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1.  Loss and Recovery of Genetic Diversity in Adapting Populations of HIV 
PLoS Genetics  2014;10(1):e1004000.
The evolution of drug resistance in HIV occurs by the fixation of specific, well-known, drug-resistance mutations, but the underlying population genetic processes are not well understood. By analyzing within-patient longitudinal sequence data, we make four observations that shed a light on the underlying processes and allow us to infer the short-term effective population size of the viral population in a patient. Our first observation is that the evolution of drug resistance usually occurs by the fixation of one drug-resistance mutation at a time, as opposed to several changes simultaneously. Second, we find that these fixation events are accompanied by a reduction in genetic diversity in the region surrounding the fixed drug-resistance mutation, due to the hitchhiking effect. Third, we observe that the fixation of drug-resistance mutations involves both hard and soft selective sweeps. In a hard sweep, a resistance mutation arises in a single viral particle and drives all linked mutations with it when it spreads in the viral population, which dramatically reduces genetic diversity. On the other hand, in a soft sweep, a resistance mutation occurs multiple times on different genetic backgrounds, and the reduction of diversity is weak. Using the frequency of occurrence of hard and soft sweeps we estimate the effective population size of HIV to be ( confidence interval ). This number is much lower than the actual number of infected cells, but much larger than previous population size estimates based on synonymous diversity. We propose several explanations for the observed discrepancies. Finally, our fourth observation is that genetic diversity at non-synonymous sites recovers to its pre-fixation value within 18 months, whereas diversity at synonymous sites remains depressed after this time period. These results improve our understanding of HIV evolution and have potential implications for treatment strategies.
Author Summary
It is well known that HIV can evolve to become drug resistant if it acquires specific drug-resistance mutations, but the underlying population genetic processes are not well understood. We found that the evolution of drug resistance in HIV populations within infected patients occurs by one mutation at a time (as opposed to multiple mutations simultaneously) and involves both hard and soft sweeps. In a hard sweep, a mutation originates in a single viral particle and then spreads to the entire viral population within the patient. As this mutation increases in frequency, other mutations linked to it hitchhike to high frequencies, which greatly reduces genetic diversity in the population. In a soft sweep, on the other hand, the same resistance mutation originates multiple times on different genetic backgrounds, and hitchhiking may have very little or no effect on diversity. The fact that drug resistance evolves by means of both hard and soft sweeps implies that the HIV populations are limited by the supply of resistance mutations. Using the frequency of hard and soft sweeps we obtain a point estimate of 150,000 for the effective population size of the virus, a number that is much higher than estimates based on diversity at neutral (synonymous) sites, but much lower than the actual number of HIV infected cells in a human patient.
PMCID: PMC3900388  PMID: 24465214
2.  Raiders from the sky: slavemaker founding queens select for aggressive host colonies 
Biology Letters  2012;8(5):748-750.
Reciprocal selection pressures in host–parasite systems drive coevolutionary arms races that lead to advanced adaptations in both opponents. In the interactions between social parasites and their hosts, aggression is one of the major behavioural traits under selection. In a field manipulation, we aimed to disentangle the impact of slavemaking ants and nest density on aggression of Temnothorax longispinosus ants. An early slavemaker mating flight provided us with the unique opportunity to study the influence of host aggression and demography on founding decisions and success. We discovered that parasite queens avoided colony foundation in parasitized areas and were able to capture more brood from less aggressive host colonies. Host colony aggression remained consistent over the two-month experiment, but did not respond to our manipulation. However, as one-fifth of all host colonies were successfully invaded by parasite queens, slavemaker nest foundation acts as a strong selection event selecting for high aggression in host colonies.
PMCID: PMC3441009  PMID: 22809720
parasite; personality; dispersal; aggression; fitness
3.  HIV-1 Transmission Networks in a Small World 
The Journal of Infectious Diseases  2013;209(2):180-182.
