A biophysical protein folding model accounts for most mutational fitness effects in viruses

Proceedings of the National Academy of Sciences of the United States of America
Christopher S Wylie, Eugene I Shakhnovich


Fitness effects of mutations fall on a continuum ranging from lethal to deleterious to beneficial. The distribution of fitness effects (DFE) among random mutations is an essential component of every evolutionary model and a mathematical portrait of robustness. Recent experiments on five viral species all revealed a characteristic bimodal-shaped DFE featuring peaks at neutrality and lethality. However, the phenotypic causes underlying observed fitness effects are still unknown and presumably, are thought to vary unpredictably from one mutation to another. By combining population genetics simulations with a simple biophysical protein folding model, we show that protein thermodynamic stability accounts for a large fraction of observed mutational effects. We assume that moderately destabilizing mutations inflict a fitness penalty proportional to the reduction in folded protein, which depends continuously on folding free energy (ΔG). Most mutations in our model affect fitness by altering ΔG, whereas based on simple estimates, ~10% abolish activity and are unconditionally lethal. Mutations pushing ΔG > 0 are also considered lethal. Contrary to neutral network theory, we find that, in mutation/selection/drift steady state, high mutati...Continue Reading


Jul 5, 1974·Journal of Molecular Biology·P L Privalov, N N Khechinashvili
Aug 18, 1999·Proceedings of the National Academy of Sciences of the United States of America·E van NimwegenM Huynen
Sep 15, 1999·Proceedings of the National Academy of Sciences of the United States of America·Erich Bornberg-Bauer, Hue Sun Chan
Aug 11, 2001·Bulletin of Mathematical Biology·Claus O Wilke
Dec 18, 2001·Proteins·Darin M Taverna, Richard A Goldstein
May 25, 2002·Nature·Mario A FaresEladio Barrio
Jul 30, 2002·Journal of Molecular Biology·Beth M Beadle, Brian K Shoichet
Jan 11, 2003·Proceedings of the National Academy of Sciences of the United States of America·Roeland C H J van HamAndrés Moya
Oct 25, 2003·Evolution; International Journal of Organic Evolution·J Arjan G M de VisserMichael C Whitlock
May 26, 2004·Proceedings of the National Academy of Sciences of the United States of America·Rafael SanjuánSantiago F Elena
Jan 13, 2005·Proceedings of the National Academy of Sciences of the United States of America·Jesse D BloomFrances H Arnold
Mar 2, 2005·Nature Reviews. Molecular Cell Biology·H Jane Dyson, Peter E Wright
Aug 3, 2005·Nature Reviews. Genetics·Mark A DepristoDaniel L Hartl
Nov 8, 2005·Nature Genetics·Sophie Maisnier-PatinDan I Andersson
Dec 31, 2005·Nucleic Acids Research·M D Shaji KumarAkinori Sarai
Feb 3, 2006·EMBO Reports·Santiago F ElenaRafael Sanjuán
Apr 8, 2006·Science·Daniel M WeinreichDaniel L Hartl
Nov 18, 2006·Genetics·Jesse D BloomClaus O Wilke
May 8, 2007·Journal of Molecular Biology·Nobuhiko TokurikiDan S Tawfik
Jun 19, 2007·PLoS Genetics·Rafael SanjuánAndrés Moya
Jul 20, 2007·Nature Reviews. Genetics·Adam Eyre-Walker, Peter D Keightley
Sep 28, 2007·Journal of Virology·Purificación CarrascoSantiago F Elena
Oct 5, 2007·Proceedings of the National Academy of Sciences of the United States of America·Konstantin B ZeldovichEugene I Shakhnovich
Aug 30, 2008·Proceedings of the National Academy of Sciences of the United States of America·Ville MustonenMichael Lässig
Dec 9, 2008·Trends in Biochemical Sciences·Nobuhiko TokurikiDan S Tawfik
Jan 24, 2009·Proceedings of the National Academy of Sciences of the United States of America·Muyoung HeoEugene I Shakhnovich
May 9, 2009·The New Phytologist·John Z Kiss
Jul 22, 2009·Genetics·Peiqiu Chen, Eugene I Shakhnovich
Dec 4, 2009·PLoS Genetics·Pilar Domingo-CalapRafael Sanjuán
May 19, 2010·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Rafael Sanjuán
Jul 17, 2010·Nature Reviews. Genetics·Misha Soskine, Dan S Tawfik


