28-way vertebrate alignment and conservation track in the ucsc genome browser journal club dec. 7,...
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28-Way vertebrate alignment and conservation track in the
UCSC Genome Browser
Journal club Dec. 7, 2007
Vertebrate genome sequencing
the Broad Institute of MIT (Massachusetts Institute of Technology) and Harvard
the Human Genome Sequencing Center at the Baylor College of Medicine
the Genome Sequencing Center at Washington University. the Sanger Center the Department of Energy’s (DOE’s) Joint Genome Institut
e the National Institute of Genetics in Japan.
Alignment:
Similarities & differences between genome sequences:
1. functional noncoding regions2. protein-coding genes3. non-coding RNA genes
Aims
1. to more reliably identify functional elements via sequence alignment
2. To enhance the effectiveness of the disease-model species for experiment
3. To determine the course of evolution & reconstruct the ancestral genome sequence
April 2007:17 2811 old species data6 updated old species11 new species
>79%
Heterogeneous mix
Coverage:2 – >99%16 – 5.1% ~ 8.5%10 – ~2x(2x – 87.5%, 5x – 99.4%)Cloning bias…
Applications
Application 1: indels in protein-coding regions
Application 2: conservation of start and stop codons
Application 3: phylogenetic extent of alignment of funct
ional regions
Application 1 Indels accumulated at a uniform rate during th
e evolution?
The phenotypic consequence of human- specific protein indels?
Positions of potentially disease-associated indels resisted substitution over evolutionary time – interspecies conservation
6-bp indel near the start of PRNP
Primate & glires
P G D
Total Indel: 209
# of Indel / # per MY
Parametric bootstrap test ---- significantly differ from hypothesis
4/MY
2/MY
Human specific protein indels
SULF1: human specific 3-bp insertion in exon 11
Replication slippage1. Fixed in humans
2. Very conserved region (retain 4Es over 2 billion years)
3. Without 3D data
GFM2: human specific 6-bp insertion
1. Not conserved region
2. This insertion only occurs in some human individuals
3. Similar protein 3D data implied no phynotypic consequence
Human replacement disease-associated amino acid mutations are overabundant occur predominantly in positions essential to the structure and function of the proteins
Subramanian and Kumar, BMC Genomics 2006, 7:306
Disease-associated deletion More species considering Data from PhenCode Locus Variants PAH Simplified distance -- # of distinct aa.
6
>79%
<
Hard to identify precise gene boundaries based on comparative genomics data
Drift away
Hypothesis 1:
the CpG islands that are common near gene starts are more difficult to sequence
Hypothesis 2:
Selection at the start codon might be more relaxed in genes with multiple promoters (alternate promoters)
4%1.65%
Hypothesis 3:
the program may not have enough surrounding conserved sequence to reliably align the small initial coding exon around the start codon
Hypothesis 3:
the program may not have enough surrounding conserved sequence to reliably align the small initial coding exon around the start codon
similar
Conclusion A bias against CpG islands in the draft sequ
ence combined with difficulty in aligning small initial coding exons does explain a great deal of the observed unalignability of start codons compared with stop codons
Gene model based on multiple genomic alignments must be aware of the start codon
Background – finding functional elements conservation in noncoding regions is much
more subject to evolutionary turnover than in protein-coding regions.
Evolutionary(conservation) turnover-- Most studies tacitly equate homology of functional elements with sequence homology. This assumption is violated by the phenomenon of turnover, in which functionally equivalent elements reside at locations that are nonorthologous at the sequence level.
Frith et al. Genome research 2006
More species genomics data --- higher resolution
251000 coding exons of RefSeq genes 481 ultraconserved elements 94000 predicted regulatory regions(P
RPs) 3900 putative transcriptional regulato
ry regions (pTRRs)
Alignability: the fraction that aligns with a designated comparison species
Hu
ma
n