Milestones due today. Anything to report?
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Transcript of Milestones due today. Anything to report?
http://cs273a.stanford.edu [Bejerano Fall09/10] 1
Milestones due today.Anything to report?
http://cs273a.stanford.edu [Bejerano Fall09/10] 2
Lecture 17
Ultraconservation evolutionary dataFinish early – come hear the talk with us?
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Sequence Conservation implies Function
(but whichwhich function/s?...)
human
mouse
mammalianancestor
...CTTTGCGA-TGAGTAGCATCTACTATTT...
...ACGTGGGACTGACTA-CATCGACTACGA...
functional region!
Comparative Genomics of Distantly related species:
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HumanGenome:
3*109 letters
Human Genome full of Conserved Non-Coding Elements
1.5%known
function >50%junk
3x more functional DNA than known!
compare to other species
>5% human genome functional
~106 substrings do not code for protein
What do they do then?
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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
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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
UltraconservationUltraconservation
Simplebut
Unexpected
(the lure of Bioinormtaics)
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Typical DNA Conservation levels
Conserved elements between human and mouse are on average 85% identical. [mouse consortium, 2002]
(dot = base identical to human)
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Ultraconserved Elements
[Bejerano et al., Science 2004]
fish
481 elements perfectly conserved (100%id) over 200bp or more between human, mouse and rat.
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Ultraconserved Elements: Why?
Hundreds of long substrings identical between amniotes they must have rejected many different changes.But... all functions we understand in our genome are encoded using redundant codes.
*****
CDS ncRNA TFBS
seq.
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Ultras are Functional
Back in 2004 we hypothesized:
481 ultraconserved elements
exonic subset –post transcriptional regulation
[Ni et al., Genes Dev.; Lareau et al., Nature, 2007]
“nonexonic” subset –transcriptional regulators
[Pennacchio et al., Nature, 2006]
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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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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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Touch an Ultra And You - DIY
[Ahituv et al., PLoS Biology, 2007]
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What can’t we measure in the lab?
sN
s
e eeesN 21
1),|fixationPr(
Ne is population size, s selective dis/advantage.Both of which are VERY wrong in the lab.
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So it can happen – but does it FIX?
tDNA element
mouse
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Count Fraction Lost, Binned by %id
t humanmacaque
dogmouse
rat
100bpslidingwindow
count_all
count_hole
binby
%id
humandog rat mouse
macaque
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Quite Some Time Later
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Pragmatic Genomics
define goalrun sensible approachwhile (results full of artefacts*){ characterize artefact write handler into code rerun}
bio
bio
cs
cs
* eg: sequencing errors, assembly errors contaminating sequence, ambiguous situations, etc.
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Ultras are Fiercely Retained through Evolution
Ultras are>300 fold
more persistent
thanneutral DNA(25% deleted)
the genomic deletiongenomic deletion is
100%id primates-dog: 1,691,090bprodents deleted: 1,447bp (0.086%)
sN
s
e eeesN 21
1),|fixationPr(
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How special are the Ultras?
election
UltraconservationUltraconservation
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Adding More Species
Aha!!
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Adding More Species
Few species More and more species
Hmmm….
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Most Non-Coding Elements likely work in cis…
9Mb
“IRX1 is a member of the Iroquois homeobox gene family. Members of this family appear to play multiple roles during pattern formation of vertebrate embryos.”
gene deserts
regulatory jungles
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… and Ultras are the tip of a functional iceberg
9Mb
This dense regulatory jungle contain a single ultra
gene deserts
regulatory jungles