Download Ultraconserved Elements in the Human Genome

Ultraconserved Elements in
the Human Genome
Bejerano, G., et.al.
Katie Allen & Megan Mosher
Ultraconserved Elements
 Segments longer than 200 base pairs
that are absolutely conserved, showing
100% identity with no insertions or
deletions, between orthologous regions
of the human, mouse, and rat genomes
 481 such segments
Purpose
 To determine the longest segments of the
human genome that are maximally
conserved (considered ultraconserved
based on the prior definition) with
orthologous segments in rodents
Location of U.C.E.s
 Generally located in genes involving RNA
processing or near genes involved in the
regulation of transcription or development
 Widely distributed
 Often found in clusters
 ~ 5% of the human genome is more conserved
than would be expected based on neutral
evolution since the split with rodents
 These highly conserved segments contain a
large number of non-coding elements
 They exhibit almost no natural variation within
the human population
 The probability of finding one such element in
2.9 billion bases is less than 10-22 under a
neutral evolution model
Location of U.C.E.s on the Genes
 Nearly all of these ultraconserved
elements have been under extreme
negative selection for more than 300
million years
 The low level of variation suggests that
these elements are changing at a rate
roughly 20 times slower than the average
for the genome
Of the 481 Ultra Conserved Elements:
 111 are exonic – overlap the mRNA of a
known human protein coding gene
 256 are non-exonic – show no evidence
of transcription
 114 are possibly exonic
Exonic
 Randomly distributed
around the genome
 Specifically
associated with RNA
processing
Non-Exonic
 Congregate in
clusters near
transcription factors
and developmental
genes
 Regulate
transcription at the
DNA level
 Often found in “gene
deserts”
Genes that overlap with U.C.E.s
 Type 1 – overlap with exonic u.c.e.s
- show enrichment for RNA
binding and regulation of
splicing
- abundant in RNA recognition
motif
 Type 2 – near non-exonic u.c.e.s
- enriched for regulation of
transcription and DNA binding
* Genes that flank intergenic
ultraconserved elements are enriched for
developmental genes, suggests that
many u.c.e.s may be distal enhancers of
early developmental genes
PTPB2 (Type 1 Gene)
 Mostly intronic u.c.e.
 May form an RNA structure that
participates in the regulation of splicing
through interactions with the splicesome
 When this u.c.e. was folded into a
secondary structure its energy was lower
than all but 1 of 10,000 randomized
versions of this sequence
“Flip” and “Flop” Exons
 Exonic ultraconserved elements
 Exhibit RNA editing and alternative
splicing
 Regulates the editing of adenosine to
inosine
 The longest 3 ultraconserved elements
are 779, 720, and 731bp long
 All lie in the last three introns in the POLA
gene – the DNA polymerase alphacatalytic subunit on X
 May be associated with the ARX gene
 A similar u.c.e. lies near the ARX
homeobox gene – involved in CNS
development, associated with epilepsy,
mental retardation, and cerebral
malformations
Evolution of Ultraconserved
Elements
Only 5% of the orthologs of u.c.e.s could be
partially traced back to C. intestinalis, Drosiphilia,
and C. elegans
 All overlapped with coding exons
 17 of 24 were alternatively spliced in
humans
 No case where an intronic element in
humans was coding in any other species,
showing intron has a function other than
protein coding
 In cases where it could be traced beyond
vertebrates, the orthologous introns in
the more distant species were either very
small or non-existent
 It is possible that processes that
produced ultra conserved elements in
vertebrates also existed in other species
 i.e. yeast
Paralogous Sets
 12 paralogous sets of genes were found
in the u.c.e.s
 All paralogs have a highly conserved
match in the chicken
 Shows that significant divergence
between paralogs in each cluster must
have occurred in the early part of their
evolution
“Near-freezing”
 Most u.c.e.s represent chordate
innovations that evolved rapidly but then
slowed down considerably, becoming
“near-frozen”
 A significant number of shorter elements
are different in birds but conserved in
mammals – suggested that evolution
followed by “near-freezing” is ongoing
 The conservation among u.c.e.s must
result from a highly negative selection
rate, a highly reduced mutation rate, or a
combination of both
 The problem with maintenance selection
is that it does not result in total
conservation unless multiple functions
are overlaid on the same DNA
 Reduced mutation seems like a novel
reason because it means the existence
of regions of a few hundred bases with a
20-fold mutation rate reduction
 There is no evidence however for
hypomutable or hyper-repaired regions
Conclusion
 Ultraconserved elements are important for
organism development and gene regulation
 Ultraconserved elements evolved quickly and
have become “near-frozen”
 This evolution seems to be ongoing
 Conservation seems to have arisen from
increased negative selection or decreased
mutation rate