Detectability of Non-Equilibrium Molecular Evolution Caused by Fitness Shift and Drift

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dc.contributor.advisorde Koning, Jason
dc.contributor.authorKazemi Mehrabadi, Mobina
dc.contributor.committeememberLong, Quan
dc.contributor.committeememberAnderson, David
dc.dateFall Convocation
dc.date.accessioned2023-02-11T00:31:59Z
dc.date.embargolift2023-02-22
dc.date.issued2022-05-17
dc.description.abstractOne of the key interests of computational molecular evolution is the inference of the strength and direction of natural selection in protein-coding genes. The non-synonymous to synonymous rate ratio (dN/dS) is widely used to evaluate the effect of natural selection on genes, lineages, and sites. When dN/dS is inferred to be greater than one along a particular branch and at a specific site, this is often taken as evidence of episodic positive selection and adaptive change in function. Despite the simplicity and widespread use of dN /dS approaches, they are funda- mentally unable to differentiate between fit and unfit states, and the stationary distributions in all widely-used approaches are (unrealistically) identical across sites. To address these short- comings, the mutation-selection framework, which is a class of codon substitution models that allows a mechanistic relationship between fitness and sequence has been proposed. Recently, due to developments in Markov-Chain Monte Carlo (MCMC) methods and penalized maximum likelihood approaches, computationally tractable models have been implemented that enable in- ference under site-heterogeneous mutation-selection models, though substantial computational barriers to using such methods on large datasets persist.Here, in my thesis, I introduce time-heterogeneous mutation-selection models as an ideal representation of how episodic adaptation occurs. Using these models, I study how true dN /dS changes over time following a wide variety of fitness shifts (when the fitness profile at a site is completely replaced with a new fitness profile) and fitness drift scenarios (when the fitness of the two most favorable states is swapped). Both simulation and direct (simulation-free) analysis are used to characterize non-equilibrium molecular evolution under time-heterogeneous mutation- selection models of codon substitution. Additionally, I evaluate the performance of existing branch-site type methods to distinguish fitness shift from a relaxation of constraints at a small number of sites. In general, I find that the more different the starting and ending fitness profiles are, the more reliably an adaptive burst is produced, which is potentially detectable using dN /dS approaches. Although all existing methods we considered in the simulation performed poorly and have very low power to detect fitness shifts, I find that covariate information that helps inform which sites might be targets of positive selection can rescue high power of dN/dS type methods to detect modest to strong fitness shifts.Our desire in this project has been to improve our understanding of non-equilibrium molecular evolution under mechanistic models of adaptive change in function and to illuminate how well relatively simple statistical approaches perform in inference tasks. I hope this body of work will broaden the horizon for more realistic, mechanistic, and tractable models of non-equilibrium molecular evolution.
dc.identifier.citationKazemi Mehrabadi, M. (2022). Detectability of Non-Equilibrium Molecular Evolution Caused by Fitness Shift and Drift (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.
dc.identifier.urihttp://hdl.handle.net/1880/115846
dc.identifier.urihttps://dx.doi.org/10.11575/PRISM/40740
dc.language.isoenen
dc.language.isoEnglish
dc.publisher.facultyGraduate Studiesen
dc.publisher.facultyCumming School of Medicine
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en
dc.subjectMolecular evolution
dc.subjectdN/dS
dc.subjectPositive selection
dc.subjectBurst of amino acid substitutions
dc.subjectBranch-site methods
dc.subjectPower estimation
dc.subjectMutation-selection model
dc.subjectPhylogenetic methods
dc.subjectEvolutionary modeling
dc.subjectProtein evolution
dc.subject.classificationBiological Sciences
dc.subject.classificationHealth Sciences--General
dc.subject.classificationChemistry--Biochemistry
dc.titleDetectability of Non-Equilibrium Molecular Evolution Caused by Fitness Shift and Drift
dc.typemaster thesis
thesis.degree.disciplineMedicine – Biochemistry and Molecular Biology
thesis.degree.grantorUniversity of Calgaryen
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameMaster of Science (MSc)
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