Why to account for finite sites in population genetic studies and how to do this with Jaatha 2.0

With the advent of next‐generation sequencing technologies, large data sets of several thousand loci from multiple conspecific individuals are available. Such data sets should make it possible to obtain accurate estimates of population genetic parameters, even for complex models of population history. In the analyses of large data sets, it is difficult to consider finite‐sites mutation models (FSMs). Here, we use extensive simulations to demonstrate that the inclusion of FSMs is necessary to avoid severe biases in the estimation of the population mutation rate θ, population divergence times, and migration rates. We present a new version of Jaatha, an efficient composite‐likelihood method for estimating demographic parameters from population genetic data and evaluate the usefulness of Jaatha in two biological examples. For the first application, we infer the speciation process of two wild tomato species, Solanum chilense and Solanum peruvianum. In our second application example, we demonstrate that Jaatha is readily applicable to NGS data by analyzing genome‐wide data from two southern European populations of Arabidopsis thaliana. Jaatha is now freely available as an R package from the Comprehensive R Archive Network (CRAN).     

Identification of X-linked quantitative trait loci affecting cold tolerance in Drosophila melanogaster and fine mapping by selective sweep analysis

Drosophila melanogaster is a cosmopolitan species that colonizes a great variety of environments. One trait that shows abundant evidence for naturally segregating genetic variance in different populations of D. melanogaster is cold tolerance. Previous work has found quantitative trait loci (QTL) exclusively on the second and the third chromosomes. To gain insight into the genetic architecture of cold tolerance on the X chromosome and to compare the results with our analyses of selective sweeps, a mapping population was derived from a cross between substitution lines that solely differed in the origin of their X chromosome: one originates from a European inbred line and the other one from an African inbred line. We found a total of six QTL for cold tolerance factors on the X chromosome of D. melanogaster. Although the composite interval mapping revealed slightly different QTL profiles between sexes, a coherent model suggests that most QTL overlapped between sexes, and each explained around 5–14% of the genetic variance (which may be slightly overestimated). The allelic effects were largely additive, but we also detected two significant interactions. Taken together, this provides evidence for multiple QTL that are spread along the entire X chromosome and whose effects range from low to intermediate. One detected transgressive QTL influences cold tolerance in different ways for the two sexes. While females benefit from the European allele increasing their cold tolerance, males tend to do better with the African allele. Finally, using selective sweep mapping, the candidate gene CG16700 for cold tolerance colocalizing with a QTL was identified.     

Robust E-values for gapped local alignments.

We examine a Poisson heuristic for judging the significance of local sequence alignments with gaps. Model parameters are estimated directly from the sequences to be aligned, so that laborious prior simulation studies or database comparisons for the estimation of parameters describing the connection between score and E-value are unnecessary. Simulation studies give evidence that this method gives reasonable results even when the usual assumptions like the independence of sequence positions are violated.     

Environmental change, bog history and human impact around 2900 b.c. in NW Germany–preliminary results from a dendroecological study of a sub-fossil pine woodland at Campemoor, Dümmer Basin

This paper presents a detailed dendroecological analysis of remains from a sub-fossil pine forest at the Campemoor in the Dümmer basin, NW Germany and of pine timbers from a contemporaneous Neolithic trackway Pr 32 through the Campemoor. Changes in growth pattern and population dynamics of the pines are discussed in context with the time of construction of the trackway. The findings date to the period around 3000 b.c. Together with palaeobotanical investigations (pollen and macro remains) and the archaeological results (trackway) the dendroecological analysis mirrors environmental changes and the response of people to these changes. In order to test this local development for a possible climate background, ring-width variability and population dynamics of the Campemoor pines and of the overall data set of Lower Saxonian sub-fossil oaks from bogs have been compared. The results of these investigations clearly indicate a common widespread turn from drier to more humid climate conditions as trigger for the transition period, initiating the raised bog growth. It happened in two phases at the beginning of the 3rd millennium, interrupted by a drier period between 2825 and 2770 b.c. Afterwards large areas of former settlement sites within today's Campemoor became inaccessible and were covered by raised bog.     

Short term protective effects of iron in a murine model of ischemia/reperfusion

The role of iron in the pathogenesis of cardio-vascular disorders is still controversial. We studied the effects of iron perturbations on myocardial injury upon temporary ischemia/reperfusion. C57BL/6J male mice were injected with iron dextran for 2 weeks while controls received saline. Mice were then subjected to 30 min of myocardial ischemia and subsequent reperfusion for 6–24 h. Tissue damage was quantified histologically and by troponin T determination. The expressions of tumor necrosis factor-α (TNF-α), superoxide dismutase (SOD) and inducible nitric oxide synthase (iNOS) were investigated in non-ischemic and ischemic regions of both groups. After myocardial ischemia and reperfusion, troponin T levels, as a marker of myocardial damage, were significantly reduced in iron-treated mice as compared to control mice (P < 0.05). Under the same conditions the infarction area and damage score were significantly lower in iron-treated animals. In parallel, TNF-α and SOD expressions were increased in infarcted regions of iron-treated mice as compared to controls, whereas myocardial iNOS expression was significantly lower in iron-treated mice. Although, iron challenge increased radical formation and TNF-α expression in vivo, this did not result in myocardial damage which may be linked to the parallel induction of SOD. Importantly, iron treatment inhibited iNOS expression. Since, an increased nitric oxide (NO) formation has been linked to cardiac damage after acute myocardial infarction, iron may exert short time cardio-protective effects after induction of ischemia/reperfusion via decreasing iNOS formation. Both authors contributed equally to this work.     

