finding orthologous groups rené van der heijden. what is this lecture about? what is...
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Finding Orthologous Groups
René van der Heijden
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What is this lecture about?
• What is ‘orthology’?• Why do we study gene-ancestry/gene-trees
(phylogenies)?• Several approaches to find orthologous genes• High-resolution orthology• Steps involved• Things to think about (homework)
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Homology
Genes are homologous if and only if theyderive from the same ancestral gene
• Sufficient sequence similarity proofs homology
• Very dissimilar sequences:PSI blast, HMM searches
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Homologous genes tend to have similar functions
The usual range
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Homologous genes tend to have similar functions
Accurate function prediction requires something better than
homology
OrthologyOrthology
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Duplications, Speciations, and Orthology
Evolution results in:• Growing number of genes
– Gene duplications– Horizontal gene transfer– De novo generation
• Growing number of species
The fate of gene duplicates:• Perish• Find a new functional niche
Tendency for functional expansionTendency for functional expansion
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Duplications, Speciations, and Orthology
Two genes in two species are orthologous ifthey derive from one gene
in their last common ancestor
• Orthologous genes are likely to have the same function
• Much stronger than “tend to have similar function”
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Duplications, Speciations, and Orthology
primalancestor
present genes
evolutionary distance
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Homologs, Orthologs,and Paralogs
• Homologous: one common ancestral gene
• Orthologous: separated by a speciation event
• Paralogous: separated by a duplication event
• Orthologs and Paralogs must be Homologs
Are there homologous genes whichare not orthologous nor paralogous?
The view on orthology and The view on orthology and paralogy is relative to a paralogy is relative to a
certain speciationcertain speciation
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Inparalogs and Outparalogs
• Both, In- and Outparalogous genes are separated by a gene duplication event
• For Inparalogs, the duplication event is not followed by speciation(s)
• Outparalogs are separated by a duplication event, followed by speciation(s)
• Inparalogs are recent paralogs• Outparalogs are more ancient paralogs
Are Inparalogs Orthologs ?Are Inparalogs Orthologs ?Depends on your definition:
Yes: two genes are orthologous ifthey derive from one gene
in their last common ancestorNo: two genes are orthologous if
they are only separated by cell division events
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Reading Gene-Trees
Although genes spec1,1 and spec2,1 are closer relatives, their distance is larger than that between spec1,1 and spec3,1
The tree suggests at least 2 gene losses
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In-, and Outparalogs, Orthologs, and Co-orthologs
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More examples
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www = What, Why, and hoW?
• What: Orthologous genes are separated by cell division only
• Why:Orthologous genes are likely to have the same function
• How:Yes, how can orthologous relations be established ?
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Several approaches
• The COG approach
• InParanoid
• Tree-based methods
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COG approach
• Based on blast hits
• Establishment and extension of triangles:
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COG approachII
Extension oforthologous groups
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InParanoid I
• Method denotes– IN- and OUTparalogs– For TWO species
• Find all hits from species A on B
• Find all hits from species B on A
• Find all bi-directional best hits (BBH)– These for putative orthologs
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InParanoid II
• Find all hits from A on A
• Find all hits from B on B
• Find all InParalogs– These are all hits better than the orthologs– Better => more recently split
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InParanoid III
• Putative orthologous pairs are curated by an outgroup species C
• InParalogs are given a confidence value
• Bootstrapping is used to give confidence values for orthologous pairs
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Genes with promiscuous domains
• Gene A may hit on gene B because of a shared domain X
• Gene B may hit on gene C because of a shared domain Y
• Promiscuous domains require (manual) curation
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Tree-based methods
1. Get all homologous genes
2. Make multiple alignments
3. Generate phylogenetic gene trees
4. Analyze trees
• Uncertainty in multiple alignment?• Different methods for distance calculations• Superpose a trusted species tree?• How to assess a level of accuracy?
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The Phylogenetic Gene-Tree• Multiple alignment for all genes
• Distance matrix calculation– Kimura correction– PAM model– Categories model
• Large trees: distance-based methods– Neighbor Joining
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Uncertainty in trees
• Evolutionary noise– Differing rates of evolution
– Convergent evolution (low complexity, coiled coils)
– Promiscuous domains (recombination, fusion, fission)
• Use of heuristic methods– Multiple alignment
– Tree making
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Analyze trees … but don’t trust them fully
• Rigid analysis suggests many duplications and losses• Presume scp branch is wrongly placed!
If this is correct …. this can’t be
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Three orthologous groups suggesting 15 gene losses
Considering one wrongly placedgene leaves only 2 gene losses
Analyze trees … but don’t trust them fully
• And if we accept wrong placement of branches …
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High-res versus Low-res
• Many,
• Complete, and
• Closely related
genomes
Challenge:Automatic Orthology assignment
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Things to think about (homework)
• Select a partner• Collect a gene tree (and some copies)• Carefully deduce which nodes are duplications and
which are speciations• Denote which genes are orthologous to each other
(orthologous groups)• Select interesting parts to predict what
– The COG procedure would say– InParanoid would say– What would have happened if some genes (or species) where
not involved in the analysis
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Homework: also think about …