A stochastic microscopic model for the dynamics of antigenic variation


A stochastic microscopic model for the dynamics of antigenic variation

Gustavo Guerberoff, Fernando Alvarez-Valin
(Submitted on 8 Nov 2013)

We present a novel model that describes the within-host evolutionary dynamics of parasites undergoing antigenic variation. The approach uses a multi-type branching process with two types of entities defined according to their relationship with the immune system: clans of resistant parasitic cells (i.e. groups of cells sharing the same antigen not yet recognized by the immune system) that may become sensitive, and individual sensitive cells that can acquire a new resistance thus giving rise to the emergence of a new clan. The simplicity of the model allows analytical treatment to determine the subcritical and supercritical regimes in the space of parameters. By incorporating a density-dependent mechanism the model is able to capture additional relevant features observed in experimental data, such as the characteristic parasitemia waves. In summary our approach provides a new general framework to address the dynamics of antigenic variation which can be easily adapted to cope with broader and more complex situations.

Mapping of the Influenza-A Hemagglutinin Serotypes Evolution by the ISSCOR Method

Mapping of the Influenza-A Hemagglutinin Serotypes Evolution by the ISSCOR Method
Jan P. Radomski, Piotr P. Slonimski, Włodzimierz Zagórski-Ostoja, Piotr Borowicz
(Submitted on 8 Nov 2013)

Analyses and visualizations by the ISSCOR method of influenza virus hemagglutinin genes of different A-subtypes revealed some rather striking temporal relationships between groups of individual gene subsets. Based on these findings we consider application of the ISSCOR-PCA method for analyses of large sets of homologous genes to be a worthwhile addition to a toolbox of genomics – allowing for a rapid diagnostics of trends, and ultimately even aiding an early warning of newly emerging epidemiological threats.

The hemagglutinin mutation E391K of pandemic 2009 influenza revisited

The hemagglutinin mutation E391K of pandemic 2009 influenza revisited
Jan P. Radomski, Piotr Płoński, Włodzimierz Zagórski-Ostoja
(Submitted on 8 Nov 2013)

Phylogenetic analyses based on small to moderately sized sets of sequential data lead to overestimating mutation rates in influenza hemagglutinin (HA) by at least an order of magnitude. Two major underlying reasons are: the incomplete lineage sorting, and a possible absence in the analyzed sequences set some of key missing ancestors. Additionally, during neighbor joining tree reconstruction each mutation is considered equally important, regardless of its nature. Here we have implemented a heuristic method optimizing site dependent factors weighting differently 1st, 2nd, and 3rd codon position mutations, allowing to extricate incorrectly attributed sub-clades. The least squares regression analysis of distribution of frequencies for all mutations observed on a partially disentangled tree for a large set of unique 3243 HA sequences, along all nucleotide positions, was performed for all mutations as well as for non-equivalent amino acid mutations: in both cases demonstrating almost flat gradients, with a very slight downward slope towards the 3′-end positions. The mean mutation rates per sequence per year were 3.83*10^-4 for the all mutations, and 9.64*10^-5 for the non-equivalent ones.

Reliable reconstruction of HIV-1 whole genome haplotypes reveals clonal interference and genetic hitchhiking among immune escape variants

Reliable reconstruction of HIV-1 whole genome haplotypes reveals clonal interference and genetic hitchhiking among immune escape variants
Aridaman Pandit, Rob J de Boer
(Submitted on 26 Sep 2013)

Following transmission, HIV-1 evolves into a diverse population, and next generation sequencing enables us to detect variants occurring at low frequencies. Studying viral evolution at the level of whole genomes was hitherto not possible because next generation sequencing delivers relatively short reads. We here provide a proof of principle that whole HIV-1 genomes can be reliably reconstructed from short reads, and use this to study the selection of immune escape mutations at the level of whole genome haplotypes. Using realistically simulated HIV-1 populations, we demonstrate that reconstruction of complete genome haplotypes is feasible with high fidelity. We do not reconstruct all genetically distinct genomes, but each reconstructed haplotype represents one or more of the quasispecies in the HIV-1 population. We then reconstruct 30 whole genome haplotypes from published short sequence reads sampled longitudinally from a single HIV-1 infected patient. We confirm the reliability of the reconstruction by validating our predicted haplotype genes with single genome amplification sequences, and by comparing haplotype frequencies with observed epitope escape frequencies. Phylogenetic analysis shows that the HIV-1 population undergoes selection driven evolution, with successive replacement of the viral population by novel dominant strains. We demonstrate that immune escape mutants evolve in a dependent manner with various mutations hitchhiking along with others. As a consequence of this clonal interference, selection coefficients have to be estimated for complete haplotypes and not for individual immune escapes.

