19,396 research outputs found
Inferring HIV escape rates from multi-locus genotype data
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
Recommended from our members
Methodological implementation of mixed linear models in multi-locus genome-wide association studies
The mixed linear model has been widely used in genome-wide association studies (GWAS), but its application to multi-locus GWAS analysis has not been explored and assessed. Here, we implemented a fast multi-locus random-SNP-effect EMMA (FASTmrEMMA) model for GWAS. The model is built on random single nucleotide polymorphism (SNP) effects and a new algorithm. This algorithm whitens the covariance matrix of the polygenic matrix K and environmental noise, and specifies the number of nonzero eigenvalues as one. The model first chooses all putative quantitative trait nucleotides (QTNs) with ≤ 0.005 P-values and then includes them in a multi-locus model for true QTN detection. Owing to the multi-locus feature, the Bonferroni correction is replaced by a less stringent selection criterion. Results from analyses of both simulated and real data showed that FASTmrEMMA is more powerful in QTN detection and model fit, has less bias in QTN effect estimation and requires a less running time than existing single- and multi-locus methods, such as empirical Bayes, settlement of mixed linear model under progressively exclusive relationship (SUPER), efficient mixed model association (EMMA), compressed MLM (CMLM) and enriched CMLM (ECMLM). FASTmrEMMA provides an alternative for multi-locus GWAS
Efficient network-guided multi-locus association mapping with graph cuts
As an increasing number of genome-wide association studies reveal the
limitations of attempting to explain phenotypic heritability by single genetic
loci, there is growing interest for associating complex phenotypes with sets of
genetic loci. While several methods for multi-locus mapping have been proposed,
it is often unclear how to relate the detected loci to the growing knowledge
about gene pathways and networks. The few methods that take biological pathways
or networks into account are either restricted to investigating a limited
number of predetermined sets of loci, or do not scale to genome-wide settings.
We present SConES, a new efficient method to discover sets of genetic loci
that are maximally associated with a phenotype, while being connected in an
underlying network. Our approach is based on a minimum cut reformulation of the
problem of selecting features under sparsity and connectivity constraints that
can be solved exactly and rapidly.
SConES outperforms state-of-the-art competitors in terms of runtime, scales
to hundreds of thousands of genetic loci, and exhibits higher power in
detecting causal SNPs in simulation studies than existing methods. On flowering
time phenotypes and genotypes from Arabidopsis thaliana, SConES detects loci
that enable accurate phenotype prediction and that are supported by the
literature.
Matlab code for SConES is available at
http://webdav.tuebingen.mpg.de/u/karsten/Forschung/scones/Comment: 20 pages, 6 figures, accepted at ISMB (International Conference on
Intelligent Systems for Molecular Biology) 201
Analytical study of the effect of recombination on evolution via DNA shuffling
We investigate a multi-locus evolutionary model which is based on the DNA
shuffling protocol widely applied in \textit{in vitro} directed evolution. This
model incorporates selection, recombination and point mutations. The simplicity
of the model allows us to obtain a full analytical treatment of both its
dynamical and equilibrium properties, for the case of an infinite population.
We also briefly discuss finite population size corrections
Multi-locus analysis of genomic time series data from experimental evolution.
Genomic time series data generated by evolve-and-resequence (E&R) experiments offer a powerful window into the mechanisms that drive evolution. However, standard population genetic inference procedures do not account for sampling serially over time, and new methods are needed to make full use of modern experimental evolution data. To address this problem, we develop a Gaussian process approximation to the multi-locus Wright-Fisher process with selection over a time course of tens of generations. The mean and covariance structure of the Gaussian process are obtained by computing the corresponding moments in discrete-time Wright-Fisher models conditioned on the presence of a linked selected site. This enables our method to account for the effects of linkage and selection, both along the genome and across sampled time points, in an approximate but principled manner. We first use simulated data to demonstrate the power of our method to correctly detect, locate and estimate the fitness of a selected allele from among several linked sites. We study how this power changes for different values of selection strength, initial haplotypic diversity, population size, sampling frequency, experimental duration, number of replicates, and sequencing coverage depth. In addition to providing quantitative estimates of selection parameters from experimental evolution data, our model can be used by practitioners to design E&R experiments with requisite power. We also explore how our likelihood-based approach can be used to infer other model parameters, including effective population size and recombination rate. Then, we apply our method to analyze genome-wide data from a real E&R experiment designed to study the adaptation of D. melanogaster to a new laboratory environment with alternating cold and hot temperatures
Clonal Complexes in Biomedical Ontologies
An accurate classification of bacteria is essential for the proper identification of patient infections and subsequent treatment decisions. Multi-Locus Se-quence Typing (MLST) is a genetic technique for bacterial classification. MLST classifications are used to cluster bacteria into clonal complexes. Importantly, clonal complexes can serve as a biological species concept for bacteria, facilitating an otherwise difficult taxonomic classification. In this paper, we argue for the inclusion of terms relating to clonal complexes in biomedical ontologies
Multi-locus phylogeny of Pleosporales: a taxonomic, ecological and evolutionary re-evaluation
Five loci, nucSSU, nucLSU rDNA, TEF1, RPB1 and RPB2, are used for analysing 129 pleosporalean taxa representing 59 genera and 15 families in the current classification of Pleosporales. The suborder Pleosporineae is emended to include four families, viz. Didymellaceae, Leptosphaeriaceae, Phaeosphaeriaceae and Pleosporaceae. In addition, two new families are introduced, i.e. Amniculicolaceae and Lentitheciaceae. Pleomassariaceae is treated as a synonym of Melanommataceae, and new circumscriptions of Lophiostomataceae s. str, Massarinaceae and Lophiotrema are proposed. Familial positions of Entodesmium and Setomelanomma in Phaeosphaeriaceae, Neophaeosphaeria in Leptosphaeriaceae, Leptosphaerulina, Macroventuria and Platychora in Didymellaceae, Pleomassaria in Melanommataceae and Bimuria, Didymocrea, Karstenula and Paraphaeosphaeria in Montagnulaceae are clarified. Both ecological and morphological characters show varying degrees of phylogenetic significance. Pleosporales is most likely derived from a saprobic ancestor with fissitunicate asci containing conspicuous ocular chambers and apical rings. Nutritional shifts in Pleosporales likely occured from saprotrophic to hemibiotrophic or biotrophic
Genotypic characterisation of Giardia from domestic dogs in the USA
The first large-scale urban survey of Giardia infections in dogs was undertaken in the USA. It involved several locations in the Western United States with Giardia isolates from microscopy-positive samples characterised by multi-locus PCR and sequencing. A high prevalence of Giardia was confirmed in asymptomatic domestic dogs, and for the first time, provides evidence that zoonotic assemblages/subgroups of Giardia occur frequently in domestic dogs living in urban environments, and more frequently than the dog specific assemblages
- …