CSB472 Homology: Ancestry and Similarity

• CSB472 Computational Genomics & Bioinformatics given by David Guttman at the University of Toronto

Introduction to Homology

• Homology study includes:
  • Homology vs. Similarity
  • Classes of homology
  • Introduction to identification of homologous sequences

Why Study Homology

• DNA & Protein Sequence Data or Gene Expression Data leads to Identification of Genes & Proteins that provide Functional Prediction
• Prediction of function is based on a prediction of homology using sequences of known function

Similarity & Homology

• Homology:
  • Statement of common ancestry
  • Homologous sequences have a shared evolutionary origin
  • Qualitative statement that sequences either are or are not descendant from a common ancestor
• Similarity:
  • Measure of degree of 'likeness' between sequences regardless of their evolutionary origin
  • Quantitative measure that Sequences can vary in their similarity along a continuous scale from 0% - 100%
• Similarity ≠ Homology
• Similarity & Homology are often incorrectly interchangeable

Homology and Similarity

• Sequences can diverge from a common ancestor but no longer have functional or even sequence similarity, Genetic divergence is proportional to time since common ancestry
• Similarity can suggest homology but does not confirm it
• Sequences can be similar but not homologous due to chance or convergent evolution

Homology without Similarity

• PA clan of Proteases, Proteases of mixed nucleophile, superfamily A has:
  • Over 23 families distributed among plants, animals, fungi, eubacteria, archaea, & viruses
  • Common ancestry inferred by structural homology
  • Two perpendicular B-barrels held together with hydrophobic residues
  • All perform nucleophilic catalysis with same catalytic triad motif
    • Some families use serine as the nucleophile
    • Other families use cysteine as the nucleophile
  • No clear sequence similarity (often less than 10% identity)

Similarity without Homology

• Serine and cysteine proteases are:
  • Found in over 20 distinct enzyme superfamilies
  • Same geometric arrangement of the triad of catalytic residues
  • Have different structural fold
  • Each superfamily is the result of convergent evolution

Homologous Genes

• Homologous Genes share a common ancestor.
• Orthologous Genes:
  • Related through a speciation event
  • Typically, share highest relative degree of sequence similarity
  • Typically, most similar in function
• Paralogous Genes:
  • Related through a gene duplication event
  • Found in same organism (in-paralogs) or different organisms (out-paralogs)
  • Often members of multigene families

Gene Duplication & Protein Function

• Diversification of a duplicated gene can produce new functions
• Possible fates include:
  • Redundancy
  • Non-functionalization
  • Sub-functionalization, partitioning of ancestral function
  • Neo-functionalization, gain of novel function

Homology: orthology vs. paralogy

• Orthologous genes are assumed to have similar functions
• Distinguishing orthology from paralogy
  • Similarity
  • Synteny
  • Phylogeny
  • Gene expression
  • Functional work

Homology: orthology vs. paralogy: Similarity

• BLAST - Basic Local Alignment Search Tool
• Identifies database sequences with SIMILARITY to a query sequence

Homology Prediction via Phylogenetics

• MutS homologs in humans & yeast
• Mismatch repair & chromosome segregation
• Red represents mismatch repair
• Blue represents chromosome segregation