A network approach to analyzing highly recombinant malaria parasite genes

A network approach to analyzing highly recombinant malaria parasite genes
Daniel B. Larremore, Aaron Clauset, Caroline O. Buckee
(Submitted on 23 Aug 2013)

The var genes of the human malaria parasite Plasmodium falciparum present a challenge to population geneticists due to their extreme diversity, which is generated by high rates of recombination. These genes encode a primary antigen protein called PfEMP1, which is expressed on the surface of infected red blood cells and elicits protective immune responses. Var gene sequences are characterized by pronounced mosaicism, precluding the use of traditional phylogenetic tools that require bifurcating tree-like evolutionary relationships. We present a new method that identifies highly variable regions (HVRs), and then maps each HVR to a complex network in which each sequence is a node and two nodes are linked if they share an exact match of significant length. Here, networks of var genes that recombine freely are expected to have a uniformly random structure, but constraints on recombination will produce network communities that we identify using a stochastic block model. We validate this method on synthetic data, showing that it correctly recovers populations of constrained recombination, before applying it to the Duffy Binding Like-{\alpha} (DBL{\alpha}) domain of var genes. We find nine HVRs whose network communities map in distinctive ways to known DBL{\alpha} classifications and clinical phenotypes. We show that the recombinational constraints of some HVRs are correlated, while others are independent. These findings suggest that this micromodular structuring facilitates independent evolutionary trajectories of neighboring mosaic regions, allowing the parasite to retain protein function while generating enormous sequence diversity. Our approach therefore offers a rigorous method for analyzing evolutionary constraints in var genes, and is also flexible enough to be easily applied more generally to any highly recombinant sequences.

Simultaneous reconstruction of evolutionary history and epidemiological dynamics from viral sequences with the birth-death SIR model

Simultaneous reconstruction of evolutionary history and epidemiological dynamics from viral sequences with the birth-death SIR model
Denise Kühnert, Tanja Stadler, Timothy G. Vaughan, Alexei J. Drummond
(Submitted on 23 Aug 2013)

Evolution of RNA viruses such as HIV, Hepatitis C and Influenza virus occurs so rapidly that the viruses’ genomes contain information on past ecological dynamics. The interaction of ecological and evolutionary processes demands their joint analysis. Here we adapt a birth-death-sampling model, which allows for serially sampled data and rate changes over time to estimate epidemiological parameters of the underlying population dynamics in terms of a compartmental susceptible-infected-removed (SIR) model. Our proposed approach results in a phylodynamic method that enables the joint estimation of epidemiological parameters and phylogenetic history. In contrast to standard coalescent process approaches this method provides separate information on incidence and prevalence of infections. Detailed information on the interaction of host population dynamics and evolutionary history can inform decisions on how to contain or entirely avoid disease outbreaks.
We apply our Birth-Death SIR method (BDSIR) to five human immunodeficiency virus type 1 clusters sampled in the United Kingdom (UK) between 1999 and 2003. The estimated basic reproduction ratio ranges from 1.9 to 3.2 among the clusters. Our results imply that these local epidemics arose from introduction of infected individuals into populations of between 900 and 3000 effectively susceptible individuals, albeit with wide margins of uncertainty. All clusters show a decline in the growth rate of the local epidemic in the middle or end of the 90’s. The effective reproduction ratio of cluster 1 drops below one around 1994, with the local epidemic having almost run its course by the end of the sampled period. For the other four clusters the effective reproduction ratio also decreases over time, but stays above 1. The method is implemented as a BEAST2 package.

Our paper: Inferring HIV escape rates from multi-locus genotype data

This guest post is by Richard Neher on his paper with Taylor Kessinger and Alan Perelson: Kessinger et al. Inferring HIV escape rates from multi-locus genotype data. arXived here.
This is cross posted from the Neher lab website.

We have a new preprint on the arXiv (here on Haldane’s sieve). This work is the result of a collaboration between us and Alan Perelson, LANL, and explores methods to estimate parameters of the HIV-immune system interaction from time resolved sequence data. The focus of this paper is on early infeImagection dominated by a few rapid substitutions that fix because they prevent or reduce recognition of infected cells by the immune system via cytotoxic T-lymphocytes (CTL). CTL escape is one of the fastest instances of evolution I have come across. 4-6 mutations spread within a few weeks. It happens in most HIV infections and is partly predictable based on the HLA genotype of the infected person. These substitutions are so rapid that clonal interference has to be modeled. Our method fits a reduced model of clonal interference to the typically very sparse data and thereby estimates the selection coefficients, aka escape rates.

Why do we want to know these numbers?
The number of viruses in the blood of an infected person peaks 2-3 weeks after infection and thereafter drops by 2-3 order of magnitude. This drop is partly due to a response by the adaptive immune system. However, it has proved difficult to attribute this drop to specific parts of the immune response. The rates at which different mutations sweep through the population gives us information about the pressure exerted by the T-cell clones that target the epitope containing this mutation.

