5 Open Problems in Bioinformatics Pedigrees from Genomes Comparative Genomics of Alternative...
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Transcript of 5 Open Problems in Bioinformatics Pedigrees from Genomes Comparative Genomics of Alternative...
5 Open Problems in Bioinformatics
•Pedigrees from Genomes
•Comparative Genomics of Alternative Splicing
•Viral Annotation
•Evolving Turing Patterns
•Protein Structure Evolution
Three Processes1. Recombination
2. Choosing Parents
3. The Mutational Process
Ped
igree p
rocess
Co
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pro
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Se
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From genomes to pedigrees
Probability of Data given a pedigree.Elston-Stewart (1971) -Temporal Peeling Algorithm:
Lander-Green (1987) - Genotype Scanning Algorithm:
Mother Father
Condition on parental states
Recombination and mutation are Markovian
Mother Father
Condition on paternal/maternal inheritance
Recombination and mutation are Markovian
Comment: Obvious parallel to Wiuf-Hein99 reformulation of Hudson’s 1983 algorithm
Genomes with and --> infinity
recombination rate, mutation rate
•Counting within a small interval would reveal the length of the path connecting the two segments.
•Siblings are readily revealed, since they will have segments with 2 density of mutations
•The distribution of path lengths are readily observable between two sequences
•All embedded phylogenies are observable
Benevolent Mutation and Recombination Process
From Phylogenies to PedigreesMike’s counter example, linkage and individuals
1 2
1 2
1 2
1 2
1 2
1 2
1 2
1 2
Pedigree 1 Pedigree 2
grand
paren
tsIndividual 1
Individual 2
Different PedigreesSame Phylogenies
Gluing Phylogenies together
?
Sibling Sequences come from different parents.
A recombinants’ parent are sister sequences.
Comparative Genomics of Alternative Splicing
From Transcripts to the AS-Graph
EES S
1. How well known is the AS-graph as a function number of transcripts?
2. A family and distribution of transcripts, can they be explained an AS-graph with probabilities at donor sites or do we need probabilities for (donor,acceptor) pairs? Or possibly even more complicated situations. And is sampling transcripts good enough to distinguish these situations.
Mini-project: reliability of AS-detection.Choose Idealized AS-Graph:
1. Genome
2. Choose donor and acceptor sites in random pairs.
3. For each possible splice pair assign probability for choosing it.
This should define a probability for all transcripts.
• Generate a set of transcripts.
• Reconstruct AS-Graph.
Key questions:
1. How many transcripts must be sampled to detect AS.
2. How well will the AS-Graph be recovered?
Optimal DAG (directed acyclic graph) under restrictionsO
pt i
mal
Pat
hs:
Su
b-o
pti
mal
Pat
hs:
Finding a set of annotations:
1. Find set of paths, maximizing sum of scores.
2. The score of minimal path must be above threshold.
Two paths must differ significantly: An enclosed area, the maximal height must be d higher than the boundary defining it. Height(i,j) = di,j + di,j
1. Does known AS genes have more CTO structure than non-AS genes?
2. Do the AS correspond to the CTO structure
3. Is the CTO structure evolutionary conserved?
Phylogenetically related ASGs
1. Is ASG conserved?
2. What is conserved?
3. How is selection along position dependent on splicing status?
EESS EESS EESS
http://www.tulane.edu/~dmsander/WWW/335/Diarrhoea.html
http://www.tulane.edu/~dmsander/WWW/335/Papovaviruses.htmlhttp://www.tulane.edu/~dmsander/WWW/335/Retroviruses.html
Virus AnnotationClasses of Gene Structures
Retroviridae Arrangements Papoviridae Arrangement
Diarrhoea Causing Arrangements
Illustrating the 3 main classes of gene structures: Unidirectional, Convergent and Divergent.
The Problems of Viral Annotation
•HMM gene structure generator (McCauley)
•Gene Structure Evolution (de Groot)
•Alignment (Caldeira, Lunter, Rocco)
•Recombination (Lyngsø, Song)
•Multiple constraints: RNA secondary structure,
gene conservation, binding/transcriptional
instructional sites.
Our 8 State HMM which allows for Unidirectional overlapping gene structures
HMM States• Non-coding • Coding RF1• Coding RF2• Coding RF3• Coding RF1,2• Coding RF1,3• Coding RF2,3• Coding RF1,2,3
Combining Levels of Selection.
