ISMB Tutorial: Computational methods for comparative

Phylogenomictreeconstruction

ISMBTutorial:Computationalmethodsforcomparativeregulatorygenomics

Lecture3SiavashMirarab

smirarab@ucsd.edu

Topicsinthislecture

• Phylogenomics:premiseandchallenges

• Speciestreesversusgenetrees

• Causesfordiscordance

• Phylogeneticinferencedespitediscordance

• Questions

• Models

• Methodchoices

Phylogeny

OrangutanGorilla ChimpanzeeHuman

Phylogeny

Treeoflife

source: http://www.evogeneao.com/

“Nothing in biology makes sense except in the light of evolution.” Dobzhansky, 1973

Treeoflife

source: http://www.evogeneao.com/

“Nothing in biology makes sense except in the light of evolution.” Dobzhansky, 1973

“Nothing in evolution makes sense except in the light of phylogeny.” multiple coinage

Treeoflife

ACTGCACACCG ACTGCCCCCG AATGCCCCCG CTGCACACGGOrangutanGorilla ChimpanzeeHuman

PhylogeneticreconstructionfromDNA

CTGCACACCGCTGCACACCG

CTGCACACGG

Orangutan

Gorilla

ChimpanzeeHuman

ACTGCACACCG

ACTGC-CCCCG

AATGC-CCCCG

-CTGCACACGG

CTGCACACGG

Orangutan

Gorilla

ChimpanzeeHuman

ACTGCACACCG

ACTGC-CCCCG

AATGC-CCCCG

-CTGCACACGG

D TP (D|T )

Orangutan

Gorilla

Chimpanzee

CTGCACACGG

Orangutan

Gorilla

ChimpanzeeHuman

ACTGCACACCG

ACTGC-CCCCG

AATGC-CCCCG

-CTGCACACGG

D TP (D|T )

Orangutan

Gorilla

Chimpanzee

CTGCACACGG

statistical support

Phylogenomics:promise

gene 999gene 2ACTGCACACCG ACTGC-CCCCG AATGC-CCCCG -CTGCACACGG

CTGAGCATCG CTGAGC-TCG ATGAGC-TC- CTGA-CAC-G

AGCAGCATCGTG AGCAGC-TCGTG AGCAGC-TC-TG C-TA-CACGGTG

CAGGCACGCACGAA AGC-CACGC-CATA ATGGCACGC-C-TA AGCTAC-CACGGAT

gene 1000gene 1

Data (#genes)

Species tree error

Orangutan

Gorilla

Chimpanzee

“gene” here simply means a (recombination-free) parts of the genome

more data ⟶ better inference

Phylogenomics:promise

gene 999gene 2ACTGCACACCG ACTGC-CCCCG AATGC-CCCCG -CTGCACACGG

gene 1000gene 1

Data (#genes)

Species tree error

Orangutan

Gorilla

Chimpanzee

“gene” here simply means a (recombination-free) parts of the genome

more data ⟶ better inference

Phylogenomics: onlyafewyearslater

Genetreediscordance

Orang.Gorilla ChimpHuman Orang.Gorilla Chimp Human

gene1000gene 1

Genetreediscordance

OrangutanGorilla ChimpHuman

The species tree

A gene treeOrang.Gorilla ChimpHuman Orang.Gorilla Chimp Human

gene1000gene 1

Genetreediscordance

The species tree

A gene treeOrang.Gorilla ChimpHuman Orang.Gorilla Chimp Human

Causes of gene tree discordance include:– Duplication and loss – Horizontal Gene Transfer (HGT) and Hybridization – Incomplete Lineage Sorting (ILS)

gene1000gene 1

Geneduplicationandloss

• Insomespecies(e.g.plants)geneduplicationandlossisrampant.

picture from evolution-textbook.org (Fig 5-20), redrawn from Eisen, Genome Research, 1998�9

• RecallfromColin’stalk:Paralogs:genesthatdivergedinaduplicationevent;e.g:2Aand3BOrthologs:genesthatdivergedinaspeciationevent;e.g:1Band3B

• Agenetreethatincludesparalogousgenesmaydifferfromthespeciestree

– Westriveforfindingorthologousgenes,butwemayfail

HorizontalGeneTransfer(HGT)

• Horizontalgenetransfer:anorganismpicksupDNAfromanotherorganismortheenvironmentratherfromitsancestors

• Itmayreplaceasimilargenepresentinthetargetormaycreateanewcopy

• Rampantinprokaryotes;observedinplantsandothereukaryotes

�10[Degnan & Rosenberg, 2009]

HorizontalGeneTransfer(HGT)

• Horizontalgenetransfer:anorganismpicksupDNAfromanotherorganismortheenvironmentratherfromitsancestors

• Itmayreplaceasimilargenepresentinthetargetormaycreateanewcopy

• Rampantinprokaryotes;observedinplantsandothereukaryotes

• Atreemaybeinsufficient.Aphylogeneticnetworkmaybeneeded.