How do we do it?
Early in infection, the viral population is large and selection is strong. In these conditions, recombination is of minor importance since most double/triple… mutants are more efficiently produced by recurrent mutation than recombination. This implies that mutations accumulate sequentially always on a background one which already all previous mutations are present. The time at which a novel mutation happens in tightly constrained by the trajectory of preceding genotype. These constraints regularize the fitting problem to some degree and the multi-locus fitting is more robust than single locus fitting.

What do we learn about evolution in general?
In addition to the intrinsic interest in the HIV/CTL interaction, CTL escape is an ideal setting to study rapidly evolving populations. This evolution happens in its “natural” habitat and the selective pressure as well as the functional consequences of the observed molecular changes can be quantified via immunological data, protein structure, and replication assays. In addition, we have ample cross-sectional data (HIV sequences from many different patients) that allows us to look at prevalence of the escape mutations and potential compensatory mutations. None of this is done in this paper, but studying HIV/immune-system coevolution is a fascinating show case of rapid evolution.

Inferring HIV escape rates from multi-locus genotype data

Inferring HIV escape rates from multi-locus genotype data
Taylor A. Kessinger, Alan S. Perelson, Richard A. Neher
(Submitted on 6 Aug 2013)

Cytotoxic T-lymphocytes (CTLs) recognize viral protein fragments displayed by major histocompatibility complex (MHC) molecules on the surface of virally infected cells and generate an anti-viral response that can kill the infected cells. Virus variants whose protein fragments are not efficiently presented on infected cells or whose fragments are presented but not recognized by CTLs therefore have a competitive advantage and spread rapidly through the population. We present a method that allows a more robust estimation of these escape rates from serially sampled sequence data. The proposed method accounts for competition between multiple escapes by explicitly modeling the accumulation of escape mutations and the stochastic effects of rare multiple mutants. Applying our method to serially sampled HIV sequence data, we estimate rates of HIV escape that are substantially larger than those previously reported. The method can be extended to complex escapes that require compensatory mutations. We expect our method to be applicable in other contexts such as cancer evolution where time series data is also available.

The genome of the medieval Black Death agent

The genome of the medieval Black Death agent (extended abstract)
Ashok Rajaraman, Eric Tannier, Cedric Chauve
(Submitted on 29 Jul 2013)

The genome of a 650 year old Yersinia pestis bacteria, responsible for the medieval Black Death, was recently sequenced and assembled into 2,105 contigs from the main chromosome. According to the point mutation record, the medieval bacteria could be an ancestor of most Yersinia pestis extant species, which opens the way to reconstructing the organization of these contigs using a comparative approach. We show that recent computational paleogenomics methods, aiming at reconstructing the organization of ancestral genomes from the comparison of extant genomes, can be used to correct, order and complete the contig set of the Black Death agent genome, providing a full chromosome sequence, at the nucleotide scale, of this ancient bacteria. This sequence suggests that a burst of mobile elements insertions predated the Black Death, leading to an exceptional genome plasticity and increase in rearrangement rate.

Speed of adaptation and genomic signatures in arms race and trench warfare models of host-parasite coevolution

Speed of adaptation and genomic signatures in arms race and trench warfare models of host-parasite coevolution
Aurelien Tellier, Stefany Moreno-Game, Wolfgang Stephan
(Submitted on 25 Jul 2013)

Host and parasite population genomic data are increasingly used to discover novel major genes underlying coevolution, assuming that natural selection generates two distinguishable polymorphism patterns: selective sweeps and balancing selection. These genomic signatures would result from two coevolutionary dynamics, the trench warfare with fast cycles of allele frequencies and the arms race with slow recurrent fixation of alleles. However, based on genome scans for selection, few genes for coevolution have yet been found in hosts. To address this issue, we build a gene-for-gene model with genetic drift, mutation and integrating coalescent simulations to study observable genomic signatures at host and parasite loci. In contrast to the conventional wisdom, we show that coevolutionary cycles are not faster under the trench warfare model compared to the arms race, except for large population sizes and high values of coevolutionary costs. Based on the generated SNP frequencies, the expected balancing selection signature under the trench warfare dynamics appears to be only observable in parasite sequences in a limited range of parameter, if effective population sizes are sufficiently large (>1000) and if selection has been acting for a long time (>4N generations). On the other hand, the typical signature of the arms race dynamics, i.e. selective sweeps, can be detected in parasite and to a lesser extent in host populations even if coevolution is recent. We suggest to study signatures of coevolution via population genomics of parasites rather than hosts, and caution against inferring coevolutionary dynamics based on the speed of coevolution.