My paper ” HIV drug resistance: problems and perspectives”

Our next guest post is by Pleuni Pennings (@pleunipennings) on her paper HIV drug resistance: problems and perspectives arXived here, cross posted from her website here.

A few days ago, I submitted a review paper to Infectious Disease Reports. The review is an invited essay for the special issue they are planning around the World AIDS Day (December 1st).

I was pleasantly surprised to see that the author guidelines of Infectious Disease Reports said: “Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.” So, I decided to upload the manuscript to the arXiv.

The essay describes the current situation of drug resistance in HIV. The main conclusion is that, overall, drug resistance is not as big a problem as one may think. Treatments have become very good, which means that the rate of evolution of drug resistance is low. At the same time, many new drugs have become available so that when drug resistance evolves, the patient can be switched to another set of drugs. However, in poor countries, where viral genotyping, viral load monitoring and many new drugs are not available, drug resistance still poses a serious threat to people’s health.

In the essay, I explain that transmitted drug resistance occurs, but at a level that is lower than many would have expected. Roughly 10% of newly infected patients are infected with an HIV strain with at least one major drug-resistance mutation. If the virus is genotyped before treatment is started (as is standard in rich, but not in poor, countries), then treatment success is very high for these patients.

Acquired drug resistance (when resistance evolves during treatment) is more common than transmitted drug resistance, and resistance can evolve even after many years of successful treatment. It can also happen that the virus becomes resistant against multiple drugs. Nowadays, there are many different drugs available, so that even patients with multi-class drug resistance can often be treated successfully, although this is not the case in poor countries, simply because the newer drugs are expensive.

I also describe what is known about resistance due to treatment for the prevention of mother-to-child-transmission (which is a big problem) and resistance due to pre-exposure prophylaxis (which occurs, but is uncommon). I also discuss the issue of low-frequency resistance mutations and their clinical relevance. Throughout the essay, I explain how certain effects are expected or surprising from an evolutionary perspective.

I thank my collaborators Daniel Rosenbloom and Alison Hill (both at Harvard) for useful comments on an earlier version of the manuscript.

Pleuni Pennings


Membrane environment imposes unique selection pressures on transmembrane domains of G protein-coupled receptors

Membrane environment imposes unique selection pressures on transmembrane domains of G protein-coupled receptors
Stephanie J. Spielman, Claus O. Wilke
(Submitted on 25 Nov 2012)

We have investigated the influence of the plasma membrane environment on the molecular evolution of G protein-coupled receptors (GPCRs), the largest receptor family in Metazoa. In particular, we have analyzed the site-specific rate variation across the two primary structural partitions, transmembrane (TM) and extramembrane (EM), of these membrane proteins. We find that transmembrane domains evolve more slowly than do extramembrane domains, though TM domains display increased rate heterogeneity relative to their EM counterparts. Although the majority of residues across GPCRs experience strong to weak purifying selection, many GPCRs experience positive selection at both TM and EM residues, albeit with a slight bias towards the EM. Further, a subset of GPCRs, chemosensory receptors (including olfactory and taste receptors), exhibit increased rates of evolution relative to other GPCRs, an effect which is more pronounced in their TM spans. Although it has been previously suggested that the TM’s low evolutionary rate is caused by their high percentage of buried residues, we show that their attenuated rate seems to stem from the strong biophysical constraints of the membrane itself, or by functional requirements.

HIV drug resistance: problems and perspectives

HIV drug resistance: problems and perspectives
Pleuni S Pennings
(Submitted on 25 Nov 2012)

Many HIV patients now have access to combination antiretroviral treatment (ART). At the end of 2011, more than eight million people were receiving antiretroviral therapy 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.