�10[Degnan & Rosenberg, 2009]

[Degnan & Rosenberg, 2009]

Hybridization

• Aviablespeciesiscreatedasaresultsofhybridizationbetweentwodifferentspecies

– Thecontributionoftheparentspeciestothenewspeciesneednotbeequal.

• Atreeisnotsufficient;networksneeded

[Degnan & Rosenberg, 2009]

Hybridization

• Aviablespeciesiscreatedasaresultsofhybridizationbetweentwodifferentspecies

– Thecontributionoftheparentspeciestothenewspeciesneednotbeequal.

• Atreeisnotsufficient;networksneeded

• Whatdoesaspeciesevenmean?

– 17differentdefinitions…amatterofgreatdebate

– Speciesdelineationisanactiveareaofresearch

• A random process related to the coalescence of alleles across various populations

Tracing alleles through generations

IncompleteLineageSorting(ILS)

• Omnipresent:

• Possible for every gene tree

• Likely for short branches or large population sizes

Phylogeneticinferencedespitediscordance

Genetreediscordancehastobeaccountedfor.

Howso?

Sofar…

welearnedvariousreasonsfordiscordance.

Fourmainquestionsinphylogenomics

• Reconciliation:

• Mapagiven(i.e.,known)genetreeontoaspeciestree

• Explainshowagenetreeevolvedinsidethespeciestree

• Reconciliation:

• Inferthespeciestreegivenacollectionofknown(orinferred)genetrees

• Reconciliation:

• Inferagenetreegivenaknownspeciestreeandsequencedataforthatgene(a.k.atreefixing)

• Reconciliation:

• Co-estimategenetreesandthespeciestreegiventhesequencedataforacollectionofgenes

• Reconciliation:

• Co-estimategenetreesandthespeciestreegiventhesequencedataforacollectionofgenes

• …andothers…

Approachestophylogenomicsinference

A. Parsimony-basedB. Model-basedC. Summary-based

Parsimony-based

• Describediscordancesbetweengenetreesandthespeciestreeusingtheminimumnumberof“events”

• Events:Duplications,losses,transfers,deepcoalescences

• Reliesheavilyonfast(lineartime)parsimoniousreconciliationbetweengenetreesandthespeciestree

FigurefromDoyonetal.,BriefingsinBioinformatics,2011doi:10.1093/bib/bbr045�16

Parsimony-based

• Describediscordancesbetweengenetreesandthespeciestreeusingtheminimumnumberof“events”

• Events:Duplications,losses,transfers,deepcoalescences

• Reliesheavilyonfast(lineartime)parsimoniousreconciliationbetweengenetreesandthespeciestree

FigurefromDoyonetal.,BriefingsinBioinformatics,2011doi:10.1093/bib/bbr045�16

Orang.GorillaChimp

Human Orang.Gorilla ChimpHuman

Orang.Gorilla

ChimpHuman

Orang.Chimp Human

ACTGCACACCG ACTGC-CCCCG AATGC-CCCCG -CTGCACACGG

Model-based A. Designagenerativemodelofgenetreeevolution

Gene tree

Sequence data(Alignments)

Gene tree Gene tree Gene tree

Gene evolution model

Sequence evolution model P(D |G)

P(G |S)

Orang.GorillaChimp

Human Orang.Gorilla ChimpHuman

Orang.Gorilla

ChimpHuman

Orang.Chimp Human

ACTGCACACCG ACTGC-CCCCG AATGC-CCCCG -CTGCACACGG

CAGGCACGCACGAA AGC-CACGC-CATA ATGGCACGC-C-TA AGCTAC-CACGGAT 18

Gene tree

Gene tree Gene tree Gene tree

Gene evolution model

Sequence evolution model P(D |G)

P(G |S)

B. MLorBayesianinferenceunderthemodel

Model-based

Modelsofgenetreeevolution

• ILS:modeledbytheMulti-SpeciesCoalescentmodel(MSC):anextensionoftheKingman’scoalescenttomultiplespecies

• Duploss:typicallymodeledusingbirthdeathprocesses,requiringarateofbirthanddeath(oftenfixed)

• HGT,geneflow/hybridization:thespeciesphylogenyismodeledasanetwork(DAG)andgenetreesarestochasticallyembeddedinthenetwork.

