scholarly journals The population genetics of drug resistance evolution in natural populations of viral, bacterial and eukaryotic pathogens

2015 ◽  
Vol 25 (1) ◽  
pp. 42-66 ◽  
Author(s):  
Benjamin A. Wilson ◽  
Nandita R. Garud ◽  
Alison F. Feder ◽  
Zoe J. Assaf ◽  
Pleuni S. Pennings
Keyword(s):  
Drug Resistance ◽  
Population Genetics ◽  
Natural Populations ◽  
Resistance Evolution

scholarly journals The clarifying role of time series data in the population genetics of HIV

PLoS Genetics ◽  
2021 ◽  
Vol 17 (1) ◽  
pp. e1009050
Author(s):  
Alison F. Feder ◽  
Pleuni S. Pennings ◽  
Dmitri A. Petrov
Keyword(s):  
Time Series ◽  
Drug Resistance ◽  
Population Genetics ◽  
Time Series Data ◽  
Series Data ◽  
Selective Sweeps ◽  
Resistance Mutations ◽  
Resistance Evolution ◽  
Drug Resistance Mutations ◽  
Traditional Population

HIV can evolve remarkably quickly in response to antiretroviral therapies and the immune system. This evolution stymies treatment effectiveness and prevents the development of an HIV vaccine. Consequently, there has been a great interest in using population genetics to disentangle the forces that govern the HIV adaptive landscape (selection, drift, mutation, and recombination). Traditional population genetics approaches look at the current state of genetic variation and infer the processes that can generate it. However, because HIV evolves rapidly, we can also sample populations repeatedly over time and watch evolution in action. In this paper, we demonstrate how time series data can bound evolutionary parameters in a way that complements and informs traditional population genetic approaches. Specifically, we focus on our recent paper (Feder et al., 2016, eLife), in which we show that, as improved HIV drugs have led to fewer patients failing therapy due to resistance evolution, less genetic diversity has been maintained following the fixation of drug resistance mutations. Because soft sweeps of multiple drug resistance mutations spreading simultaneously have been previously documented in response to the less effective HIV therapies used early in the epidemic, we interpret the maintenance of post-sweep diversity in response to poor therapies as further evidence of soft sweeps and therefore a high population mutation rate (θ) in these intra-patient HIV populations. Because improved drugs resulted in rarer resistance evolution accompanied by lower post-sweep diversity, we suggest that both observations can be explained by decreased population mutation rates and a resultant transition to hard selective sweeps. A recent paper (Harris et al., 2018, PLOS Genetics) proposed an alternative interpretation: Diversity maintenance following drug resistance evolution in response to poor therapies may have been driven by recombination during slow, hard selective sweeps of single mutations. Then, if better drugs have led to faster hard selective sweeps of resistance, recombination will have less time to rescue diversity during the sweep, recapitulating the decrease in post-sweep diversity as drugs have improved. In this paper, we use time series data to show that drug resistance evolution during ineffective treatment is very fast, providing new evidence that soft sweeps drove early HIV treatment failure.

scholarly journals The clarifying role of time series data in the population genetics of HIV

2018 ◽  
Author(s):  
Alison F Feder ◽  
Pleuni S Pennings ◽  
Dmitri A Petrov
Keyword(s):  
Time Series ◽  
Drug Resistance ◽  
Population Genetics ◽  
Time Series Data ◽  
Hiv Treatment ◽  
Series Data ◽  
Adaptive Landscape ◽  
Resistance Evolution ◽  
Hiv Drugs ◽  
Traditional Population

HIV can evolve remarkably quickly in response to anti-retroviral therapies and the immune system. This evolution stymies treatment effectiveness and prevents the development of an HIV vaccine. Consequently, there has been great interest in using population genetics to disentangle the forces that govern the HIV adaptive landscape (selection, drift, mutation, recombination). Traditional population genetics approaches look at the current state of genetic variation and infer the processes that can generate them. However, because HIV evolves rapidly, we can also sample populations repeatedly over time and watch evolution in action. In this paper, we demonstrate how time series data can bound evolutionary parameters in a way that complements and informs traditional population genetic approaches. Specifically, we focus on our recent paper (Feder et al. 2016), in which we show that, as improved HIV drugs have led to fewer patients failing therapy due to resistance evolution, less genetic diversity has been maintained following the fixation of drug resistance mutations. We interpret this as evidence that resistance to early HIV drugs that failed quickly and predictably was driven by soft sweeps while evolution of resistance to better drugs is both less frequent and when it takes place it is associated with harder sweeps due to an effectively lower HIV population mutation rate (θ). Recently, Harris et al. 2018 have proposed an alternative interpretation: the signal could be due to an increase in the selective benefit of mutations conferring resistance to better drugs. Therefore, better drugs lead to faster sweeps with less opportunity for recombination to rescue diversity. In this paper, we use time series data to show that drug resistance evolution during ineffective treatment is very fast, providing new evidence that soft sweeps drove early HIV treatment failure.