Aug 29, 2012·Proceedings of the National Academy of Sciences of the United States of America·Tobias SikosekErich Bornberg-Bauer
Mar 14, 2012·Proceedings of the National Academy of Sciences of the United States of America·Shimon BershteinEugene I Shakhnovich
Jul 24, 2013·Proceedings of the National Academy of Sciences of the United States of America·Hervé JacquierOlivier Tenaillon
Nov 2, 2012·Proceedings of the National Academy of Sciences of the United States of America·Michael Lynch
Sep 29, 2011·Genome Biology and Evolution·Benjamin A Wilson, Joanna Masel
Feb 15, 2013·Journal of Virology·Isabel S NovellaClaus O Wilke
Dec 12, 2012·MBio·Ariel D WeinbergerEugene V Koonin
Jan 18, 2012·Journal of Molecular Microbiology and Biotechnology·Isabel GordoAna Sousa
Aug 10, 2012·PLoS Computational Biology·Christopher S Wylie, Eugene I Shakhnovich
Apr 18, 2013·PLoS Computational Biology·Purushottam D Dixit, Sergei Maslov
Nov 19, 2013·PLoS Computational Biology·Murat Cetinbaş, Eugene I Shakhnovich
Jul 5, 2013·PLoS Genetics·Marjon G J de VosSander J Tans
Jul 5, 2013·PLoS Genetics·Li JiangDaniel N Bolon
Jul 23, 2013·PloS One·Claude Loverdo, James O Lloyd-Smith
Sep 27, 2013·PloS One·María-Carmen TurrientesJuan-Carlos Galán
Sep 12, 2012·Genetics·Hiroshi AkashiTomoko Ohta
Aug 2, 2012·Genetics·Natalja Strelkowa, Michael Lässig
Feb 28, 2014·Nature·Marta Luksza, Michael Lässig
Dec 7, 2013·Molecular Biology and Evolution·Andrew J Bordner, Hans D Mittelmann
Oct 15, 2013·Molecular Biology and Evolution·Adrian W R Serohijos, Eugene I Shakhnovich
Feb 26, 2014·Molecular Biology and Evolution·Elad FirnbergMarc Ostermeier
Jun 11, 2014·Nature Reviews. Genetics·J Arjan G M de Visser, Joachim Krug
May 2, 2014·Trends in Genetics : TIG·Katja M TauteSander J Tans
Mar 13, 2012·Annual Review of Biophysics·Canan AtilganAli Rana Atilgan
Oct 31, 2014·Genome Biology and Evolution·Pouria DasmehEugene I Shakhnovich
Jan 20, 2016·Nature Reviews. Genetics·Julian EchaveClaus O Wilke
Jun 10, 2015·Proceedings of the National Academy of Sciences of the United States of America·Premal ShahJoshua B Plotkin
Oct 9, 2015·Molecular Biology and Evolution·Matteo FigliuzziMartin Weigt
Jan 8, 2015·Biophysical Journal·Luca TubianaRudolf Podgornik
Feb 28, 2015·Cell·Michael A StifflerRama Ranganathan
Apr 25, 2012·Protein Science : a Publication of the Protein Society·David A LiberlesSimon Whelan
Aug 6, 2015·Molecular Biology and Evolution·Christopher J R Illingworth
Sep 6, 2011·Theoretical Population Biology·Joanna Masel, David N Lyttle
Mar 5, 2016·Protein Science : a Publication of the Protein Society·Nicolas ChéronEugene I Shakhnovich
Dec 3, 2013·Current Opinion in Genetics & Development·Armita NourmohammadMichael Lässig
Jun 22, 2014·Current Opinion in Structural Biology·Adrian W R Serohijos, Eugene I Shakhnovich
Sep 4, 2012·Cell Reports·Adrian W R SerohijosEugene I Shakhnovich
Jul 17, 2012·Current Opinion in Virology·Susanna Manrubia
