CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Brief Introduction to the Theory of Evolution Anders Gorm Pedersen Molecular Evolution Group Center for Biological.

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Brief Introduction to the Theory of Evolution Anders Gorm Pedersen Molecular Evolution Group Center for Biological Sequence Analysis gorm@cbs.dtu.dk

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Classification: Linnaeus Carl Linnaeus 1707-1778

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Classification: Linnaeus Hierarchical systemHierarchical system –Kingdom –Phylum –Class –Order –Family –Genus –Species

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Classification depicted as a tree

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Classification depicted as a tree SpeciesGenusFamilyOrderClass

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Theory of evolution Charles Darwin 1809-1882

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Phylogenetic basis of systematics Linnaeus:Linnaeus: Ordering principle is God. Darwin:Darwin: Ordering principle is shared descent from common ancestors. Today, systematics is explicitly based on phylogeny.Today, systematics is explicitly based on phylogeny.

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Darwin’s four postulates More young are produced each generation than can survive to reproduce.More young are produced each generation than can survive to reproduce. Individuals in a population vary in their characteristics.Individuals in a population vary in their characteristics. Some differences among individuals are based on genetic differences.Some differences among individuals are based on genetic differences. Individuals with favorable characteristics have higher rates of survival and reproduction.Individuals with favorable characteristics have higher rates of survival and reproduction. Evolution by means of natural selectionEvolution by means of natural selection Presence of ”design-like” features in organisms:Presence of ”design-like” features in organisms: quite often features are there “for a reason”quite often features are there “for a reason”

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Theory of evolution as the basis of biological understanding ”Nothing in biology makes sense, except in the light of evolution. Without that light it becomes a pile of sundry facts - some of them interesting or curious but making no meaningful picture as a whole” T. Dobzhansky

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Phylogenetic Reconstruction: Distance Matrix Methods Anders Gorm Pedersen Molecular Evolution Group Center for Biological Sequence Analysis Technical University of Denmark gorm@cbs.dtu.dk

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Trees: terminology

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Trees: representations Three different representations of the same tree

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Trees: rooted vs. unrooted A rooted tree has a single node (the root) that represents a point in time that is earlier than any other node in the tree. A rooted tree has directionality (nodes can be ordered in terms of “earlier” or “later”). In the rooted tree, distance between two nodes is represented along the time-axis only (the second axis just helps spread out the leafs) EarlyLate

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Trees: rooted vs. unrooted In unrooted trees there is no directionality: we do not know if a node is earlier or later than another nodeIn unrooted trees there is no directionality: we do not know if a node is earlier or later than another node Distance along branches directly represents node distanceDistance along branches directly represents node distance

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Reconstructing a tree using non- contemporaneous data

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Reconstructing a tree using present-day data

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Molecular phylogeny A A G C G T T G G G C A A B A G C G T T T G G C A A C A G C T T T G T G C A A D A G C T T T T T G C A A 1 2 3 1 2 3 DNA and protein sequencesDNA and protein sequences Homologous characters inferred from alignment.Homologous characters inferred from alignment. Other molecular data: absence/presence of restriction sites, DNA hybridization data, antibody cross-reactivity, etc. (but losing importance due to cheap, efficient sequencing).Other molecular data: absence/presence of restriction sites, DNA hybridization data, antibody cross-reactivity, etc. (but losing importance due to cheap, efficient sequencing).

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Morphology vs. molecular data African white-backed vulture (old world vulture) Andean condor (new world vulture) New and old world vultures seem to be closely related based on morphology. Molecular data indicates that old world vultures are related to birds of prey (falcons, hawks, etc.) while new world vultures are more closely related to storks Similar features presumably the result of convergent evolution

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Molecular data: single-celled organisms Molecular data useful for analyzing single-celled organisms (which have only few prominent morphological features).