scholarly journals Drug resistance evolution in HIV in the late 1990s: hard sweeps, soft sweeps, clonal interference and the accumulation of drug resistance mutations

2019 ◽  
Author(s):  
Kadie-Ann Williams ◽  
Pleuni Pennings
Keyword(s):  
Drug Resistance ◽  
Population Genetics ◽  
Evolutionary Dynamics ◽  
Resistance Mutations ◽  
Clonal Interference ◽  
Resistance Evolution ◽  
Drug Resistance Mutations

1AbstractThe goal of this paper is to provide examples of evolutionary dynamics of HIV within patients who are treated with antiretrovirals. We hope that the figures in this paper will be used in evolution and population genetics classes. We show a wide variety of patterns, specifically: soft sweeps, hard sweeps, softening sweeps and hardening sweeps, simultaneous sweeps, accumulation of mutations and clonal interference.

scholarly journals THE EVOLUTION OF SELECTIVELY SIMILAR ELECTRO-PHORETICALLY DETECTABLE ALLELES IN FINITE NATURAL POPULATIONS

Genetics ◽  
1975 ◽  
Vol 80 (2) ◽  
pp. 375-394
Author(s):  
C F Wehrhahn
Keyword(s):  
Population Genetics ◽  
Genetic Variation ◽  
Generating Functions ◽  
Natural Populations ◽  
Net Charge ◽  
Electrophoretic Variants ◽  
Allelic State ◽  
Competing Hypotheses ◽  
State Difference ◽  
General Method

Abstract Most of the models of population genetics are not realistic when applied to data on electrophoretic variants of proteins because the same net charge may result from any of several amino acid combinations. In the absence of realistic models they have, however, been widely used to test competing hypotheses about the origin and maintenance of genetic variation in populations. In this paper I present a general method for determining probability generating functions for electrophoretic state differences. Then I use the method to find allelic state difference distributions for selectively similar electrophoretically detectable alleles in finite natural populations. Predicted patterns of genetic variation, both within and among species, are in reasonable accord with those found in the Drosophila willistoni group by Ayala et al. (1972) and by Ayala and Tracey (1974).

HIV-1 Drug Resistance Evolution Among Patients on Potent Combination Antiretroviral Therapy With Detectable Viremia

2005 ◽  
Vol 40 (1) ◽  
pp. 34-40 ◽  
Author(s):  
Sonia Napravnik ◽  
David Edwards ◽  
Paul Stewart ◽  
Brant Stalzer ◽  
Elizabeth Matteson ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antiretroviral Therapy ◽  
Combination Antiretroviral Therapy ◽  
Resistance Evolution ◽  
Hiv 1

scholarly journals Sewall Wright, 21 December 1889 - 3 March 1988

1990 ◽  
Vol 36 ◽  
pp. 567-579 ◽  
Keyword(s):  
Population Genetics ◽  
Evolutionary Biology ◽  
Natural Populations ◽  
Coat Colour ◽  
Balance Theory ◽  
Theory Of Evolution ◽  
Shifting Balance Theory ◽  
Sewall Wright ◽  
Shifting Balance ◽  
Active Research

Sewall Wright's active life spanned the development of genetics from a new discipline when the principles of inheritance were still being elucidated to the technology of recombinant gene construction and insertion. He was one of the major pioneers of population genetics, which gave a quantitative basis to the studies of evolution, of variation in natural populations and of animal and plant breeding. He contributed most significantly to methods and ideas over a long period, indeed his four volume treatise was written long after he formally ‘retired’ and his last paper (211) was published a few days before his death at the age of 98. In the field of population genetics Wright developed the method of path coefficients, which he used to analyse quantitative genetic variation and relationship, but which has been applied to subjects as diverse as economics, the ideas of inbreeding coefficient and F -statistics which form the basis of analysis of population structure, the theory of variation in gene frequency among populations, and the shifting balance theory of evolution, which remains a topic of active research and controversy. Wright contributed to physiological genetics, notably analysis of the inheritance of coat colour in the guinea pig, and in particular the epistatic relationships among the genes involved. There was a critical interplay between his population and physiological work, in that the analysis of finite populations on the one hand and of epistatic interactions on the other are the bases of Wright’s development of the shifting balance theory. A full and enlightening biography of Sewall Wright which traces his influence on evolutionary biology and his interactions with other important workers was published recently (Provine 1986) and shorter appreciations have appeared since his death, notably by Crow (1988), Wright’s long-time colleague. This biography relies heavily on Provine’s volume, and does no more than summarize Wright’s extensive contributions. Many of his important papers have been reprinted recently (1986).

