ismb tutorial: computational methods for comparative

Phylogenomictreeconstruction

ISMBTutorial:Computationalmethodsforcomparativeregulatorygenomics

Lecture3SiavashMirarab

[email protected]

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mailto:[email protected]

Topicsinthislecture

• Phylogenomics:premiseandchallenges

• Speciestreesversusgenetrees

• Causesfordiscordance

• Phylogeneticinferencedespitediscordance

• Questions

• Models

• Methodchoices

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Phylogeny

OrangutanGorilla ChimpanzeeHuman

Phylogeny

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Treeoflife

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

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

Treeoflife

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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

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5

ACTGCACACCG ACTGCCCCCG AATGCCCCCG CTGCACACGGOrangutanGorilla ChimpanzeeHuman

PhylogeneticreconstructionfromDNA

5


CTGCACACCGCTGCACACCG

CTGCACACGG


5

Orangutan

Gorilla

ChimpanzeeHuman

ACTGCACACCG

ACTGC-CCCCG

AATGC-CCCCG

-CTGCACACGG

D



CTGCACACGG


5

Orangutan

Gorilla

ChimpanzeeHuman

ACTGCACACCG

ACTGC-CCCCG

AATGC-CCCCG

-CTGCACACGG

D TP (D|T )

Orangutan

Gorilla

Chimpanzee

Human



CTGCACACGG


5

Orangutan

Gorilla

ChimpanzeeHuman

ACTGCACACCG

ACTGC-CCCCG

AATGC-CCCCG

-CTGCACACGG

D TP (D|T )

Orangutan

Gorilla

Chimpanzee

Human



CTGCACACGG

statistical support

81%


Phylogenomics:promise

6

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

Human

81%

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

more data ⟶ better inference

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Phylogenomics: onlyafewyearslater

Genetreediscordance

Orang.Gorilla ChimpHuman Orang.Gorilla Chimp Human

gene1000gene 1

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Genetreediscordance

OrangutanGorilla ChimpHuman

The species tree

A gene treeOrang.Gorilla ChimpHuman Orang.Gorilla Chimp Human

gene1000gene 1

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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

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Geneduplicationandloss

• Insomespecies(e.g.plants)geneduplicationandlossisrampant.

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

http://evolution-textbook.org



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





• 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

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[Degnan & Rosenberg, 2009]

Hybridization

• Aviablespeciesiscreatedasaresultsofhybridizationbetweentwodifferentspecies

– Thecontributionoftheparentspeciestothenewspeciesneednotbeequal.

• Atreeisnotsufficient;networksneeded

• Whatdoesaspeciesevenmean?

– 17differentdefinitions…amatterofgreatdebate

– Speciesdelineationisanactiveareaofresearch

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

Tracing alleles through generations

IncompleteLineageSorting(ILS)

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

• Omnipresent:

• Possible for every gene tree

• Likely for short branches or large population sizes

Tracing alleles through generations

IncompleteLineageSorting(ILS)

Phylogeneticinferencedespitediscordance

Genetreediscordancehastobeaccountedfor.

Howso?

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Sofar…

welearnedvariousreasonsfordiscordance.

Fourmainquestionsinphylogenomics

• Reconciliation:

• Mapagiven(i.e.,known)genetreeontoaspeciestree

• Explainshowagenetreeevolvedinsidethespeciestree

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• Reconciliation:



• Inferthespeciestreegivenacollectionofknown(orinferred)genetrees

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• Reconciliation:




• Inferagenetreegivenaknownspeciestreeandsequencedataforthatgene(a.k.atreefixing)

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• Reconciliation:





• Co-estimategenetreesandthespeciestreegiventhesequencedataforacollectionofgenes

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• Reconciliation:





• Co-estimategenetreesandthespeciestreegiventhesequencedataforacollectionofgenes

• …andothers…

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Approachestophylogenomicsinference

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

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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



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

Model-based A. Designagenerativemodelofgenetreeevolution

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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

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• Duploss:typicallymodeledusingbirthdeathprocesses,requiringarateofbirthanddeath(oftenfixed)

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

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• Modelsofcombinedeffectsalsoexist

• DTLSR,DLCoal,ODT,Hybridization+ILS

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• Modelsofcombinedeffectsalsoexist

• DTLSR,DLCoal,ODT,Hybridization+ILS

• Caution:inferenceundermanyofthesemodelsisdifficult

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Summary-basedmethods

• Useexpectationsunderastatisticalmodelbutavoidcomputingthelikelihood

• Oftenarestatisticallyconsistentundersomemodelofgenetreeevolution

• Oftenbasedonsummarystatisticsordistancemeasures

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Summary-basedmethods

• Useexpectationsunderastatisticalmodelbutavoidcomputingthelikelihood

• Oftenarestatisticallyconsistentundersomemodelofgenetreeevolution

• Oftenbasedonsummarystatisticsordistancemeasures

• Usuallyworkintwosteps:

• Genetreesareindependentlyinferredfromsequencedata

• Genetreesarecombinedtobuildthespeciestree

• Let’sseeanexample…

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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)

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Orang.

Gorilla Chimp

HumanOrang.

GorillaChimp

Human

Orang.

Gorilla

Chimp

Human

θ2=15% θ3=15%θ1=70%Gorilla

Orang.

Chimp

Human

d=0.8

The most frequent gene tree = The most likely species tree

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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)

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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


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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

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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 ) =

mX

1

|Q(T ) \Q(ti)|

MaximumQuartetSupportSpeciesTree

• Optimization problem:

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

23

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

1

|Q(T ) \Q(ti)|

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

• Solve the Maximum Quartet Support problem exactly using dynamic programming

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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

24

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

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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,…

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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

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Whatdoyouchoose?

• Whatcause(s)ofdiscordancedoyoubelievetobeprevalent?

• Doyouneedtoworryaboutduplicationandloss?

• Orperhapsyouhavearelativelyreliablewayoffindingorthology?Maybeusingwholegenomealignments.

• Doyouexpecthybridization,geneflow,orHGTforyourtaxa?

• IsILSlikelytobepresent?

• shortinternalbranches

• veryhighpopulationsizes

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Whatdoyouchoose?

• Statisticalnoisecannotbeignored

�28[Jarvis, et al., Science, 2014]

medianmean

0

5%

10%

15%

20%

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

bran

ches

(per

cent

age)

Whatdoyouchoose?

• Statisticalnoisecannotbeignored

• Inferringgenetreesfromshortsequencesisoftenerror-prone

• Tree-fixingmethodsmayhelp

• Co-estimationislesspronetogenetreeestimationerror

�28[Jarvis, et al., Science, 2014]

medianmean

0

5%

10%

15%

20%

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

bran

ches

(per

cent

age)

Whatdoyouchoose?

• Whatisthedatasetsize?

• Methodsdiffervastlyintermsofscalability

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

• Slower:statisticalmodels,especiallywhenconsideringmultiplecausesofdiscordance

• Slowest:co-estimation

• Notallapproachesareimplementedinanoptimizedmanner

• Somemethodsareeasiertoparallelizethanothers

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Takeawaymessages

• Causesofgenetreediscordancearevariedandcanco-exist

• Inferenceunderdiscordanceisanongoingareaofresearch

• Datasetsizematters!

• Thinkingaboutuncertaintyanderrorisimportant

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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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https://doi.org/10.2307/2413694

https://doi.org/10.1016/j.tree.2009.01.009

https://doi.org/10.1093/bib/bbr045

https://doi.org/10.1093/sysbio/syu048

ismb tutorial: computational methods for comparative

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