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Distance Matrix Methods 1.Construct multiple alignment of sequences 2.Construct table listing all pairwise differences (distance matrix) 3.Construct tree from pairwise distances Gorilla : ACGTCGTA Human : ACGTTCCT Chimpanzee: ACGTTTCG GoHuCh Go-44 Hu-2 Ch- Go Hu Ch 2 1 1 1

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Finding Optimal Branch Lengths S1S1S1S1 S2S2S2S2 S3S3S3S3 S4S4S4S4 S1S1S1S1- D 12 D 13 D 14 S2S2S2S2- D 23 D 24 S3S3S3S3- D 34 S4S4S4S4- Observed distance S1 S3 S2 S4 a b c d e Distance along tree D 12  d 12 = a + b + c D 13  d 13 = a + d D 14  d 14 = a + b + e D 23  d 23 = d + b + c D 24  d 24 = c + e D 34  d 34 = d + b + e Goal:

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Exercise (handout) Construct distance matrix (count different positions)Construct distance matrix (count different positions) Reconstruct tree and find best set of branch lengthsReconstruct tree and find best set of branch lengths

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Optimal Branch Lengths: Least Squares Fit between given tree and observed distances can be expressed as “sum of squared differences”:Fit between given tree and observed distances can be expressed as “sum of squared differences”: Q =  (D ij - d ij ) 2 Q =  (D ij - d ij ) 2 Find branch lengths that minimize Q - this is the optimal set of branch lengths for this tree.Find branch lengths that minimize Q - this is the optimal set of branch lengths for this tree. S1 S3 S2 S4 a b c d e Distance along tree D 12  d 12 = a + b + c D 13  d 13 = a + d D 14  d 14 = a + b + e D 23  d 23 = d + b + c D 24  d 24 = c + e D 34  d 34 = d + b + e Goal: j>i

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Optimal Branch Lengths: Least Squares Longer distances associated with larger errorsLonger distances associated with larger errors Squared deviation may be weighted so longer branches contribute less to Q:Squared deviation may be weighted so longer branches contribute less to Q: Q =  (D ij - d ij ) 2 Q =  (D ij - d ij ) 2 Power (n) is typically 1 or 2 S1 S3 S2 S4 a b c d e Distance along tree D 12  d 12 = a + b + c D 13  d 13 = a + d D 14  d 14 = a + b + e D 23  d 23 = d + b + c D 24  d 24 = c + e D 34  d 34 = d + b + e Goal: D ij n

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Least Squares Optimality Criterion Search through all (or many) tree topologiesSearch through all (or many) tree topologies For each investigated tree, find best branch lengths using least squares criterionFor each investigated tree, find best branch lengths using least squares criterion Among all investigated trees, the best tree is the one with the smallest sum of squared errors.Among all investigated trees, the best tree is the one with the smallest sum of squared errors. Least squares criterion used both for finding branch lengths on individual trees, and for finding best tree.Least squares criterion used both for finding branch lengths on individual trees, and for finding best tree.

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Minimum Evolution Optimality Criterion Search through all (or many) tree topologiesSearch through all (or many) tree topologies For each investigated tree, find best branch lengths using least squares criterionFor each investigated tree, find best branch lengths using least squares criterion Among all investigated trees, the best tree is the one with the smallest sum of branch lengths (the shortest tree).Among all investigated trees, the best tree is the one with the smallest sum of branch lengths (the shortest tree). Least squares criterion used for finding branch lengths on individual trees, minimum tree length used for finding best tree.Least squares criterion used for finding branch lengths on individual trees, minimum tree length used for finding best tree.

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS How many unrooted trees are there? There is only one way of con- structing the first tree. This tree has 3 tips and 3 branchesThere is only one way of con- structing the first tree. This tree has 3 tips and 3 branches Each time an extra taxon is added, two branches are created.Each time an extra taxon is added, two branches are created. A tree with n tips will therefore have the following number of branches:A tree with n tips will therefore have the following number of branches: n branches = 3+(n-3)*2 = 3+2n-6 = 2n-3 A B C A B C D

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS How many unrooted trees are there? A tree with n tips has 2n-3 branchesA tree with n tips has 2n-3 branches For each tree with n tips, we can therefore construct 2n-3 derived trees (with n+1 tips).For each tree with n tips, we can therefore construct 2n-3 derived trees (with n+1 tips). The number of unrooted trees with n+1 tips is therefore:The number of unrooted trees with n+1 tips is therefore:  (2i-3) = 1 x 3 x 5 x 7 x... i=2 n

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Exhaustive search impossible for large data sets No. taxa No. trees 31 43 515 6105 7945 810,395 9135,135 102,027,025 1134,459,425 12654,729,075 1313,749,310,575 14316,234,143,225 157,905,853,580,625

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Heuristic search 1. Construct initial tree; determine sum of squares 2. Construct set of “neighboring trees” by making small rearrangements of initial tree; determine sum of squares for each neighbor 3. If any of the neighboring trees are better than the initial tree, then select it/them and use as starting point for new round of rearrangements. (Possibly several neighbors are equally good) 4. Repeat steps 2+3 until you have found a tree that is better than all of its neighbors. 5. This tree is a “local optimum” (not necessarily a global optimum!)