• Modelsofcombinedeffectsalsoexist

• DTLSR,DLCoal,ODT,Hybridization+ILS

• Modelsofcombinedeffectsalsoexist

• DTLSR,DLCoal,ODT,Hybridization+ILS

• Caution:inferenceundermanyofthesemodelsisdifficult

Summary-basedmethods

• Useexpectationsunderastatisticalmodelbutavoidcomputingthelikelihood

• Oftenarestatisticallyconsistentundersomemodelofgenetreeevolution

• Oftenbasedonsummarystatisticsordistancemeasures

Summary-basedmethods

• Useexpectationsunderastatisticalmodelbutavoidcomputingthelikelihood

• Oftenarestatisticallyconsistentundersomemodelofgenetreeevolution

• Oftenbasedonsummarystatisticsordistancemeasures

• Usuallyworkintwosteps:

• Genetreesareindependentlyinferredfromsequencedata

• Genetreesarecombinedtobuildthespeciestree

• Let’sseeanexample…

UnderMSCmodelofILS

For a quartet (4 species), the unrooted species tree topology has at least 1/3 probability of appearing in gene trees (Allman, et al. 2010)

Orang.

Gorilla Chimp

HumanOrang.

GorillaChimp

Orang.

Gorilla

θ2=15% θ3=15%θ1=70%Gorilla

Orang.

The most frequent gene tree = The most likely species tree

Orang.Gorilla ChimpHuman Rhesus

Morethan4species

For >4 species, the species tree topology can be different from the most like gene tree (called anomaly zone) (Degnan, 2013)

1. Break gene trees into (n 4 ) quartets of species

2. Find the dominant tree for all quartets of taxa

3. Combine quartet trees

Some tools (e.g.. BUCKy-p [Larget, et al., 2010])

Morethan4species

1. Break gene trees into (n 4 ) quartets of species

2. Find the dominant tree for all quartets of taxa

3. Combine quartet trees

Some tools (e.g.. BUCKy-p [Larget, et al., 2010])

Morethan4species

Alternative:

Weight all 3(n 4 ) quartet topologies by

their frequency and find the optimal tree

MaximumQuartetSupportSpeciesTree

• Optimization problem:

• Theorem: Statistically consistent under the multi-species coalescent model when solved exactly

Find the species tree with the maximum number of induced quartet trees shared with the collection of input gene trees

the set of quartet trees induced by T

a gene treeScore(T ) =

|Q(T ) \Q(ti)|

MaximumQuartetSupportSpeciesTree

• Optimization problem:

• Theorem: Statistically consistent under the multi-species coalescent model when solved exactly

Find the species tree with the maximum number of induced quartet trees shared with the collection of input gene trees

the set of quartet trees induced by T

a gene tree

NP-Hard [Lafond & Scornavaccaori, 2016]

Score(T ) =mX

|Q(T ) \Q(ti)|

[Mirarab, et al., Bioinformatics, 2014] [Mirarab and Warnow, Bioinformatics, 2015]

• Solve the Maximum Quartet Support problem exactly using dynamic programming

ASTRAL

• Constrains the search space to make large datasets feasible

• The constrained version remains statistically consistent

• Running time of constrained version increases polynomially with the input size

ASTRAL

• Constrains the search space to make large datasets feasible

• The constrained version remains statistically consistent

• Running time of constrained version increases polynomially with the input size

• Is adopted widely for incomplete lineage sorting 24

ASTRAL

Sofar…

Threeapproaches:A. Parsimony-basedB. Model-basedC. Summary-based

FourQuestions:A. ReconciliationB. SpeciestreeinferenceC. GenetreeinferenceD. Co-estimation

Threetypesofdiscordance:A. DuplicationandlossesB. HGT&HybridizationC. ILS

*Eachcapturedbymanystatisticalmodels

Manymanytools

• Speciestreeinference

• ILS:ASTRAL,STAR,MP-EST,GLASS,NJst/ASTRID,DISTIQUE,STELLS,…

• Duploss:DupTree,iGTP,DynaDup,MulRF,…

• Hybridization:Phylonet,PhyloNetworks,SNaQ,…

• Agnostic:Bucky,MRP,MRL,guenomu,…

• Genetreecorrection

• TreeFix,Giga,RefineTree,SPIDIR,SPIMAP,PrIME-GSR,SYNERGY,ALE,ODT(seealsoEnsemblCompara)