PMCID: PMC3873789  PMID: 24151310
HIV; phylogeny; transmission; network
4.  HIV Drug Resistance: Problems and Perspectives 
Infectious Disease Reports  2013;5(Suppl 1):e5.
Access to combination antiretroviral treatment (ART) has improved greatly over recent years. At the end of 2011, more than eight million HIV-infected people were receiving ART in low-income and middle-income countries. ART generally works well in keeping the virus suppressed and the patient healthy. However, treatment only works as long as the virus is not resistant against the drugs used. In the last decades, HIV treatments have become better and better at slowing down the evolution of drug resistance, so that some patients are treated for many years without having any resistance problems. However, for some patients, especially in low-income countries, drug resistance is still a serious threat to their health. This essay will review what is known about transmitted and acquired drug resistance, multi-class drug resistance, resistance to newer drugs, resistance due to treatment for the prevention of mother-to-child transmission, the role of minority variants (low-frequency drug-resistance mutations), and resistance due to pre-exposure prophylaxis.
PMCID: PMC3892620  PMID: 24470969
HIV; drug resistance; resistance; antiviral therapy; antiretroviral treatment
5.  Standing Genetic Variation and the Evolution of Drug Resistance in HIV 
PLoS Computational Biology  2012;8(6):e1002527.
Drug resistance remains a major problem for the treatment of HIV. Resistance can occur due to mutations that were present before treatment starts or due to mutations that occur during treatment. The relative importance of these two sources is unknown. Resistance can also be transmitted between patients, but this process is not considered in the current study. We study three different situations in which HIV drug resistance may evolve: starting triple-drug therapy, treatment with a single dose of nevirapine and interruption of treatment. For each of these three cases good data are available from literature, which allows us to estimate the probability that resistance evolves from standing genetic variation. Depending on the treatment we find probabilities of the evolution of drug resistance due to standing genetic variation between and . For patients who start triple-drug combination therapy, we find that drug resistance evolves from standing genetic variation in approximately 6% of the patients. We use a population-dynamic and population-genetic model to understand the observations and to estimate important evolutionary parameters under the assumption that treatment failure is caused by the fixation of a single drug resistance mutation. We find that both the effective population size of the virus before treatment, and the fitness of the resistant mutant during treatment, are key-parameters which determine the probability that resistance evolves from standing genetic variation. Importantly, clinical data indicate that both of these parameters can be manipulated by the kind of treatment that is used.
Author Summary
For HIV patients who are treated with antiretroviral drugs, treatment usually works well. However, the virus can, and sometimes does, become resistant against one or more drugs. HIV drug resistance results from the acquisition of specific and well known mutations. It is currently unknown whether drug resistance mutations usually stem from standing genetic variation, i.e., they were already present at low frequency before treatment started, or whether they tend to occur during treatment. In the current manuscript, I make use of several large datasets and evolutionary modeling to estimate the probability that drug resistance mutations are present before treatment starts and lead to viral failure. I find that for the most common type of treatment with a combination of three drugs, drug resistance evolves from pre-existing mutations in 6% of the patients. With other types of treatment, this probability varies from 0 to 39%. I conclude that there is room for improvement in preventing the evolution of drug resistance from pre-existing mutations.
PMCID: PMC3369920  PMID: 22685388
6.  Increased host aggression as an induced defense against slave-making ants 
Behavioral Ecology  2011;22(2):255-260.
Slave-making ants reduce the fitness of surrounding host colonies through regular raids, causing the loss of brood and frequently queen and worker death. Consequently, hosts developed defenses against slave raids such as specific recognition and aggression toward social parasites, and indeed, we show that host ants react more aggressively toward slavemakers than toward nonparasitic competitors. Permanent behavioral defenses can be costly, and if social parasite impact varies in time and space, inducible defenses, which are only expressed after slavemaker detection, can be adaptive. We demonstrate for the first time an induced defense against slave-making ants: Cues from the slavemaker Protomognathus americanus caused an unspecific but long-lasting behavioral response in Temnothorax host ants. A 5-min within-nest encounter with a dead slavemaker raised the aggression level in T. longispinosus host colonies. Contrarily, encounters with nonparasitic competitors did not elicit aggressive responses toward non-nestmates. Increased aggression can be adaptive if a slavemaker encounter reliably indicates a forthcoming attack and if aggression increases postraid survival. Host aggression was elevated over 3 days, showing the ability of host ants to remember parasite encounters. The response disappeared after 2 weeks, possibly because by then the benefits of increased aggression counterbalance potential costs associated with it.