Lateral Gene Transfer from the Dead

Lateral Gene Transfer from the Dead
Szöll\Hosi GJ, Eric Tannier, Nicolas Lartillot, Vincent Daubin
(Submitted on 19 Nov 2012)

In phylogenetic studies, the evolution of molecular sequences is assumed to have taken place along the phylogeny traced by the ancestors of extant species. In the presence of lateral gene transfer (LGT), however, this may not be the case, because the species lineage from which a gene was transferred may have gone extinct or not have been sampled. Because it is not feasible to specify or reconstruct the complete phylogeny of all species, we must describe the evolution of genes outside the represented phylogeny by modelling the speciation dynamics that gave rise to the complete phylogeny. We demonstrate that if the number of sampled species is small compared to the total number of existing species, the overwhelming majority of gene transfers involve speciation to, and evolution along extinct or unsampled lineages. We show that the evolution of genes along extinct or unsampled lineages can to good approximation be treated as those of independently evolving lineages described by a few global parameters. Using this result, we derive an algorithm to calculate the probability of a gene tree and recover the maximum likelihood reconciliation given the phylogeny of the sampled species. Examining 473 near universal gene families from 36 cyanobacteria, we find that nearly a third of transfer events — 28% — appear to have topological signatures of evolution along extinct species, but only approximately 6% of transfers trace their ancestry to before the common ancestor of the sampled cyanobacteria.

Journal policy change: Genome Research will consider preprints

We have been alerted to a change in the Genome Research author guidelines, which now read:

The journal only accepts papers that present original research that has not been published previously. Conference presentations or posting unrefereed manuscripts on not-for-profit community preprint servers will not be considered prior publication. Authors are responsible for updating the archived preprint with the journal reference (including DOI), and a link to the published article on the Genome Research website upon publication. [emphasis added]

We look forward to discussing preprints targeted for Genome Research at Haldane’s Sieve.

Correcting gene expression data when neither the unwanted variation nor the factor of interest are observed

Correcting gene expression data when neither the unwanted variation nor the factor of interest are observed
Laurent Jacob, Johann Gagnon-Bartsch, Terence P. Speed
(Submitted on 18 Nov 2012)

When dealing with large scale gene expression studies, observations are commonly contaminated by unwanted variation factors such as platforms or batches. Not taking this unwanted variation into account when analyzing the data can lead to spurious associations and to missing important signals. When the analysis is unsupervised, e.g., when the goal is to cluster the samples or to build a corrected version of the dataset – as opposed to the study of an observed factor of interest – taking unwanted variation into account can become a difficult task. The unwanted variation factors may be correlated with the unobserved factor of interest, so that correcting for the former can remove the latter if not done carefully. We show how negative control genes and replicate samples can be used to estimate unwanted variation in gene expression, and discuss how this information can be used to correct the expression data or build estimators for unsupervised problems. The proposed methods are then evaluated on three gene expression datasets. They generally manage to remove unwanted variation without losing the signal of interest and compare favorably to state of the art corrections.

Natural selection. V. How to read the fundamental equations of evolutionary change in terms of information theory

Natural selection. V. How to read the fundamental equations of evolutionary change in terms of information theory
Steven A. Frank
(Submitted on 16 Nov 2012)

The equations of evolutionary change by natural selection are commonly expressed in statistical terms. Fisher’s fundamental theorem emphasizes the variance in fitness. Quantitative genetics expresses selection with covariances and regressions. Population genetic equations depend on genetic variances. How can we read those statistical expressions with respect to the meaning of natural selection? One possibility is to relate the statistical expressions to the amount of information that populations accumulate by selection. However, the connection between selection and information theory has never been compelling. Here, I show the correct relations between statistical expressions for selection and information theory expressions for selection. Those relations link selection to the fundamental concepts of entropy and information in the theories of physics, statistics, and communication. We can now read the equations of selection in terms of their natural meaning. Selection causes populations to accumulate information about the environment.

