497A Lecture 6 & 7 - 1/28/11 Lectures 6 & 7 The...

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1/28/11 1 Lectures 6 & 7 The Mechanisms of Viral Evolution II The Quasispecies Useful summary references: • Holmes book (as ever ) • Bull JJ, Meyers LA & Lachmann M. (2005). Quasispecies made simple. PLoS Comp.Biol . 1 :e61. The Quasispecies Idea introduced by Manfred Eigen as a mathematical model of early life forms (RNA replicators) based upon chemical kinetics and first used in virology by Esteban Domingo in the 1970s. Now the dominant model in RNA virus evolution. • A distribution of variant genomes ordered around the fittest sequence (often called the ‘master sequence’) and produced by a combination of mutation and selection (“mutation-selection” balance). Only functions at high mutation rates . • Only considers intra-host evolution.
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1/28/11 2 • The frequency of any variant in the quasispecies is a function of its own replication rate and the probability that it is produced by the erroneous replication of other variants in the population. • Viral genomes are not independent entities due to mutational coupling (i.e. variants are linked in mutational space). The entire mutant distribution forms an organised structure which acts like (quasi) a single unit (species). • Natural selection acts on the mutant distribution as a whole, not on individual variants, and the quasispecies evolves to maximise its average replication fitness . Important implication : low fitness variants can out- compete high fitness variants if they are surrounded by beneficial mutational neighbours (“survival of the flattest”). The Quasispecies The Quasispecies ‘survival of the fittest’ ‘survival of the flattest’ “Survival of the Flattest” (also called “mutational robustness”) • Wilke CO, Wang JL, Ofria C, Lenski RE & Adami C. (2001). Evolution of digital organisms at high mutation rates leads to survival of the flattest. Nature 412 , 331-333.
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1/28/11 3 “Survival of the Flattest” Population A = red (high replication rate, low robustness) Population B = blue (low replication rate, high robustness) (a) (b) Experimental Verification of Quasispecies Dynamics • Sanjuán R, Cuevas JM, Furió V, Holmes EC & Moya A. (2007). Selection for robustness in mutagenized RNA viruses. PLoS Genet. 3 : e93. • However, this only occurs at artificially elevated mutation rates • Most people simply use the quasispecies as a synonym for genetic diversity. However, genetic diversity is not the same as the quasispecies! • The quasispecies works in theory, in “digital organisms” (AVIDA) and perhaps in some laboratory populations where mutation rates are increased artificially (i.e. when RNA viruses are about to breech the “error threshold”). However, quasispecies do not occur in laboratory populations with ‘normal’ error rates. • No good evidence as yet that RNA viruses in nature form quasispecies: - no evidence that selection acts on the whole population - mutation rates are too low • The mutation rate required for the survival of the flattest (> 2 per genome replication) is higher than that seen in nature (< 1 per genome replication) this only occurs during the treatment of viral infections with mutagens (“lethal mutagenesis”).
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This note was uploaded on 05/03/2011 for the course BIOL 497A taught by Professor Eddieholmes during the Spring '08 term at Pennsylvania State University, University Park.

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497A Lecture 6 &amp;amp; 7 - 1/28/11 Lectures 6 &amp; 7 The...

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