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MW 11:00-12:15 in Beckman B302 Profs: Serafim Batzoglou, Gill Bejerano TAs: Cory McLean, Aaron Wenger. Lecture 18. Guest Talks Ultraconservation The Projects. human. chimp. macaque. mouse. rat. cow. dog. opossum. platypus. chicken. zfish. tetra. fugu. Comparative Genomics. - PowerPoint PPT Presentation
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http://cs273a.stanford.edu [Bejerano Aut08/09] 1
MW 11:00-12:15 in Beckman B302Profs: Serafim Batzoglou, Gill BejeranoTAs: Cory McLean, Aaron Wenger
http://cs273a.stanford.edu [Bejerano Aut08/09] 2
Lecture 18
Guest TalksUltraconservation
The Projects
http://cs273a.stanford.edu [Bejerano Aut08/09] 3
human
mouserat
chimp
chicken
fugu
zfish
dog
tetra
opossum
cow
macaque
platypus
Comparative Genomics
t
*
what madeus human?
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PhenotypeGenotype
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human
mouserat
chimp
chicken
fugu
zfish
dog
tetra
opossum
cow
macaque
platypus
Comparative Genomics
t
How did some of ourrelatives go back?
*
http://cs273a.stanford.edu [Bejerano Aut08/09] 6
human
mouserat
chimp
chicken
fugu
zfish
dog
tetra
opossum
cow
macaque
platypus
Now at the Species Level
t
How did weleave the ocean?
*
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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
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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Typical DNA Conservation levels
[Bejerano et al., Science 2004]
Conserved elements between human and mouse are on average 85% identical. [mouse consortium, 2002]
http://cs273a.stanford.edu [Bejerano Aut08/09] 10
Ultraconserved Elements
[Bejerano et al., Science 2004]
fish
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No known function requires this much conservation
CDS ncRNA TFBS
*****
seq.
?
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Discovery can be fun
(compared to 4 results day before our ScienceExpress paper)
31,800
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Predictions and Proofs I
Based on public domain genome wide data:
ultraconservedelements
one subsetcodes protein
larger subsetdoes not
generate testable hypotheses for function from existing knowledge (2004)
[Pennacchio et al., Nature, 2006]
http://cs273a.stanford.edu [Bejerano Aut08/09] 14
Predictions and Proofs II
Based on public domain genome wide data:
ultraconservedelements
one subsetcodes protein
larger subsetdoes not
generate testable hypotheses for function from existing knowledge (2004)
[Pennacchio et al., Nature, 2006]
post transcriptional modification
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.
http://cs273a.stanford.edu [Bejerano Aut08/09]
Model for Homeostatic Auto/Cross-regulation
[Ni et al., Genes & Dev 2007 ]
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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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Genomic Distribution of Ultraconserved Elements
•exonic•non•possibly
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UC.338 comes from an ancient repeat
novelcoelacanthrepeat
ultraconservedexon
enhancer
[Bejerano et al, Nature ,2006]
LF-SINE
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Touch an Ultra And You - DIY
[Ahituv et al., PLoS Biology, 2007]
4-8% of documented mouse KOgenes display no phenotype(inc. Pbx2, Nkx6.2, Gli1)
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Hypothesis
Can ultraconserved element mutationsbe under extreme purifying selectionbut the whole element be expendable?
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What did Mother Nature favor?
tDNA element
mouse
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Quite Some Time Later
The horror … The horror
…
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Ultras are Fiercely Retained
rodents deleted11/15157 = 0.072%
Ultras are>300 fold
more persistent
thanneutral DNA(25% deleted)
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Enough about us….
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What we do understand..Ultraconserved elements exist.They are maintained via strong on-going selection.It is a heterogeneous bunch:Some mediate splicingSome regulate gene expressionSome 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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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