http://cs273a.stanford.edu [bejerano aut08/09]1 mw 11:00-12:15 in beckman b302 profs: serafim...
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http://cs273a.stanford.edu [Bejerano Aut08/09] 1
MW 11:00-12:15 in Beckman B302
Profs: Serafim Batzoglou, Gill Bejerano
TAs: Cory McLean, Aaron Wenger
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http://cs273a.stanford.edu [Bejerano Aut08/09] 2
Lecture 18
Guest Talks
Ultraconservation
The Projects
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http://cs273a.stanford.edu [Bejerano Aut08/09] 3
human
mouse
rat
chimp
chicken
fugu
zfish
dog
tetra
opossum
cow
macaque
platypus
Comparative Genomics
t
*
what made
us human?
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http://cs273a.stanford.edu [Bejerano Aut08/09] 44
PhenotypeGenotype
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http://cs273a.stanford.edu [Bejerano Aut08/09] 5
human
mouse
rat
chimp
chicken
fugu
zfish
dog
tetra
opossum
cow
macaque
platypus
Comparative Genomics
t
How did some of our
relatives go back?
*
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http://cs273a.stanford.edu [Bejerano Aut08/09] 6
human
mouse
rat
chimp
chicken
fugu
zfish
dog
tetra
opossum
cow
macaque
platypus
Now at the Species Level
t
How did we
leave the ocean?
*
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http://cs273a.stanford.edu [Bejerano Aut08/09] 7
Conserved elements in the Human Genome
all human-mouse alignmentshuman-mouse ancestral repeats alignment
Difference: 5% of
Human Genome
[Mouse consortium, Nature 2002]
election
human-mouse ancestral repeats alignment
85%id on average
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http://cs273a.stanford.edu [Bejerano Aut08/09] 8
Conserved elements in the Human Genome
all human-mouse alignmentshuman-mouse ancestral repeats alignment
Difference: 5% of
Human Genome
[Mouse consortium, Nature 2002]
election
human-mouse ancestral repeats alignment
85%id on average
UltraconservationUltraconservation
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http://cs273a.stanford.edu [Bejerano Aut08/09] 9
Typical DNA Conservation levels
[Bejerano et al., Science 2004]
Conserved elements between human and mouse are on average 85% identical. [mouse consortium, 2002]
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http://cs273a.stanford.edu [Bejerano Aut08/09] 10
Ultraconserved Elements
[Bejerano et al., Science 2004]
fish
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http://cs273a.stanford.edu [Bejerano Aut08/09] 11
No known function requires this much conservation
CDS ncRNA TFBS
**
*
**
seq.
?
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http://cs273a.stanford.edu [Bejerano Aut08/09] 12
Discovery can be fun
(compared to 4 results day before our ScienceExpress paper)
31,800
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http://cs273a.stanford.edu [Bejerano Aut08/09] 13
Predictions and Proofs I
Based on public domain genome wide data:
ultraconservedelements
one subset
codes protein
larger subset
does not
generate testable hypotheses for function from existing knowledge (2004)
[Pennacchio et al., Nature, 2006]
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http://cs273a.stanford.edu [Bejerano Aut08/09] 14
Predictions and Proofs II
Based on public domain genome wide data:
ultraconservedelements
one subset
codes protein
larger subset
does not
generate testable hypotheses for function from existing knowledge (2004)
[Pennacchio et al., Nature, 2006]
post transcriptional modification
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http://cs273a.stanford.edu [Bejerano Aut08/09]
[Ni et al., Genes & Dev 2007 ]
Of the 29 exonic ultraconserved elements in RNA-binding protein genes in human, 15 have human and/or mouse EST evidence suggesting the presence of AS-NMD in those regions.
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http://cs273a.stanford.edu [Bejerano Aut08/09]
Model for Homeostatic Auto/Cross-regulation
[Ni et al., Genes & Dev 2007 ]
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http://cs273a.stanford.edu [Bejerano Aut08/09] 17
Ultras are Under Strong Human Selection
Ultra DAF NonSyn DAF
[Katzman et al, Science ,2007]
Mutational cold spots? NO. Rare (new) mutations are introduced to the population.
Fierce purifying selection? YES. Very few of these get anywhere near fixation.
chimpA
humansA A G A
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http://cs273a.stanford.edu [Bejerano Aut08/09] 18
Genomic Distribution of Ultraconserved Elements
•exonic•non•possibly
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http://cs273a.stanford.edu [Bejerano Aut08/09] 19
UC.338 comes from an ancient repeat
novelcoelacanthrepeat
ultraconservedexon
enhancer
[Bejerano et al, Nature ,2006]
LF-SINE
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http://cs273a.stanford.edu [Bejerano Aut08/09] 20
Touch an Ultra And You - DIY
[Ahituv et al., PLoS Biology, 2007]
4-8% of documented mouse KO
genes display no phenotype
(inc. Pbx2, Nkx6.2, Gli1)
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http://cs273a.stanford.edu [Bejerano Aut08/09] 21
Hypothesis
Can ultraconserved element mutations
be under extreme purifying selection
but the whole element be expendable?
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http://cs273a.stanford.edu [Bejerano Aut08/09] 22
What did Mother Nature favor?
tDNA element
mouse
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http://cs273a.stanford.edu [Bejerano Aut08/09] 23
Quite Some Time Later
The horror …
The horror …
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http://cs273a.stanford.edu [Bejerano Aut08/09] 24
Ultras are Fiercely Retained
rodents deleted
11/15157 = 0.072%
Ultras are
>300 fold
more
persistent
than
neutral DNA(25% deleted)
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http://cs273a.stanford.edu [Bejerano Aut08/09] 25
Enough about us….
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http://cs273a.stanford.edu [Bejerano Aut08/09] 26
What we do understand..
Ultraconserved elements exist.
They are maintained via strong on-going selection.
It is a heterogeneous bunch:
Some mediate splicing
Some regulate gene expression
Some express ncRNAs
(categories are not necessarily mutually exclusive)
Knockouts of four regulatory ultras did not lead to severe phenotypes (similar protein cases: Pbx2, Nkx6.2, Gli1)
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What we don’t understand
Their functional density:
How did they come to be?
What is the selective advantage that lets them persist?
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http://cs273a.stanford.edu [Bejerano Aut08/09] 28
Broad Guess
It’s about 3-D structure.Observation: rDNA (18S, 28S) have ultraconserved stretches,multiple constraints in a complex 3-D structure, the Ribosome.
•ncRNA ultras: structure confers function•Splicing related ultras: the Splicosome•Cis-reg ultras: TSS 3-D proximity, chromatinand/or packed TFBS (Transcription factories?)
TSS