Protein-Protein
Hein & Støvlbæk, 1995 Codon Nucleotide Independence Heuristic
Jensen & Pedersen, 2001
Contagious Dependence
Assume multiplicativity: fA,B = fA*fB
Protein-RNA
DoubletsSinglet
Contagious Dependence
HIV2 Genomes
SS HMM Sensitivity
PHMM
Sensitivity
Del
Sensitivity
SS HMM
Specificity
PHMM
Specificity
Del
Specificity
M30502 0.8913 0.9765 0.0852 0.9878 0.9753 -0.0125
J04542 0.8458 0.9173 0.0714 1.0000 0.9956 -.0044
D00835 0.8796 0.9432 0.0636 0.9920 0.9733 -0.0187
M15390 0.9310 0.9971 0.0661 1.0000 0.9869 -0.0131
J03654 0.8261 0.9971 0.1709 1.0000 0.9865 -0.0135
AY509259 0.8697 0.9256 0.0559 1.0000 0.9886 -0.0114
AY509260 0.8257 0.9101 0.0844 0.9928 0.9792 -0.0136
J04498 0.8961 0.9737 0.0776 1.0000 0.9911 -0.0089
AF082339 0.9074 0.9650 0.0577 0.9842 0.9773 -0.0069
U22047 0.9028 0.9874 0.0847 0.9865 0.9744 -0.0121
U27200 0.8769 0.9453 0.0684 0.9928 0.9748 -0.0180
LO7625 0.8340 0.9680 0.1340 1.0000 0.9607 -0.0393
L36874 0.8653 0.9957 0.1303 0.9980 0.9766 -0.0214
MEANS 0.8732 0.9617 0.0885 0.9949 0.9800 -0.0149
Table illustrating the performance benefit in Sensitivity we obtain utilizing a Phylogenetic HMM. We extend the HMM model to include evolutionary
information from 13 aligned HIV2 sequences.
http://www.ncbi.nlm.nih.gov/Genbank/
http://www.ncbi.nlm.nih.gov/genomes/VIRUSES/viruses.html
Entrez Genomes currently contains 2120 Reference Sequences for 1510 viral genomes and 36 Reference Sequences for viroids.
Properties of overlapping genes are conserved across microbial genomes.Genome Res. 2004 Nov;14(11):2268-72.
GenBank: Centralized resource for publicly available viral sequence data.
Within microbial genomes, one third of annotated genes contain some degree of overlap, and one third of these are either Convergent or Divergent.
Krakauer, D.C. Stability and evolution of overlapping genes. Evolution 54: 731-739 (2000) Genome Res. 2004 Nov;14(11):2268-72.
General preponderance of overlapping gene structures is roughly a 90:9:1 ratio split across Unidirectional, Convergent and Divergent arrangements.
Turing Patterns
From Maini’s Home Page: http://www.maths.ox.ac.uk/~maini
Mathematical models to understand biological patterns
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[From: Leppanen et al. Dimensionality effects in Turing pattern formation, Int. J. Mod. Phys. B 17, 5541-5553 (2003)]
Different parameters lead to different patterns
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Stripes: p small Spots: p large
3 suggestions
1. Networks and Turing Patterns
2. Stochastic Partial Differential Equations
3. Phylogenetically related Turing Patterns
Evolutionary Models of Protein Structure Evolution
Known KnownUnknown
-globin Myoglobin
300 amino acid changes800 nucleotide changes1 structural change1.4 Gyr
?
?
?
?
1. Given Structure what are the possible events that could happen?
2. What are their probabilities? Old fashioned substitution + indel process with bias.
Bias: Folding(Sequence Structure) & Fitness of Structure
3. Summation over all paths.
2 suggestions
Folding(Sequence Structure)
As a first approximation similar structures should be compared and the problem could be solved by comparative modelling.
Fitness of Structure – such functions are common place in guiding prediction programs.
Fast Homology Modelling
B. MCMC
A. Structure (Homology Modelling, Topology)
Using Protein Topology as Hidden Variable
Questions to be asked
Protein Structure Analysis is much harder than Sequence Analysis. Much of the first hand impression will remain: “Structures are either trivially similar or highly dissimilar” – the middle ground is empty.
At Gyr scale other rearrangements occur.
Test of smooth/catastrophic structure evolution
Separation of analogous/homologous similarities
Protein Evolution in General
How closely linked are homologous and structurally equivalent sites?
Negative Note:
Positive Note: If it works
http://www.biochem.ucl.ac.uk/bsm/cath/
http://scop.mrc-lmb.cam.ac.uk/scop/
Summary
Pedigrees from Genomes
Does infinite genomes determine pedigrees?
How many pedigrees are there?
Comparative Genomics of Alternative Splicing
How well do you know the ASG?
How do you measure selection on the ASG?
Viral Annotation
How well can you annotate viruses from observed evolution?
Evolving Turing Patterns
Turing Patterns and Networks
Stochastic Turing Patterns
Phylogenetically Related Turing Patterns
Protein Structure Evolution
Full Model of Structure Evolution
Model of Protein Topology Evolution