Bejerano Spr06/07] 22
Co-options correlate with gene deserts
genomewide
http://cs273a.stanford.edu [Bejerano Spr06/07] 23
Co-options show clear functional preferences
GO term enrichment for nearest gene to co-opted element:10-75 Development (and system devel, nervous sys devel, etc)
10-72 Transcription Regulator Activity (and related terms)
10-23 Cell Recognition (neuron recog, tyros kinas sign, cell adhesion, etc)
Densest co-option “clouds” in the human genome:
http://cs273a.stanford.edu [Bejerano Spr06/07] 24
Britten & Davidson redux
[Britten & Davidson, 1971]
http://cs273a.stanford.edu [Bejerano Spr06/07] 25
Example: The reelin pathway
En-1 binding sites. Similar phenomenon for Oct-1 (Pou2f1), SRY, v-Myb and YY1.
involved in neuronal
development and function.
http://cs273a.stanford.edu [Bejerano Spr06/07] 26
Particular Repeat Portions More Prone To Co-option
all instances
exapted instances only
http://cs273a.stanford.edu [Bejerano Spr06/07] 27
Compare to exonization
all instances
exapted instances only
in exonization:
polyA5’ 3’
polyT5’ 3’
required for
repeat life cycle
http://cs273a.stanford.edu [Bejerano Spr06/07] 28
Compare to exonization
all instances
exapted instances only
in exonization:
polyA5’ 3’
polyT5’ 3’
required for
repeat life cyclefound in most
alt-splice exons
http://cs273a.stanford.edu [Bejerano Spr06/07] 29
A Significant Minority of Putative Cis-Reg
At least 7.5% of
conserved non coding
born after opposum split
originate in exaptation
(0.3% of all repeat instances
born in this time period)
http://cs273a.stanford.edu [Bejerano Spr06/07] 30
Inconclusive Evidence
• “Clouds” of exaptation around genes sometimes have many instances of same type, sometimes one of each, sometimes some random mix in between.
• The most frequently co-opted portions of a repeat are no more enriched for GO terms or annotated pathways than the set of all co-options of that mobile element.
• Sequence-similar (sub) families of co-options are not more enriched for GO terms or pathways either.
http://cs273a.stanford.edu [Bejerano Spr06/07] 31
SummaryCo-option of interspersed repeats into regulatory rolesappears to be a force of nature to be reckoned with.
Some open questions:What functions do repeats co-opt into?How are they pre-disposed to take these on?Prove Brittten & Davidson: Have they really contributedsignificantly/triggered the formation of any gene circuitry?(enticing to think about clade specific traits: placenta, brain, …)
Some Implications:microarray experiments, eg, ChIP-chipfunctional dissections of locicomputational analysis & modeling of cis-reg network
http://cs273a.stanford.edu [Bejerano Spr06/07] 32
discuss projects