PMCID: PMC3071747  PMID: 22476194
aggression; behavior; parasites; phenotypic plasticity; social insects
7.  Association of orthodenticle with Natural Variation for Early Embryonic Patterning in Drosophila melanogaster 
Although it is well established that cis-acting regulatory variation contributes to morphological evolution between species, few concrete examples of polymorphism affecting developmental patterning within species have been demonstrated. Early embryogenesis in Drosophila is initiated by a gradient of Bicoid morphogen activity that results in differential expression of multiple target genes. In a screen for genetic variation affecting this process, we surveyed 96 wild-type lines of Drosophila melanogaster for polymorphisms in binding sites within 16 Bicoid cis-regulatory response elements. One common polymorphism in the orthodenticle (otd) early head enhancer is associated with a complex series of indels/substitutions that define two distinct haplotypes. The middle region of this enhancer exhibits an unusual pattern of nucleotide diversity that does not easily fit into standard models of selection and demography. Population Gene Expression Maps, generated by extracting binary expression profiles from normalized embryo images, revealed a ventral reduction of otd transcript abundance in one of the haplotypes that was recapitulated in expression of transgenic constructs containing the two alleles. We thus demonstrate that even a process as robust as early developmental patterning is affected by standing genetic variation, intriguingly involving otd, whose morphogenetic function bicoid is thought to have displaced during dipteran evolution.
PMCID: PMC2784951  PMID: 19488993
8.  Soft Sweeps III: The Signature of Positive Selection from Recurrent Mutation 
PLoS Genetics  2006;2(12):e186.
Polymorphism data can be used to identify loci at which a beneficial allele has recently gone to fixation, given that an accurate description of the signature of selection is available. In the classical model that is used, a favored allele derives from a single mutational origin. This ignores the fact that beneficial alleles can enter a population recurrently by mutation during the selective phase. In this study, we present a combination of analytical and simulation results to demonstrate the effect of adaptation from recurrent mutation on summary statistics for polymorphism data from a linked neutral locus. We also analyze the power of standard neutrality tests based on the frequency spectrum or on linkage disequilibrium (LD) under this scenario. For recurrent beneficial mutation at biologically realistic rates, we find substantial deviations from the classical pattern of a selective sweep from a single new mutation. Deviations from neutrality in the level of polymorphism and in the frequency spectrum are much less pronounced than in the classical sweep pattern. In contrast, for levels of LD, the signature is even stronger if recurrent beneficial mutation plays a role. We suggest a variant of existing LD tests that increases their power to detect this signature.
Populations adapt to their environment through fixation of beneficial alleles. Such fixation events leave a signature in neutral DNA variation of the population. An accurate description of this signature, also called a selective sweep, can be used to identify genes that have been involved in recent adaptations. The classical model of a selective sweep assumes that the beneficial allele was created only once by mutation, whereas the authors have shown, in a previous paper, that this assumption does not always hold. If a substitution involves multiple copies of an allele that have originated by independent mutation, it leads to a different signature, which the authors call a soft selective sweep. In this study, Pennings and Hermisson use analytical tools and coalescent simulations to describe this soft-sweep pattern. They show that this pattern is characterized by strong linkage disequilibrium. They also analyze the power of standard tests of neutrality to detect this pattern and suggest a variant of existing linkage-disequilibrium–based tests that increase the power to detect positive selection in the form of a soft selective sweep.
PMCID: PMC1698945  PMID: 17173482

Results 1-8 (8)