Michał Startek

Genome-wide analyses of LINE–LINE-mediated nonallelic homologous recombination

Nonallelic homologous recombination (NAHR), occurring between low-copy repeats (LCRs) >10 kb in size and sharing >97% DNA sequence identity, is responsible for the majority of recurrent genomic rearrangements in the human genome. Recent studies have shown that transposable elements (TEs) can also mediate recurrent deletions and translocations, indicating the features of substrates that mediate NAHR may be significantly less stringent than previously believed. Using >4 kb length and >95% sequence identity criteria, we analyzed of the genome-wide distribution of long interspersed element (LINE) retrotransposon and their potential to mediate NAHR. We identified 17 005 directly oriented LINE pairs located <10 Mbp from each other as potential NAHR substrates, placing 82.8% of the human genome at risk of LINE–LINE-mediated instability. Cross-referencing these regions with CNVs in the Baylor College of Medicine clinical chromosomal microarray database of 36 285 patients, we identified 516 CNVs potentially mediated by LINEs. Using long-range PCR of five different genomic regions in a total of 44 patients, we confirmed that the CNV breakpoints in each patient map within the LINE elements. To additionally assess the scale of LINE–LINE/NAHR phenomenon in the human genome, we tested DNA samples from six healthy individuals on a custom aCGH microarray targeting LINE elements predicted to mediate CNVs and identified 25 LINE–LINE rearrangements. Our data indicate that LINE–LINE-mediated NAHR is widespread and under-recognized, and is an important mechanism of structural rearrangement contributing to human genomic variability.

Genomic parasites or symbionts? Modeling the effects of environmental pressure on transposition activity in asexual populations

Transposable elements are DNA segments capable of persisting in host genomes by self-replication in spite of deleterious mutagenic effects. The theoretical dynamics of these elements within genomes has been studied extensively, and population genetic models predict that they can invade and maintain as a result of both intra-genomic and inter-individual selection in sexual species. In asexuals, the success of selfish DNA is more difficult to explain. However, most theoretical work assumes constant environment. Here, we analyze the impact of environmental change on the dynamics of transposition activity when horizontal DNA exchange is absent, based on a stochastic computational model of transposable element proliferation. We argue that repeated changes in the phenotypic optimum in a multidimensional fitness landscape may induce explosive bursts of transposition activity associated with faster adaptation. However, long-term maintenance of transposition activity is unlikely. This could contribute to the significant variation in the transposable element copy number among closely related species.

Subset seed extension to Protein BLAST

The seeding technique became central in the theory of sequence alignment and there are several efficient tools applying seeds to DNA homology search. Recently, a concept of subset seeds has been proposed for similarity search in protein sequences. We experimentally evaluate the applicability of subset seeds to protein homology search. We advocate the use of multiple subset seeds derived from a hierarchical tree of amino acid residues. Our method computes, by an evolutionary algorithm, seeds that are specifically designed for a given protein family. The representation of seeds by deterministic finite automata (DFAs) is developed and built into the NCBI-BLAST software. This extended tool, named SeedBLAST, is compared to the original NCBI-BLAST and PSI-BLAST on several protein families. Our results demonstrate a superiority of SeedBLAST in terms of efficiency, especially in the case of twilight zone hits. SeedBLAST is an open source software freely available http://bioputer.mimuw.edu.pl/papers/sblast . Supplementary material and user manual are also provided.

TIRfinder: A Web Tool for Mining Class II Transposons Carrying Terminal Inverted Repeats

Transposable elements (TEs) can be found in virtually all known genomes; plant genomes are exceptionally rich in this kind of dispersed repetitive sequences. Current knowledge on TE proliferation dynamics places them among the main forces of molecular evolution. Therefore efficient tools to analyze TE distribution in genomes are needed that would allow for comparative genomics studies and for studying TE dynamics in a genome. This was our main motivation underpinning TIRfinder construction–-an efficient tool for mining class II TEs carrying terminal inverted repeats. TIRfinder takes as an input a genomic sequence and information on structural properties of a TE family, and identifies all TEs in the genome showing the desired structural characteristics. The efficiency and small memory requirements of our approach stem from the use of suffix trees to identify all DNA segments surrounded by user-specified terminal inverse repeats (TIR) and target site duplications (TSD) which together constitute a mask. On the other hand, the flexibility of the notion of the TIR/TSD mask makes it possible to use the tool for de novo detection. The main advantages of TIRfinder are its speed, accuracy and convenience of use for biologists. A web-based interface is freely available at http:/bioputer.mimuw.edu.pl/tirfindertool/.