Structural abnormalities in spermatids together with reduced sperm counts and motility underlie the reproductive defect in HIP1-/- mice

Huntingtin interacting protein 1 (HIP1) is an endocytic adaptor protein with clathrin assembly activity that binds to cytoplasmic proteins, such as F-actin, tubulin, and huntingtin (htt). To gain insight into diverse functions of HIP1, we characterized the male reproductive defect of HIP1(-/-) mice from 7 to 30 weeks of age. High levels of HIP1 protein were expressed in the testis of wild-type mice as seen by Western blots and as a reaction over Sertoli cells and elongating spermatids as visualized by immunocytochemistry. Accordingly, major structural abnormalities were evident in HIP1(-/-) mice with vacuolation of seminiferous tubules caused by an apparent loss of postmeiotic spermatids and a significant reduction in mean profile area. Remaining spermatids revealed deformations of their heads, flagella, and/or acrosomes. In some Sertoli cells, ectoplasmic specializations (ES) were absent or altered in appearance accounting for the presence of spherical germ cells in the epididymal lumen. Quantitative analyses of sperm counts from the cauda epididymidis demonstrated a significant decrease in HIP1(-/-) mice compared to wild-type littermates. In addition, computer-assisted sperm analyses indicated that velocities, amplitude of lateral head displacements (ALH), and numbers and percentages of sperm in the motile, rapid, and progressive categories were all significantly reduced in HIP1(-/-) mice, while the numbers and percentages of sperm in the static category were greatly increased. Taken together, these various abnormalities corroborate reduced fertility levels in HIP1(-/-) mice and suggest a role for HIP1 in stabilizing actin and microtubules, which are important cytoskeletal elements enabling normal spermatid and Sertoli cell morphology and function.     

ReformAlign: improved multiple sequence alignments using a profile-based meta-alignment approach

Background

Obtaining an accurate sequence alignment is fundamental for consistently analyzing biological data. Although this problem may be efficiently solved when only two sequences are considered, the exact inference of the optimal alignment easily gets computationally intractable for the multiple sequence alignment case. To cope with the high computational expenses, approximate heuristic methods have been proposed that address the problem indirectly by progressively aligning the sequences in pairs according to their relatedness. These methods however are not flexible to change the alignment of an already aligned group of sequences in the view of new data, resulting thus in compromises on the quality of the deriving alignment. In this paper we present ReformAlign, a novel meta-alignment approach that may significantly improve on the quality of the deriving alignments from popular aligners. We call ReformAlign a meta-aligner as it requires an initial alignment, for which a variety of alignment programs can be used. The main idea behind ReformAlign is quite straightforward: at first, an existing alignment is used to construct a standard profile which summarizes the initial alignment and then all sequences are individually re-aligned against the formed profile. From each sequence-profile comparison, the alignment of each sequence against the profile is recorded and the final alignment is indirectly inferred by merging all the individual sub-alignments into a unified set. The employment of ReformAlign may often result in alignments which are significantly more accurate than the starting alignments.

Results

We evaluated the effect of ReformAlign on the generated alignments from ten leading alignment methods using real data of variable size and sequence identity. The experimental results suggest that the proposed meta-aligner approach may often lead to statistically significant more accurate alignments. Furthermore, we show that ReformAlign results in more substantial improvement in cases where the starting alignment is of relatively inferior quality or when the input sequences are harder to align.

Conclusions

The proposed profile-based meta-alignment approach seems to be a promising and computationally efficient method that can be combined with practically all popular alignment methods and may lead to significant improvements in the generated alignments.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2105-15-265) contains supplementary material, which is available to authorized users.     

Detection of atypical genes in virus families using a one-class SVM

Background

The diversity of viruses, the absence of universally common genes in them, and their ability to act as carriers of genetic material make assessment of evolutionary paths of viral genes very difficult. One important factor contributing to this complexity is horizontal gene transfer.

Results

We explore the possibility for the systematic identification of atypical genes within virus families, including viruses whose genome is not encoded by a double-stranded DNA. Our method is based on gene statistical features that differ in genes that were subject of recent horizontal gene transfer from those of the genome in which they are observed. We employ a one-class SVM approach to detect atypical genes within a virus family basing of their statistical signatures and without explicit knowledge of the source species. The simplicity of the statistical features used makes the method applicable to various viruses irrespective of their genome size or type.

Conclusions

On simulated data, the method can robustly identify alien genes irrespective of the coding nucleic acid found in a virus. It also compares well to results obtained in related studies for double-stranded DNA viruses. Its value in practice is confirmed by the identification of isolated examples of horizontal gene transfer events that have already been described in the literature. A Python package implementing the method and the results for the analyzed virus families are available at http://svm-agp.bioinf.mpi-inf.mpg.de.