Transcript Co-option in the human genome - A computational tour of the

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]
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Lecture 14
Co-option: Case study to Survey
Course Project
http://cs273a.stanford.edu [Bejerano Spr06/07]
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Genomic Distribution of Ultraconserved Elements
•exonic
•non
•possibly
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Looks Like A Novel Coelacanth Repeat
http://cs273a.stanford.edu [Bejerano Spr06/07]
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Uniquely Abundant in Coelacanth
Upto 80%id between Coelacanth instances
and some human instances, inc uc.338.
?
x
100 diverged copies in a Gigabase
60 highly similar copies in a Megabase
http://cs273a.stanford.edu [Bejerano Spr06/07]
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Repeats /
obile Elements ("selfish DNA")
Human
Genome:
3*109 letters
1.5%
known
function
http://cs273a.stanford.edu [Bejerano Spr06/07]
>50%
junk
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The LF SINE (for Lobefin Fish / “Living Fossil”)
not similar to any known repeat
out
Reconstruction
back
target site
duplications
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>360My Old and Going Strong
Upto 80%id between Coelacanth SINE
and some human instances, inc uc.338.
D
?
B
x
http://cs273a.stanford.edu [Bejerano Spr06/07]
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Cis-reg & Ultra elements from
Co-option event,
probably due to
favorable genomic
context
obile Elements
All other copies
are destined to
decay over time
at a neutral rate
[Yass is a small town in
New South Wales, Australia.]
http://cs273a.stanford.edu [Bejerano Spr06/07]
[Bejerano et al., Nature 2006]
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Exapted Into Which Cellular Roles?
No evidence for Transcription (Tx) as small RNAs,
no orientation preference in introns, not in antisense Tx.
?
x
Human instances cluster together,
found <1Mb from 35 TFs (P<3*10-6).
http://cs273a.stanford.edu [Bejerano Spr06/07]
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Instance 500kb Downstream of ISL1
1Mb
ISL1 is a neuro-developmental gene, also expressed in testis.
Three previously known enhancers are conserved across vertebrates.
http://cs273a.stanford.edu [Bejerano Spr06/07]
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Repeat made Regulatory Region
in situ
Conserved
Minimal Promoter
Element
Reporter Gene
transgenic
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Co-option into Different Roles
protein
coding
repeat
gene
regulating
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Age old Hypothesis: Repeat to Rewire!
[Davidson & Erwin, 2006]
[Britten & Davidson, 1971]
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Elsewhere…
Screened repeat copies found in
all annotated human promoters
for many TF binding site matrices
Found many enrichments:
…
…
[Thornburg et al., Gene, 2006]
http://cs273a.stanford.edu [Bejerano Spr06/07]
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The Co-Optionome
quantify co-option
transposition
event
functional
elements
?
x
LF-SINE, DeuSINE, MER121, …
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?
[Lowe, Bejerano & Haussler, PNAS, 2007]
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Computationally Driven Biology Simplified
hypothesis
BIO
case
study
set
CS
candidates
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How to Generalize?
?
x
http://cs273a.stanford.edu [Bejerano Spr06/07]
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In Search of the Co Optionome
5%
[%age
of H.G]
repetitive
conserved
1.5%
20%
>100Mya
highly conserved non-coding
(think functional, regulatory)
50%
>100Mya
mobile element
instances
10,000 elements!
1Mb, 0.04% H.G
50-489bp, avg 100bp
http://cs273a.stanford.edu [Bejerano Spr06/07]
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Specimen
ZFPM2: Zinc Finger TF,
Regulator of GATA TFs.
Alus
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Co-options are from all Repeat Classes
1Mb
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Co-options correlate with gene deserts
genome
wide
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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:
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Britten & Davidson redux
[Britten & Davidson, 1971]
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Example: The reelin pathway
involved in neuronal
development and function.
En-1 binding sites. Similar phenomenon for
Oct-1 (Pou2f1), SRY, v-Myb and YY1.
http://cs273a.stanford.edu [Bejerano Spr06/07]
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Particular Repeat Portions More Prone To Co-option
all instances
exapted instances only
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Compare to exonization
all instances
exapted instances only
required for
repeat life cycle
in exonization:
5’
5’
polyA 3’
polyT
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3’
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Compare to exonization
all instances
exapted instances only
required for
repeat life cycle
in exonization:
found in most
alt-splice exons
5’
5’
polyA 3’
polyT
http://cs273a.stanford.edu [Bejerano Spr06/07]
3’
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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]
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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]
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Summary
Co-option of interspersed repeats into regulatory roles
appears 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 contributed
significantly/triggered the formation of any gene circuitry?
(enticing to think about clade specific traits: placenta, brain, …)
Some Implications:
microarray experiments, eg, ChIP-chip
functional dissections of loci
computational analysis & modeling of cis-reg network
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discuss projects
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