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Heuristic search: hill-climbing

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Heuristic search: local vs. global optimum

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Types of rearrangement I: nearest neighbor interchange (NNI) Original tree Two neighbors per internal branch: tree with n tips has 2(n-3) neighbors (For example, a tree with 20 tips has 34 neighbbors)

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Types of rearrangement II: subtree pruning and regrafting (SPR)

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Types of rearrangement III: tree bisection and reconnection (TBR)

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Clustering Algorithms Starting point: Distance matrixStarting point: Distance matrix Cluster least different pair of sequences:Cluster least different pair of sequences: –Tree: pair connected to common ancestral node, compute branch lengths from ancestral node to both descendants –Distance matrix: combine two entries into one. Compute new distance matrix, by finding distance from new node to all other nodes Repeat until all nodes are linkedRepeat until all nodes are linked Results in only one tree, there is no measure of tree-goodness.Results in only one tree, there is no measure of tree-goodness.

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm For each tip compute u i =  j D ij /(n-2)For each tip compute u i =  j D ij /(n-2) (this is essentially the average distance to all other tips, except the denominator is n-2 instead of n) Find the pair of tips, i and j, where D ij -u i -u j is smallestFind the pair of tips, i and j, where D ij -u i -u j is smallest Connect the tips i and j, forming a new ancestral node. The branch lengths from the ancestral node to i and j are:Connect the tips i and j, forming a new ancestral node. The branch lengths from the ancestral node to i and j are: v i = 0.5 D ij + 0.5 (u i -u j ) v j = 0.5 D ij + 0.5 (u j -u i ) Update the distance matrix: Compute distance between new node and each remaining tip as follows:Update the distance matrix: Compute distance between new node and each remaining tip as follows: D ij,k = (D ik +D jk -D ij )/2 Replace tips i and j by the new node which is now treated as a tipReplace tips i and j by the new node which is now treated as a tip Repeat until only two nodes remain.Repeat until only two nodes remain.

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Superimposed Substitutions Actual number ofActual number of evolutionary events:5 Observed number ofObserved number of differences:2 Distance is (almost) always underestimatedDistance is (almost) always underestimated ACGGTGC C T GCGGTGA

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Model-based correction for superimposed substitutions Goal: try to infer the real number of evolutionary events (the real distance) based onGoal: try to infer the real number of evolutionary events (the real distance) based on 1. Observed data (sequence alignment) 2. A model of how evolution occurs

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Jukes and Cantor Model Four nucleotides assumed to be equally frequent (f=0.25)Four nucleotides assumed to be equally frequent (f=0.25) All 12 substitution rates assumed to be equalAll 12 substitution rates assumed to be equal Under this model the corrected distance is:Under this model the corrected distance is: D JC = -0.75 x ln(1-1.33 x D OBS ) For instance:For instance: D OBS =0.43 => D JC =0.64 ACGT A -3     C    G    T   

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Other models of evolution

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm For each tip compute u i =  j D ij /(n-2)For each tip compute u i =  j D ij /(n-2) (this is essentially the average distance to all other tips, except the denominator is n-2 instead of n) Find the pair of tips, i and j, where D ij -u i -u j is smallestFind the pair of tips, i and j, where D ij -u i -u j is smallest Connect the tips i and j, forming a new ancestral node. The branch lengths from the ancestral node to i and j are:Connect the tips i and j, forming a new ancestral node. The branch lengths from the ancestral node to i and j are: v i = 0.5 D ij + 0.5 (u i -u j ) v j = 0.5 D ij + 0.5 (u j -u i ) Update the distance matrix: Compute distance between new node and each remaining tip as follows:Update the distance matrix: Compute distance between new node and each remaining tip as follows: D ij,k = (D ik +D jk -D ij )/2 Replace tips i and j by the new node which is now treated as a tipReplace tips i and j by the new node which is now treated as a tip Repeat until only two nodes remain.Repeat until only two nodes remain.

