1 / 25

Orthologs: Two genes, each from a different species , that descended from

Orthology & Paralogy (etc. etc.). Orthologs: Two genes, each from a different species , that descended from a single common ancestral gene. (note no regard to function! and does NOT require one-to-one relationships).

marlaj
Download Presentation

Orthologs: Two genes, each from a different species , that descended from

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Orthology & Paralogy (etc. etc.) Orthologs: Two genes, each from a different species, that descended from a single common ancestral gene (note no regard to function! and does NOT require one-to-one relationships) Paralogs: Two or more genes, often thought of as within the same species, that originated by one or more gene duplication events

  2. Ancestral species Ancestral Gene 1 A B C D E A1 B1 C1 D1 E1 SPECIES TREE GENE TREE Clear case of orthology: each gene 1 in each species is an ortholog Of the others - all descended from a single common ancestor

  3. Ancestral species Ancestral Gene 1 Gene duplication along this species branch A B C D E E1 A1 B1 C1 C2 D1 D2 SPECIES TREE GENE TREE Duplication event along branch to species C & D C1 and C2 are paralogs, D1 and D2 are paralogs What about A1 to C1? To C2?

  4. Orthology & Paralogy (etc. etc.) Orthologs: Two genes, each from a different species, that descended from a single common ancestral gene (note no regard to function!) Paralogs: Two or more genes, within the same species, that originated by one or more gene duplication events Also now many subtle variants: Outparalogs: cross-species paralogs (i.e. gene duplication BEFORE speciation) Inparalogs: lineage-specific duplication (i.e. duplication AFTER speciation) Ohnolog: duplicates originating from a whole-genome duplication (WGD) Xenolog: genes related by horizontal gene transfer between species

  5. Phenology vs. Phylogeny Phenology: tree based on similarity of characteristics Phylogeny: tree based on evolutionary history Align protein & score alignment (# of identical and ‘conserved’ amino acids) Build a tree based on sequence similarity Requires inferring history across the species A1 B1 C1 C2 A1 B1 C1 C2 A1 is more similar to C1 than C2 - A1 & C1 are likely (* but not guaranteed!) more similar functionally But historically, A1 is equally distant to C1 and C2

  6. Methods of orthology prediction 1. Reciprocal best-BLAST hits (RBH): simplest method Species A Species B Gene A1 Gene B1 Gene A2 Gene B2 . . . . . . Gene An Gene Bn BLAST Gene A1 against Species B genome Take top BLAST hit in Species B and use as the query against Species A If Gene A1 is the top blast hit in the genome, then call A1 & B4 orthologs

  7. Methods of orthology prediction 1. Reciprocal best-BLAST hits (RBH): simplest method Species A Species B Gene A1 Gene B1 Gene A2 Gene B2 . . . . . . Gene An Gene Bn BLAST Gene A1 against Species B genome Take top BLAST hit in Species B and use as the query against Species A If Gene A1 is the top blast hit in the genome, then call A1 & B4 orthologs

  8. Problems with RBH * Clear cases where the top BLAST hit is NOT the ortholog e.g. top hits can be highly conserved common domains * Gene duplications in one species can completely obscure orthologous hits * Orthologs with very low sequence homology can be missed altogether

  9. Methods of orthology prediction 2. Reciprocal Smallest Distance (RSD): slightly more complicated Species A Species B Gene A1 Gene B1 Gene A2 Gene B2 . . . . . . Gene An Gene Bn BLAST Gene A1 against Species B genome Take X number of top BLAST hits (user determined)

  10. Methods of orthology prediction 2. Reciprocal Smallest Distance (RSD): slightly more complicated BLAST Gene A1 against Species B genome Take X number of top BLAST hits (user determined) Do a global multiple alignment - throw out proteins with >Y% gapped positions

  11. Methods of orthology prediction 2. Reciprocal Smallest Distance (RSD): slightly more complicated BLAST Gene A1 against Species B genome Take X number of top BLAST hits (user determined) Do a global multiple alignment - throw out proteins with <Y% gapped positions Take remaining proteins and find the single one with the closest evolutionary distance

  12. Methods of orthology prediction 2. Reciprocal Smallest Distance (RSD): slightly more complicated Species A Species B Gene A1 Gene B1 Gene A2 Gene B2 . . . . . . Gene An Gene Bn BLAST Gene A1 against Species B genome Take X number of top BLAST hits (user determined) Do a global multiple alignment - throw out proteins with <Y% gapped positions Take remaining proteins and find the single one with the closest evolutionary distance Final reciprocal BLAST using remaining gene in Species B as query against Genome A

  13. Problems with RSD * Clear cases where the top BLAST hit is NOT the ortholog e.g. top hits can be highly conserved common domains * Gene duplications in one species can completely obscure orthologous hits * Orthologs with very low sequence homology can be missed altogether

  14. Methods of orthology prediction 3. Newest methods take synteny into account Syntenic = conserved gene/sequence order Gene A1 A2 A3 A4 Gene B1 B2 B3 B4

  15. Problems with Synteny-based Methods * Clear cases where the top BLAST hit is NOT the ortholog e.g. top hits can be highly conserved common domains * Gene duplications in one species less likely to obscure things * Orthologs with low sequence homology not part of a larger duplication could still be missed

  16. Methods of orthology prediction 4. Clusters of Orthologs (COG) approach: - Addresses the restriction of 1:1 orthologs - Identifies inparalogs and then id’s orthologous relationships between groups Species A B C D Several approaches can assign COGs across many species at once (InParanoid, Fuzzy RB)

  17. Lots of different databases of orthologs (esp. for model organisms)

  18. Of course, different methods of orthology assignment can give very different results

  19. AND … genome errors can really obscure things Bad genome annotations can affect orthology & paralogy relationships - missing genes, fused genes, incorrect start/stop annotations Bad assembly can affect ortho clusters: - amplifications or decreases of gene family numbers

  20. Why is orthology-paralogy so important? Allows us to study the history of protein evolution & infer constraints Ancestral Gene 1 Gene duplication along this species branch Separate gene duplication in Species A E1 A1 B1 C1 C2 D1 D2 A2 GENE TREE

  21. Ligand Governs Glucocorticoid Receptor (GR) Mineralocorticoid Receptor (MR) Cortisol Stress Response Aldosterone (tetrapods) DOC (teleosts) Electrolyte Homeostasis * Teleosts don’t make aldosterone

  22. Figure 1 Blue = Aldo binding Red = Cortisol ONLY

  23. Two amino-acid changes in AncCR can alter specificity Blue = DOC Red = Cortisol Green = Aldo S106P likely occurred FIRST, then L111Q

  24. Model for evolution of ligand binding & hormone response Ancestral protein could bind Aldo, even though no Aldo present Duplication ~450 mya = redundant receptors Two successive changes in GR = switch to Cortisol Specificity Emergence of Aldosterone Hormone

More Related