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Comparative Genomics Overview of the Talk • Comparing Genomes • Homologies & Families • Sequence Alignments 2/28 Comparative genomics Protein trees Protein sequence (Compara & Pan-Compara) Homologues Genome alignments Nucleotide sequence (Compara) Syntenic regions 3/28 How Does Ensembl Predict Homology? • Uses all the species • Uses a representative protein (the longest) for every gene • Builds a gene tree • EnsemblCompara GeneTrees: Analysis of complete, duplication aware phylogenetic trees in vertebrates. Vilella AJ, Severin J, Ureta-Vidal A, Durbin R, Heng L, Birney E. Genome Res. 2008 Nov 24. 4/28 Steps in Homology Prediction ..MEDPATA… Load longest protein for every gene from all species WU Blastp + SmithWaterman longest translation of every gene against every other (Blast Reciprocal Hit/ Blast Score Ratio) Protein clustering, build multiple alignments (MCoffee) From each alignment, build a gene tree (TreeBest) Reconcile each gene tree with the species tree to determine internal nodes (TreeBest) Orthologues, paralogues… 5/28 Viewing Trees in Ensembl 6/28 Types of Homologues • Orthologues : any gene pairwise relation where the ancestor node is a speciation event • Paralogues : any gene pairwise relation where the ancestor node is a duplication event 7/28 The Gene Tree for INS (insulin precursor) A blue square is a speciation event (Orthologues) A red square is a duplication event (Paralogues) 8/28 Orthologue Types What is „1 to 1‟? What is „1 to many‟? 9/28 Quick exercise MYO6 is a myosin that has been shown (when mutated) to be associated with deafness. 1. Does human MYO6 have a homologue in dog? 2. If so, in what location (chromosome and base pairs) is the dog homologue found? 3. Can you find the cDNA alignment between the human and dog homologues? Pan-taxonomic compara Anolis carolinensis Ciona savignyi Danio rerio Equus caballus Gallus gallus Homo sapiens Macaca mulatta Monodelphis domestica Mus musculus Ornithorhynchus anatinus Pan troglodytes Pongo pygmaeus Xenopus tropicalis Anopheles gambiae Caenorhabditis elegans Drosophila melanogaster Dictyostelium discoideum Plasmodium falciparum Plasmodium vivax Arabidopsis thaliana Oryza sativa Vitis vinifera B_aphidicola_Tokyo_1998 B_burgdorferi_DSM_4680 B_subtilis E_coli_K12 M_tuberculosis_H37Rv N_meningitidis_A P_horikoshii S_aureus_N315 S_pneumoniae_TIGR4 S_pyogenes_SF370 W_pipientis_wMel Aspergillus nidulans Neurospora crassa Saccharomyces cerevisiae Schizosaccharomyces pombe 11/28 www.ensemblgenomes.org 12/28 Protein Families • How: Cluster proteins for every isoform in every species + UniProt proteins. • BLASTP comparison of: – all Ensembl ENSP… – all metazoan (animal) proteins in UniProt 13/28 Overview of the Talk • Comparing Genomes • Homologies and Families • Sequence Alignments 14/28 Comparative genomics Genome Alignments Nucleotide sequence (Compara) Syntenic regions Protein trees Protein sequence (Compara & Pan-Compara) Homologues 15/28 Whole Genome Alignments • BLASTZ-net (nucleotide level) closer species e.g. human – mouse • Translated BLAT (amino acid level) more distant species, e.g. human – zebrafish • EPO/PECAN multispecies alignments • ORTHEUS used to determine ancestral alleles 16/28 Quick exercise Go to the „Genomic alignments‟ view for MYO6. Turn on the alignment with dog. 1. What do you see? Why are there so many regions for dog listed? 2. What are the red, highlighted basepairs? 3. Is there a dog gene in this region? 4. What multiple alignments are available for human? Which Multispecies Alignments? Mercator-Pecan • 19 amniota vertebrates + constrained elements Enredo-Pecan-Ortheus (EPO) • 3 neognath birds • For 6 primates • For 5 teleost fish + constrained elements • For 12 eutherian mammals • For 35 eutherian mammals + constrained elements 18/28 What are Constrained Elements? GERP scoring of every nucleotide in the alignment (Cooper GM et al., Genome Res., 2005; 15:901-913) 19/28 Quick exercise Go to the Location tab for human MYO6 (region in detail view). Turn on the „conservation score‟ and „constrained elements‟ for the 35 eutherian mammals. 1. Zoom in to one or a few exons. Do the constrained elements match up to the exons? Non-Coding Regions • “Phylogenetic Footprinting” – conserved noncoding regions can be functional • Regulatory regions discovered in this way for genes: Hoxb-1, Hoxb4, PAX6, SOX9 21/28 Regulatory Features of the PDX1 gene Region in Detail shows conservation of sequence in regions involved in PDX1 transcriptional regulation (1.6-2.8 kb upstream of the gene). 22/28 Comparative genomics Pairwise alignments Nucleotide sequence (Compara) Syntenic regions Protein trees Protein sequence (Compara & Pan-Compara) Homologues 23/28 Syntenic regions Syntenic regions Blastz/ Lastz 24/28 Synteny 25/28 Synteny exercise Go to the Synteny view in the location tab. 1. How many chromosomes in dog have syntenic regions to human chromosome 6? 2. Click „15 downstream genes‟. Are there missing dog homologues to the human gene list? Advanced views Go to the Synteny view in the location tab. Explore the Alignments (image), Alignments (text) and Multi-species view in the location tab. 1. View alignments between human and dog in these three views. Acknowledgements • • • • • • Javier Herrero Kathryn Beal Stephen Fitzgerald Leo Gordon Matthieu Muffato Miguel Pignatelli 28/28