Feb 28, 2013·Biophysical Journal·Adrian W R SerohijosEugene I Shakhnovich
Dec 3, 2013·Current Opinion in Genetics & Development·Daniel M WeinreichRobert B Heckendorn
Nov 5, 2016·Current Opinion in Structural Biology·Shimon BershteinEugene I Shakhnovich
Dec 3, 2014·Current Opinion in Microbiology·Daniel L Hartl
Jan 1, 2011·Genes·Jessica Siltberg-LiberlesDavid A Liberles
Nov 12, 2017·Journal of Molecular Evolution·Devin P BendixsenEric J Hayden
Dec 21, 2017·ELife·Kristina CronaNiko Beerenwinkel
Jun 22, 2018·ELife·Michael Lynch
Mar 24, 2018·Proteins·Suvethigaa ShanthirabalanMathilde Carpentier
Jun 30, 2018·Molecular Biology and Evolution·Assaf RotemEugene I Shakhnovich
Sep 28, 2017·ELife·Angela M PhillipsMatthew D Shoulders
Jul 27, 2018·Annual Review of Virology·Patrick T DolanRaul Andino
Nov 15, 2018·Molecular Biology and Evolution·Ashley I TeufelClaus O Wilke
Feb 10, 2018·BMC Evolutionary Biology·Alexander PlattDavid A Liberles
Oct 16, 2014·Genetics·Jeffrey I BoucherDaniel N Bolon
Aug 11, 2019·Molecular Biology and Evolution·Matthew S FaberTimothy A Whitehead
Jan 23, 2020·Physical Chemistry Chemical Physics : PCCP·Celia BlancoIrene A Chen
Jun 7, 2019·Nature Communications·Torsten HeldMichael Lässig
Nov 20, 2016·Proceedings of the National Academy of Sciences of the United States of America·Claudia BankJeffrey D Jensen
Dec 28, 2016·Molecular Biology and Evolution·Peter A LindDan I Andersson
Oct 25, 2017·Nature Ecology & Evolution·Richard A Goldstein, David D Pollock
Jul 25, 2018·Proceedings of the National Academy of Sciences of the United States of America·Jakub OtwinowskiJoshua B Plotkin
Aug 31, 2019·Nature Communications·Xianghua LiBen Lehner
Aug 16, 2017·Nature Ecology & Evolution·Michael LässigAleksandra M Walczak
Aug 24, 2018·Genes·Anna PosfaiDavid M McCandlish
May 15, 2019·Annual Review of Genomics and Human Genetics·Júlia DomingoBen Lehner
Jun 10, 2020·Annual Review of Chemical and Biomolecular Engineering·Luca AgozzinoKen A Dill
Feb 24, 2015·Physical Review Letters·Imre Derényi, Gergely J Szöllősi
May 16, 2019·Annual Review of Genomics and Human Genetics·Justin B Kinney, David M McCandlish
Sep 25, 2019·Evolutionary Applications·Harry KembleOlivier Tenaillon
May 17, 2019·Protein Science : a Publication of the Protein Society·João V RodriguesEugene I Shakhnovich
Apr 27, 2019·Virus Evolution·Lei ZhaoChristopher J R Illingworth
Apr 25, 2019·PLoS Computational Biology·Shou-Wen WangNed S Wingreen
Oct 29, 2017·Proceedings of the National Academy of Sciences of the United States of America·Leyuan MaDaniel N Bolon
Feb 24, 2017·Journal of the Royal Society, Interface·Ashley I Teufel, Claus O Wilke
Jul 7, 2020·Quarterly Reviews of Biophysics·Kasper P Kepp
Oct 20, 2020·International Journal of Infectious Diseases : IJID : Official Publication of the International Society for Infectious Diseases·Anwar MohammadFahd Al-Mulla

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