Short Primer on Comparative Genomics Today: Special guest lecture 12pm, Alway M108 Comparative genomics of animals and plants Adam Siepel Assistant Professor of Biological Statistics and Computational Biology Cornell University

Evolution at the DNA level …ACGGTGCAGTTACCA… …AC----CAGTCCACCA… Mutation SEQUENCE EDITS REARRANGEMENTS Deletion Inversion Translocation Duplication

Orthology and Paralogy HB Human WB Worm HA1 Human HA2 Human Yeast WA Worm Orthologs: Derived by speciation Paralogs: Everything else Orthologs: Derived by speciation Paralogs: Everything else

Orthology, Paralogy, Inparalogs, Outparalogs

Synteny maps Comparison of human and mouse

Synteny maps

Building synteny maps Recommended local aligners BLASTZ  Most accurate, especially for genes  Chains local alignments WU-BLAST  Good tradeoff of efficiency/sensitivity  Best command-line options BLAT  Fast, less sensitive  Good for comparing very similar sequences finding rough homology map

Index-based local alignment Dictionary: All words of length k (~10) Alignment initiated between words of alignment score  T (typically T = k) Alignment: Ungapped extensions until score below statistical threshold Output: All local alignments with score > statistical threshold …… query DB query scan Question: Using an idea from overlap detection, better way to find all local alignments between two genomes?

Local Alignments

After chaining

Chaining local alignments 1.Find local alignments 2.Chain -O(NlogN) L.I.S. 3.Restricted DP

Progressive Alignment When evolutionary tree is known:  Align closest first, in the order of the tree  In each step, align two sequences x, y, or profiles p x, p y, to generate a new alignment with associated profile p result Weighted version:  Tree edges have weights, proportional to the divergence in that edge  New profile is a weighted average of two old profiles x w y z

Threaded Blockset Aligner Human–Cow HMR – CD Restricted Area Profile Alignment

Reconstructing the Ancestral Mammalian Genome Human: C Baboon: C Cat: C Dog: G C C or G G

Neutral Substitution Rates

Finding Conserved Elements (1) Binomial method  25-bp window in the human genome  Binomial distribution of k matches in N bases given the neutral probability of substitution

Finding Conserved Elements (2) Parsimony Method  Count minimum # of mutations explaining each column  Assign a probability to this parsimony score given neutral model  Multiply probabilities across 25-bp window of human genome A C A A G

Finding Conserved Elements

Finding Conserved Elements (3) GERP

Phylo HMMs HMM Phylogenetic Tree Model Phylo HMM

Finding Conserved Elements (3)

How do the methods agree/disagree?

Statistical Power to Detect Constraint L N C: cutoff # mutations D: neutral mutation rate  : constraint mutation rate relative to neutral

Statistical Power to Detect Constraint L N C: cutoff # mutations D: neutral mutation rate  : constraint mutation rate relative to neutral