Evolution of male life histories and age-dependent sexual signals under female choice

Evolution of male life histories and age-dependent sexual signals under female choice
Joel James Adamson
(Submitted on 16 Nov 2012)

Strategic models have predicted that males could benefit from age-dependent sexual advertisement following evolution of increased lifespan. Dynamical considerations may play a crucial role in the origin of age-dependent sexual signals, despite strategic advantages in populations with established signals and preferences. I investigated the problem that rare trait-bearing males may suffer low viability due to small young-age signals, restricting the favorable conditions for age-dependent trait evolution. I also ask when age-dependence will prevail during trait evolution if males bearing age-dependent traits co-occur with males carrying age-independent traits. I used numerical simulations to analyze the evolution of an age-structured haploid population with no genetic drift. Age-dependence limits the evolution of male traits to cases of relatively weak selection against the trait, but the trait fixes at smaller sizes when age-dependent than when age-independent. When mode of expression (age-dependence versus age-independence) evolved along with the trait, age-independence prevailed over much of parameter space, although mode of expression remained polymorphic at small trait sizes under weak selection. The ubiquity of age-dependent traits in nature shows that many species’ life-histories satisfy the conditions for age-dependent trait evolution. My results suggest that high adult male survival facilitates sexual selection by favoring the evolution of age-dependent sexual signals under fairly broad conditions.

Bacterial diversity associated with Drosophila in the laboratory and in the natural environment

Bacterial diversity associated with Drosophila in the laboratory and in the natural environment
Fabian Staubach, John F. Baines, Sven Kuenzel, Elisabeth M. Bik, Dmitri A. Petrov
(Submitted on 14 Nov 2012)

All higher organisms are associated with bacterial communities. Bacteria have a range of effects on their metazoan hosts from being indispensable for survival to being lethal pathogens. Because bacteria have phenotypic effects on their hosts, they can also be involved in host adaptation to the environment. The fruit fly Drosophila is a classic model organism to study adaptation as well as the relationship between genetic variation and phenotypes. Recently, Drosophila has received attention in immunology and studies of host-microbe interaction. Although bacterial communities associated with Drosophila might be important for many aspects of Drosophila biology, little is known about their diversity and composition or the factors shaping these communities. We used 454-based sequencing of a variable region of the bacterial 16S ribosomal gene to characterize the bacterial communities associated with wild and laboratory Drosophila isolates. In order to specifically investigate effects of food source and host species on bacterial communities, we analyzed samples from wild Drosophila melanogaster and D. simulans flies collected from a variety of natural substrates, as well as from adults and larvae of nine laboratory-reared Drosophila species. We find substantial variation of bacterial communities within and between laboratories that could interfere with phenotype studies. We show that bacterial communities associated with wild-caught Drosophila contain more bacterial species than laboratory-raised flies, but that they are on average less diverse than vertebrate communities. The natural Drosophila-associated microbiota appears to be predominantly shaped by food substrate with an additional but smaller effect of host species identity.

The genetic architecture of adaptations to high altitude in Ethiopia

The genetic architecture of adaptations to high altitude in Ethiopia

Gorka Alkorta-Aranburu, Cynthia M. Beall, David B. Witonsky, Amha Gebremedhin, Jonathan K. Pritchard, Anna Di Rienzo
(Submitted on 13 Nov 2012)

Although hypoxia is a major stress on physiological processes, several human populations have survived for millennia at high altitudes, suggesting that they have adapted to hypoxic conditions. This hypothesis was recently corroborated by studies of Tibetan highlanders, which showed that polymorphisms in candidate genes show signatures of natural selection as well as well-replicated association signals for variation in hemoglobin levels. We extended genomic analysis to two Ethiopian ethnic groups: Amhara and Oromo. For each ethnic group, we sampled low and high altitude residents, thus allowing genetic and phenotypic comparisons across altitudes and across ethnic groups. Genome-wide SNP genotype data were collected in these samples by using Illumina arrays. We find that variants associated with hemoglobin variation among Tibetans or other variants at the same loci do not influence the trait in Ethiopians. However, in the Amhara, SNP rs10803083 is associated with hemoglobin levels at genome-wide levels of significance. No significant genotype association was observed for oxygen saturation levels in either ethnic group. Approaches based on allele frequency divergence did not detect outliers in candidate hypoxia genes, but the most differentiated variants between high- and lowlanders have a clear role in pathogen defense. Interestingly, a significant excess of allele frequency divergence was consistently detected for genes involved in cell cycle control, DNA damage and repair, thus pointing to new pathways for high altitude adaptations. Finally, a comparison of CpG methylation levels between high- and lowlanders found several significant signals at individual genes in the Oromo.