Biology subjects

Pennings, P.

Publications and source records attributed to Pennings, P..

4 recordsLinked to original sources

bioRxiv2023

Compensatory adaptation does not fully alleviate the costs associated with rifampicin resistance and occurs predominantly through off-target mutations

The manner in which costs associated with antibiotic resistance mutations are alleviated through the acquisition of compensatory mutations has bearing on the dynamics of resistance accumulation and spread as well as on our more general understanding of the persistence of adaptive genotypes. Here, we combine evolutionary experiments, fitness analyses, and whole genome sequencing to examine the way compensation to alleviate costs associated with rifampicin resistance is achieved, both when resistance is fixed and when initial majorities of resistant cells are grown alongside susceptible cells. We found compensatory mutations to occur across all examined populations. However, compensation never fully alleviates the initial costs of resistance. In contrast to prevalent assumptions, compensatory mutations mostly occurred outside of the RNA polymerase core enzyme, which serves as the target of rifampicin. The target size for compensatory mutations appears to be high, as great variation exists in compensatory mutations, even within a single population. At the same time, the pathways of compensation are quite convergent, meaning that, across independent populations, we often observe compensatory mutations in the same loci and sometimes even observe the precise same compensatory mutations across populations.

evolutionary biology↗

bioRxiv2019

The genetic interaction between HIV and the antibody repertoire

The interaction between human immunodeficiency virus (HIV) and the antibody repertoire (AbR) during chronic infection can provide important information for HIV vaccine research, yet has not been well-characterized on a systems level. We deeply sequenced the HIV population and the AbR of ten HIV-infected, antiretroviral (ART)-naive individuals, each with 10-20 longitudinal samples spanning 4-14 years. Our unbiased sequencing approach identified partitions of AbRs showing evidence of interaction with autologous HIV populations. We show that these HIV-associated partitions are enriched for the V gene segments of known HIV broadly neutralizing antibodies (bnAbs), indicating that the HIV-responding component of the AbR can be identified via time-series genetic data. Despite this evidence for larger-scale AbR/HIV interactions at the sub-population level, we found little to no evidence for antagonistic coevolution (i.e. an arms race). This suggests that antagonistic coevolution is either rare, or hard to detect, which has important vaccine design implications.

evolutionary biology↗

bioRxiv2018

Polygenic Adaptation: From sweeps to subtle frequency shifts

1Evolutionary theory has produced two conflicting paradigms for the adaptation of a polygenic trait. While population genetics views adaptation as a sequence of selective sweeps at single loci underlying the trait, quantitative genetics posits a collective response, where phenotypic adaptation results from subtle allele frequency shifts at many loci. Yet, a synthesis of these views is largely missing and the population genetic factors that favor each scenario are not well understood. Here, we study the architecture of adaptation of a binary polygenic trait (such as resistance) with negative epistasis among the loci of its basis. The genetic structure of this trait allows for a full range of potential architectures of adaptation, ranging from sweeps to small frequency shifts. By combining computer simulations and a newly devised analytical framework based on Yule branching processes, we gain a detailed understanding of the adaptation dynamics for this trait. Our key analytical result is an expression for the joint distribution of mutant alleles at the end of the adaptive phase. This distribution characterizes the polygenic pattern of adaptation at the underlying genotype when phenotypic adaptation has been accomplished. We find that a single compound parameter, the population-scaled background mutation rate {Theta}bg, explains the main differences among these patterns. For a focal locus, {Theta}bg measures the mutation rate at all redundant loci in its genetic background that offer alternative ways for adaptation. For adaptation starting from mutation-selection-drift balance, we observe different patterns in three parameter regions. Adaptation proceeds by sweeps for small {Theta}bg [prsim] 0.1, while small polygenic allele frequency shifts require large {Theta}bg [scsim] 100. In the large intermediate regime, we observe a heterogeneous pattern of partial sweeps at several interacting loci. 2 Author summaryIt is still an open question how complex traits adapt to new selection pressures. While population genetics champions the search for selective sweeps, quantitative genetics proclaims adaptation via small concerted frequency shifts. To date the empirical evidence of clear sweep signals is more scarce than expected, while subtle shifts remain notoriously hard to detect. In the current study we develop a theoretical framework to predict the expected adaptive architecture of a simple polygenic trait, depending on parameters such as mutation rate, effective population size, size of the trait basis, and the available genetic variability at the onset of selection. For a population in mutation-selection-drift balance we find that adaptation proceeds via complete or partial sweeps for a large set of parameter values. We predict adaptation by small frequency shifts for two main cases. First, for traits with a large mutational target size and high levels of genetic redundancy among loci, and second if the starting frequencies of mutant alleles are more homogeneous than expected in mutation-selection-drift equilibrium, e.g. due to population structure or balancing selection.

evolutionary biology↗

bioRxiv2017

High resolution spatio-temporal assessment of simian/human immunodeficiency virus (SHIV) evolution reveals a highly dynamic process within the host

The process by which drug-resistant HIV-1 arises and spreads spatially within an infected individual is poorly understood. Studies have found variable results relating how HIV-1 in the blood differs from virus sampled in tissues, offering conflicting findings about whether HIV-1 throughout the body is homogeneously distributed. However, most of these studies sample only two compartments and few have data from multiple time points. To directly measure how drug resistance spreads within a host and to assess how spatial structure impacts its emergence, we examined serial sequences from four macaques infected with RT-SHIVmne027, a simian immunodeficiency virus encoding HIV-1 reverse transcriptase (RT), and treated with RT inhibitors. Both viral DNA and RNA (vDNA and vRNA) were isolated from the blood (including plasma and peripheral blood mononuclear cells), lymph nodes, gut, and vagina at a median of four time points and RT was characterized via single-genome sequencing. The resulting sequences reveal a dynamic system in which vRNA rapidly acquires drug resistance concomitantly across compartments through multiple independent mutations. Fast migration results in the same viral genotypes present across compartments, but not so fast as to equilibrate their frequencies through time. The blood and lymph nodes were found to be compartmentalized rarely, while both the blood and lymph node were more frequently different from mucosal tissues. There is some evidence for an increase in compartmentalization after the onset of selective pressure. This study suggests that even oft-sampled blood does not fully capture the viral dynamics in other parts of the body, especially the gut where vRNA turnover was faster than the plasma and vDNA retained fewer wild-type viruses than other sampled compartments. Our findings of transient compartmentalization across multiple tissues may help explain the varied results of previous compartmentalization studies in HIV-1.\n\nAuthor SummaryHIV-1 is difficult to treat because the virus can evolve to become drug-resistant within the body, but we have an incomplete understanding of where drug resistant viruses originate and how they spread within a person. In this study, four macaques were infected with RT-SHIV, a simian immunodeficiency virus with an HIV-1 reverse transcriptase coding region, which can be targeted with standard HIV drugs. We sampled virus from the macaques before, during and after they became resistant to administered drugs and determined the genetic viral sequences in several parts of the body: blood, lymph nodes, gut, and vagina. We found that drug resistance emerged across compartments nearly simultaneously, and drug resistance evolved multiple independent times within each macaque. Although migration of RT-SHIV between compartments is fast, compartments do not have the same distribution of viral genotypes. This is important because although studies typically sample virus from the blood to study how HIV-1 evolution in humans, our study suggests that it is not fully representative of other parts of the body, particularly the gut.

evolutionary biology↗