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Integrating Sequence Evolution into Probabilistic Orthology Analysis
Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Stockholm University, Science for Life Laboratory (SciLifeLab).
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Number of Authors: 5
2015 (English)In: Systematic Biology, ISSN 1063-5157, E-ISSN 1076-836X, Vol. 64, no 6, 969-982 p.Article in journal (Refereed) Published
Abstract [en]

Orthology analysis, that is, finding out whether a pair of homologous genes are orthologs - stemming from a speciation - or paralogs - stemming from a gene duplication - is of central importance in computational biology, genome annotation, and phylogenetic inference. In particular, an orthologous relationship makes functional equivalence of the two genes highly likely. A major approach to orthology analysis is to reconcile a gene tree to the corresponding species tree, (most commonly performed using the most parsimonious reconciliation, MPR). However, most such phylogenetic orthology methods infer the gene tree without considering the constraints implied by the species tree and, perhaps even more importantly, only allow the gene sequences to influence the orthology analysis through the a priori reconstructed gene tree. We propose a sound, comprehensive Bayesian Markov chain Monte Carlo-based method, DLRSOrthology, to compute orthology probabilities. It efficiently sums over the possible gene trees and jointly takes into account the current gene tree, all possible reconciliations to the species tree, and the, typically strong, signal conveyed by the sequences. We compare our method with PrIME-GEM, a probabilistic orthology approach built on a probabilistic duplication-loss model, and MRBAYESMPR, a probabilistic orthology approach that is based on conventional Bayesian inference coupled with MPR. We find that DLRSOrthology outperforms these competing approaches on synthetic data as well as on biological data sets and is robust to incomplete taxon sampling artifacts.

Place, publisher, year, edition, pages
2015. Vol. 64, no 6, 969-982 p.
Keyword [en]
Comparative genomics, gene duplication, gene loss, orthology, paralogy, phylogenetics, probabilistic modeling, relaxed molecular clock, sequence evolution, tree realization, tree reconciliation
National Category
Biological Sciences Computer Science
Research subject
Computer Science
Identifiers
URN: urn:nbn:se:su:diva-123513DOI: 10.1093/sysbio/syv044ISI: 000363168100007OAI: oai:DiVA.org:su-123513DiVA: diva2:875005
Available from: 2015-11-30 Created: 2015-11-27 Last updated: 2015-11-30Bibliographically approved
In thesis
1. Reconciling gene family evolution and species evolution
Open this publication in new window or tab >>Reconciling gene family evolution and species evolution
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Species evolution can often be adequately described with a phylogenetic tree. Interestingly, this is the case also for the evolution of homologous genes; a gene in an ancestral species may – through gene duplication, gene loss, lateral gene transfer (LGT), and speciation events – give rise to a gene family distributed across contemporaneous species. However, molecular sequence evolution and genetic recombination make the history – the gene tree – non-trivial to reconstruct from present-day sequences. This history is of biological interest, e.g., for inferring potential functional equivalences of extant gene pairs.

In this thesis, we present biologically sound probabilistic models for gene family evolution guided by species evolution – effectively yielding a gene-species tree reconciliation. Using Bayesian Markov-chain Monte Carlo (MCMC) inference techniques, we show that by taking advantage of the information provided by the species tree, our methods achieve more reliable gene tree estimates than traditional species tree-uninformed approaches.

Specifically, we describe a comprehensive model that accounts for gene duplication, gene loss, a relaxed molecular clock, and sequence evolution, and we show that the method performs admirably on synthetic and biological data. Further-more, we present two expansions of the inference procedure, enabling it to pro-vide (i) refined gene tree estimates with timed duplications, and (ii) probabilistic orthology estimates – i.e., that the origin of a pair of extant genes is a speciation.

Finally, we present a substantial development of the model to account also for LGT. A sophisticated algorithmic framework of dynamic programming and numerical methods for differential equations is used to resolve the computational hurdles that LGT brings about. We apply the method on two bacterial datasets where LGT is believed to be prominent, in order to estimate genome-wide LGT and duplication rates. We further show that traditional methods – in which gene trees are reconstructed and reconciled with the species tree in separate stages – are prone to yield inferior gene tree estimates that will overestimate the number of LGT events.

Abstract [sv]

Arters evolution kan i många fall beskrivas med ett träd, vilket redan Darwins anteckningsböcker från HMS Beagle vittnar om. Detta gäller också homologa gener; en gen i en ancestral art kan – genom genduplikationer, genförluster, lateral gentransfer (LGT) och artbildningar – ge upphov till en genfamilj spridd över samtida arter. Att från sekvenser från nu levande arter rekonstruera genfamiljens framväxt – genträdet – är icke-trivialt på grund av genetisk rekombination och sekvensevolution. Genträdet är emellertid av biologiskt intresse, i synnerhet för att det möjliggör antaganden om funktionellt släktskap mellan nutida genpar.

Denna avhandling behandlar biologiskt välgrundade sannolikhetsmodeller för genfamiljsevolution. Dessa modeller tar hjälp av artevolutionens starka inverkan på genfamiljens historia, och ger väsentligen upphov till en förlikning av genträd och artträd. Genom Bayesiansk inferens baserad på Markov-chain Monte Carlo (MCMC) visar vi att våra metoder presterar bättre genträdsskattningar än traditionella ansatser som inte tar artträdet i beaktning.

Mer specifikt beskriver vi en modell som omfattar genduplikationer, genförluster, en relaxerad molekylär klocka, samt sekvensevolution, och visar att metoden ger högkvalitativa skattningar på både syntetiska och biologiska data. Vidare presenterar vi två utvidgningar av detta ramverk som möjliggör (i) genträdsskattningar med tidpunkter för duplikationer, samt (ii) probabilistiska ortologiskattningar – d.v.s. att två nutida gener härstammar från en artbildning.

Slutligen presenterar vi en modell som inkluderar LGT utöver ovan nämnda mekanismer. De beräkningsmässiga svårigheter som LGT ger upphov till löses med ett intrikat ramverk av dynamisk programmering och numeriska metoder för differentialekvationer. Vi tillämpar metoden för att skatta LGT- och duplikationsraten hos två bakteriella dataset där LGT förmodas ha spelat en central roll. Vi visar också att traditionella metoder – där genträd skattas och förlikas med artträdet i separata steg – tenderar att ge sämre genträdsskattningar, och därmed överskatta antalet LGT-händelser.

Place, publisher, year, edition, pages
Stockholm: Numerical Analysis and Computer Science (NADA), Stockholm University, 2013. 59 p.
Keyword
Computational biology, Bioinformatics, Phylogenetics, Phylogenomics, Comparative genomics, Evolutionary biology
National Category
Computer Science
Research subject
Computer Science
Identifiers
urn:nbn:se:su:diva-93346 (URN)978-91-7447-760-3 (ISBN)
Public defence
2013-11-04, Inghesalen, Widerströmska huset, Karolinska Institutet, Tomtebodavägen 18, Solna, 13:30 (English)
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Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 5: Manuscript.

Available from: 2013-10-13 Created: 2013-09-09 Last updated: 2015-11-30Bibliographically approved

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