• Reconciliation

• Notung,DLCoalRecon,PrIME,Phylonet,TreeMap,Korak,CoRe-Pa,Jane,Mowgli,AnGST,…

• Co-estimation

• PHYLDOG,*BEAST,BEST,BBCA,PhyloNet,…

Manymanytools

• Speciestreeinference

• ILS:ASTRAL,STAR,MP-EST,GLASS,NJst/ASTRID,DISTIQUE,STELLS,…

• Duploss:DupTree,iGTP,DynaDup,MulRF,…

• Hybridization:Phylonet,PhyloNetworks,SNaQ,…

• Agnostic:Bucky,MRP,MRL,guenomu,…

• Genetreecorrection

• TreeFix,Giga,RefineTree,SPIDIR,SPIMAP,PrIME-GSR,SYNERGY,ALE,ODT(seealsoEnsemblCompara)

• Reconciliation

• Notung,DLCoalRecon,PrIME,Phylonet,TreeMap,Korak,CoRe-Pa,Jane,Mowgli,AnGST,…

• Co-estimation

• PHYLDOG,*BEAST,BEST,BBCA,PhyloNet,…

Noscalablespecies/genetreeinferencemethodcancurrentlyaddressallcausesofdiscordance

Whatdoyouchoose?

• Whatcause(s)ofdiscordancedoyoubelievetobeprevalent?

• Doyouneedtoworryaboutduplicationandloss?

• Orperhapsyouhavearelativelyreliablewayoffindingorthology?Maybeusingwholegenomealignments.

• Doyouexpecthybridization,geneflow,orHGTforyourtaxa?

• IsILSlikelytobepresent?

• shortinternalbranches

• veryhighpopulationsizes

Whatdoyouchoose?

• Statisticalnoisecannotbeignored

�28[Jarvis, et al., Science, 2014]

medianmean

0% 25% 50% 75% 100%branch bootstrap support

Whatdoyouchoose?

• Statisticalnoisecannotbeignored

• Inferringgenetreesfromshortsequencesisoftenerror-prone

• Tree-fixingmethodsmayhelp

• Co-estimationislesspronetogenetreeestimationerror

�28[Jarvis, et al., Science, 2014]

medianmean

0% 25% 50% 75% 100%branch bootstrap support

Whatdoyouchoose?

• Whatisthedatasetsize?

• Methodsdiffervastlyintermsofscalability

• Fast/scalable:parsimony-basedandsummarymethods(+MLgenetrees)

• Slower:statisticalmodels,especiallywhenconsideringmultiplecausesofdiscordance

• Slowest:co-estimation

• Notallapproachesareimplementedinanoptimizedmanner

• Somemethodsareeasiertoparallelizethanothers

Takeawaymessages

• Causesofgenetreediscordancearevariedandcanco-exist

• Inferenceunderdiscordanceisanongoingareaofresearch

• Datasetsizematters!

• Thinkingaboutuncertaintyanderrorisimportant

Reference

• Maddison, Wayne P. “Gene Trees in Species Trees.” Systematic Biology 46, no. 3 (September 1, 1997): 523–36. https://doi.org/10.2307/2413694.

• Degnan, James H., and Noah A. Rosenberg. “Gene Tree Discordance, Phylogenetic Inference and the Multispecies Coalescent.” Trends in Ecology and Evolution 24, no. 6 (June 1, 2009): 332–40. https://doi.org/10.1016/j.tree.2009.01.009.

• Doyon, J.-P. JP, Vincent Ranwez, Vincent Daubin, and V. Berry. “Models, Algorithms and Programs for Phylogeny Reconciliation.” Briefings in Bioinformatics 12, no. 5 (September 22, 2011): 392–400. https://doi.org/10.1093/bib/bbr045.

• Szöllõsi, G J, E Tannier, Vincent Daubin, and Bastien Boussau. “The Inference of Gene Trees with Species Trees.” Systematic Biology 64, no. 1 (July 28, 2014): e42–62. https://doi.org/10.1093/sysbio/syu048.

• Warnow, Tandy. Computational phylogenetics: An introduction to designing methods for phylogeny estimation. Cambridge University Press, 2017.

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