Transcript Ultraconserved Elements in the Human Genome

Ultraconserved Elements in
the Human Genome
Gill Bejerano, Michael Pheasant, Igor Makunin,
Stuart Stephen, W. James Kent, John S.
Mattick, David Haussler
Science Vol.304 28 May 2004
Presented By Victor Jensen
Overview
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Definition of an ultraconserved element
Diversity of the elements
Where are the elements
Possible function
Origins
Summary
Definition of an Ultraconserved
Element
• Segment of DNA with 100% sequence
identity across species (mouse, rat &
human)
• Orthologous location
• At least 200 bp
• Not rRNA
What they found
• Total of 481 sequences
• Up to 779 bp
• >5000 if you look at sequences >100bp
Diversity Across Species
500
400
300
324
Dog
Chicken
29
Mouse
Rat
Human
100
0
477
Fugu
200
481 481 481 438
67%
95%
99.20%
100%
Diversity Within Species
• Ultraconserved
elements have a total
of 106,767 bases
• Only 6 bases have
confirmed SNPs
(dbSNP)
• Expect 119 based on
neutral evolution
6
observed
119 expected SNPs
106,767 bases
Diversity Within Species
• With only 6 SNPs within these elements
they show very low diversity
• This represents 20 times lower SNP
density and rate of change compared to
the rest of the genome
•Very similar in chimpanzees, 38
SNPs found where 716 are expected
There Must be Selection
• Random chance for one of these elements
to occur is less than 10-22
• This is more conservation than most (if not
all) proteins
• Evidence for very strong selection
So, why are these so important and where
are they located??
Location of Elements
• Elements are everywhere!!
Location of Elements
300
250
200
Non-Exonic,
256
150
100
Exonic, 111
50
Possibly
Exonic, 114
0
Elements
Non-Exonic elements
• Found in clusters
• 140 are >10 kb away from a gene (88 are
>100kb away)
• Others lie in introns
• Areas around elements are enriched for
developmental genes and transcription factors
Exonic
• Randomly distributed
• Enriched for RNA processing proteins
• Shows some correlation with RNA recognition
motif often associated with alternative splicing
Location of Elements
Exonic, or
Type 1
Nonexonic, or
Type 2
•Overview of GO term abundance vs. expected
Groups of Elements
• Some elements are paralogous
• Significant divergence between paralogs
• Surrounding genes are orthologous
Possible Function
• Conservation of important biological
processes
– Transcriptional element (cis-regulatory
elements)
– RNA processing machinery (spliceosome)
– Developmental regulation
Transcriptional Regulation
• cis-regulatory elements are often conserved
between species
• Below is the 10kb upstream of PolA
RNA Processing
• Elements could represent RNA processing
enzyme binding sites
• Alternative splicing
RNA Structure
• Hypothesized that
RNA structure may
play a role in function
• Many ultraconserved
elements would have
an RNA structure
• Splicing recognition?
Development
• Defects in developmental genes/gene regulation
is often lethal
• Correlation of ultraconserved elements and
developmental genes implies relationship
Elemental Origins
• Looked for elements in other sequenced
genomes
– C. elegans
– D. melanogaster
– C. intestinalis
Elemental
Origins
• Found 24 of 481
elements
• All were exonic
• 17 show alternative
spliced
Elemental Origins
• Elements have undergone a “freezing” of DNA
code after chordate evolution
• Most are older than 300 million years
How are they conserved?
• Evolution of high negative selection
• Or
• Evolution of hypomutable regions
• Or a little of both
High Negative Selection
• Must have an
important function
• Sensitive to minor
changes
• RNA structure is very
sensitive to changes
Hypomutable
Regions
• Unlikely to be
“hypomutable”
• Possibly
“hyperrepaired”
Summary
• 481 ultraconserved elements >200bp
• Exonic found with RNA processing genes
• Non-exonic found with transcription factors
and developmental genes
• 20x less change than expected
• Connection to alternative splicing and RNA
structure
• Low diversity
Questions
• Could some of these be RNA genes?
• Did they look for related elements not found in
the same location in mice?
• What happens if there is a mutation in one of
these elements?
• ???