scholarly journals Exploiting evolutionary trade-offs for posttreatment management of drug-resistant populations

2020 ◽  
Vol 117 (30) ◽  
pp. 17924-17931
Author(s):  
Sergey V. Melnikov ◽  
David L. Stevens ◽  
Xian Fu ◽  
Hui Si Kwok ◽  
Jin-Tao Zhang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Genetic Alterations ◽  
Trna Synthetase ◽  
Molecular Defect ◽  
Antibiotic Resistant ◽  
Resistance Evolution ◽  
Growth Defects ◽  
Trade Offs ◽  
Resistant Cells

Antibiotic resistance frequently evolves through fitness trade-offs in which the genetic alterations that confer resistance to a drug can also cause growth defects in resistant cells. Here, through experimental evolution in a microfluidics-based turbidostat, we demonstrate that antibiotic-resistant cells can be efficiently inhibited by amplifying the fitness costs associated with drug-resistance evolution. Using tavaborole-resistantEscherichia colias a model, we show that genetic mutations in leucyl-tRNA synthetase (that underlie tavaborole resistance) make resistant cells intolerant to norvaline, a chemical analog of leucine that is mistakenly used by tavaborole-resistant cells for protein synthesis. We then show that tavaborole-sensitive cells quickly outcompete tavaborole-resistant cells in the presence of norvaline due to the amplified cost of the molecular defect of tavaborole resistance. This finding illustrates that understanding molecular mechanisms of drug resistance allows us to effectively amplify even small evolutionary vulnerabilities of resistant cells to potentially enhance or enable adaptive therapies by accelerating posttreatment competition between resistant and susceptible cells.

On the evolution and population genetics of hybrid-dysgenesis-causing transposable elements in Drosophila

1986 ◽  
Vol 312 (1154) ◽  
pp. 205-215 ◽  
Keyword(s):  
Population Genetics ◽  
Natural Selection ◽  
Transposable Elements ◽  
Transposable Element ◽  
Natural Populations ◽  
Element Composition ◽  
Hybrid Dysgenesis ◽  
Evolutionary Significance ◽  
Genetic Elements ◽  
Transposable Genetic Elements

Much has been learned about transposable genetic elements in Drosophila , but questions still remain, especially concerning their evolutionary significance. Three such questions are considered here, (i) Has the behaviour of transposable elements been most influenced by natural selection at the level of the organism, the population, or the elements themselves? (ii) How did the elements originate in the genome of the species? (iii) Why are laboratory stocks different from natural populations with respect to their transposable element composition? No final answers to these questions are yet available, but by focusing on the two families of hybrid dysgenesis-causing elements, the P and I factors, we can draw some tentative conclusions.

scholarly journals Effect of drug dose and timing of treatment on the emergence of drug resistance in vivo in a malaria model

2020 ◽  
Vol 2020 (1) ◽  
pp. 196-210 ◽  
Author(s):  
Mónica M Acosta ◽  
Joshua T Bram ◽  
Derek Sim ◽  
Andrew F Read
Keyword(s):  
Drug Resistance ◽  
Drug Treatment ◽  
Drug Dose ◽  
Treatment Timing ◽  
Treatment Regimens ◽  
Resistance Evolution ◽  
Timing Of Treatment ◽  
High Level ◽  
Level Resistance

Abstract Background and objectives There is a significant interest in identifying clinically effective drug treatment regimens that minimize the de novo evolution of antimicrobial resistance in pathogen populations. However, in vivo studies that vary treatment regimens and directly measure drug resistance evolution are rare. Here, we experimentally investigate the role of drug dose and treatment timing on resistance evolution in an animal model. Methodology In a series of experiments, we measured the emergence of atovaquone-resistant mutants of Plasmodium chabaudi in laboratory mice, as a function of dose or timing of treatment (day post-infection) with the antimalarial drug atovaquone. Results The likelihood of high-level resistance emergence increased with atovaquone dose. When varying the timing of treatment, treating either very early or late in infection reduced the risk of resistance. When we varied starting inoculum, resistance was more likely at intermediate inoculum sizes, which correlated with the largest population sizes at time of treatment. Conclusions and implications (i) Higher doses do not always minimize resistance emergence and can promote the emergence of high-level resistance. (ii) Altering treatment timing affects the risk of resistance emergence, likely due to the size of the population at the time of treatment, although we did not test the effect of immunity whose influence may have been important in the case of late treatment. (iii) Finding the ‘right’ dose and ‘right’ time to maximize clinical gains and limit resistance emergence can vary depending on biological context and was non-trivial even in our simplified experiments. Lay summary In a mouse model of malaria, higher drug doses led to increases in drug resistance. The timing of drug treatment also impacted resistance emergence, likely due to the size of the population at the time of treatment.

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