MuTAnT: a family of Mutator-like transposable elements targeting TA microsatellites in Medicago truncatula

Transposable elements (TEs) are mobile DNA segments, abundant and dynamic in plant genomes. Because their mobility can be potentially deleterious to the host, a variety of mechanisms evolved limiting that negative impact, one of them being preference for a specific target insertion site. Here, we describe a family of Mutator-like DNA transposons in Medicago truncatula targeting TA microsatellites. We identified 218 copies of MuTAnTs and an element carrying a complete ORF encoding a mudrA-like transposase. Most insertion sites are flanked by a variable number of TA tandem repeats, indicating that MuTAnTs are specifically targeting TA microsatellites. Other TE families flanked by TA repeats (e.g. TAFT elements in maize) were described previously, however we identified the first putative autonomous element sharing that characteristics with a related group of short non-autonomous transposons.

IsoSpec: Hyperfast Fine Structure Calculator

As high-resolution mass spectrometry (HRMS) becomes increasingly available, the need of software tools capable of handling more complex data is surging. The complexity of the HRMS data stems partly from the presence of isotopes that give rise to more peaks to interpret compared to lower resolution instruments. However, a new generation of fine isotope calculators is on the rise. They calculate the smallest possible sets of isotopologues. However, none of these calculators lets the user specify the joint probability of the revealed envelope in advance. Instead, the user must provide a lower limit on the probability of isotopologues of interest, that is, provide minimal peak height. The choice of such threshold is far from obvious. In particular, it is impossible to a priori balance the trade-off between the algorithm speed and the portion of the revealed theoretical spectrum. We show that this leads to considerable inefficiencies. Here, we present IsoSpec: an algorithm for fast computation of isotopologues of chemical substances that can alternate between joint probability and peak height threshold. We prove that IsoSpec is optimal in terms of time complexity. Its implementation is freely available under a 2-clause BSD license, with bindings for C++, C, R, and Python.

The Wasserstein Distance as a Dissimilarity Measure for Mass Spectra with Application to Spectral Deconvolution

We propose a new approach for the comparison of mass spectra using a metric known in the computer science under the name of Earth Movers Distance and in mathematics as the Wasserstein distance. We argue that this approach allows for natural and robust solutions to various problems in the analysis of mass spectra. In particular, we show an application to the problem of deconvolution, in which we infer proportions of several overlapping isotopic envelopes of similar compounds. Combined with the previously proposed generator of isotopic envelopes, IsoSpec, our approach works for a wide range of masses and charges in the presence of several types of measurement inaccuracies. To reduce the computational complexity of the solution, we derive an effective implementation of the Interior Point Method as the optimization procedure. The software for mass spectral comparison and deconvolution based on Wasserstein distance is available at https://github.com/mciach/wassersteinms.

Inferring transposons activity chronology by TRANScendence – TEs database and de-novo mining tool

BackgroundThe constant progress in sequencing technology leads to ever increasing amounts of genomic data. In the light of current evidence transposable elements (TEs for short) are becoming useful tools for learning about the evolution of host genome. Therefore the software for genome-wide detection and analysis of TEs is of great interest.ResultsHere we describe the computational tool for mining, classifying and storing TEs from newly sequenced genomes. This is an online, web-based, user-friendly service, enabling users to upload their own genomic data, and perform de-novo searches for TEs. The detected TEs are automatically analyzed, compared to reference databases, annotated, clustered into families, and stored in TEs repository. Also, the genome-wide nesting structure of found elements are detected and analyzed by new method for inferring evolutionary history of TEs.We illustrate the functionality of our tool by performing a full-scale analyses of TE landscape in Medicago truncatula genome.ConclusionsTRANScendence is an effective tool for the de-novo annotation and classification of transposable elements in newly-acquired genomes. Its streamlined interface makes it well-suited for evolutionary studies.