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm ABCD A-172127 B-1218 C-14 D-

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm ABCD A-172127 B-1218 C-14 D- i uiuiuiuiA(17+21+27)/2=32.5 B(17+12+18)/2=23.5 C(21+12+14)/2=23.5 D(27+18+14)/2=29.5

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm ABCD A-172127 B-1218 C-14 D- i uiuiuiuiA(17+21+27)/2=32.5 B(17+12+18)/2=23.5 C(21+12+14)/2=23.5 D(27+18+14)/2=29.5 ABCDA--39-35-35 B--35-35 C--39 D- D ij -u i -u j

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm ABCD A-172127 B-1218 C-14 D- i uiuiuiuiA(17+21+27)/2=32.5 B(17+12+18)/2=23.5 C(21+12+14)/2=23.5 D(27+18+14)/2=29.5 ABCDA--39-35-35 B--35-35 C--39 D- D ij -u i -u j C D X

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm ABCD A-172127 B-1218 C-14 D- i uiuiuiuiA(17+21+27)/2=32.5 B(17+12+18)/2=23.5 C(21+12+14)/2=23.5 D(27+18+14)/2=29.5 ABCDA--39-35-35 B--35-35 C--39 D- D ij -u i -u j C D v C = 0.5 x 14 + 0.5 x (23.5-29.5) = 4 v D = 0.5 x 14 + 0.5 x (29.5-23.5) = 10 4 10 X

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm ABCDX A-172127 B-1218 C-14 D- X- C D 4 10 X

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm ABCDX A-172127 B-1218 C-14 D- X- C D 4 10 X D XA = (D CA + D DA - D CD )/2 = (21 + 27 - 14)/2 = 17 D XB = (D CB + D DB - D CD )/2 = (12 + 18 - 14)/2 = 8

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm ABCDX A-17212717 B-12188 C-14 D- X- C D 4 10 X D XA = (D CA + D DA - D CD )/2 = (21 + 27 - 14)/2 = 17 D XB = (D CB + D DB - D CD )/2 = (12 + 18 - 14)/2 = 8

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm ABX A-1717 B-8 X- C D 4 10 X D XA = (D CA + D DA - D CD )/2 = (21 + 27 - 14)/2 = 17 D XB = (D CB + D DB - D CD )/2 = (12 + 18 - 14)/2 = 8

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm ABX A-1717 B-8 X- C D 4 10 Xi uiuiuiuiA (17+17)/1 = 34 B (17+8)/1 = 25 X

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm ABX A-1717 B-8 X- C D 4 10 XABXA--42-28 B--28 X- D ij -u i -u ji uiuiuiuiA (17+17)/1 = 34 B (17+8)/1 = 25 X

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm ABX A-1717 B-8 X- C D 4 10 X D ij -u i -u jABXA- -42 -28 B--28 X- i uiuiuiuiA (17+17)/1 = 34 B (17+8)/1 = 25 X

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm ABX A-1717 B-8 X- C D 4 10 X D ij -u i -u jABXA- -42 -28 B--28 X- i uiuiuiuiA (17+17)/1 = 34 B (17+8)/1 = 25 X v A = 0.5 x 17 + 0.5 x (34-25) = 13 v D = 0.5 x 17 + 0.5 x (25-34) = 4 A B Y 4 13

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm ABXY A-1717 B-8 X- Y C D 4 10 X A B Y 4 13

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm ABXY A-1717 B-8 X-4 Y C D 4 10 X A B Y 4 13 D YX = (D AX + D BX - D AB )/2 = (17 + 8 - 17)/2 = 4

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm XY X-4 Y- C D 4 10 X A B Y 4 13 D YX = (D AX + D BX - D AB )/2 = (17 + 8 - 17)/2 = 4

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm XY X-4 Y- C D 4 10 A B 4 13 4 D YX = (D AX + D BX - D AB )/2 = (17 + 8 - 17)/2 = 4

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Neighbor Joining Algorithm C D A B ABCD A-172127 B-1218 C-14 D- 10 4 13 4 4

CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Brief Introduction to the Theory of Evolution Anders Gorm Pedersen Molecular Evolution Group Center for Biological.

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CENTER FOR BIOLOGICAL SEQUENCE ANALYSIS Brief Introduction to the Theory of Evolution Anders Gorm Pedersen Molecular Evolution Group Center for Biological.

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