Jens Lagergren

Easy problems for tree-decomposable graphs

Abstract Using a variation of the interpretability concept we show that all graph properties definable in monadic second-order logic (MS properties) with quantification over vertex and edge sets can be decided in linear time for classes of graphs of fixed bounded treewidth given a tree-decomposition. This gives an alternative proof of a recent result by Courcelle. We allow graphs with directed and/or undirected edges, labeled on edges and/or vertices with labels taken from a finite set. We extend MS properties to extended monadic second-order (EMS) problems involving counting or summing evaluations over sets definable in monadic second-order logic. Our technique allows us also to solve some EMS problems in linear time or in polynomial or pseudopolynomial time for classes of graphs of fixed bounded treewidth. Moreover, it is shown that each EMS problem is in NC for graphs of bounded treewidth. Most problems for which linear time algorithms for graphs of bounded treewidth were previously known to exist, and many others, are EMS problems.

SUMOylation Mediates the Nuclear Translocation and Signaling of the IGF-1 Receptor

Attachment of SUMO lets insulin-like growth factor receptors act as transcriptional regulators in the nucleus. Alternative Pathway Insulin-like growth factor 1 receptor (IGF-1R) is a receptor tyrosine kinase (RTK) that mediates the effects of the protein hormone IGF-1. Binding of IGF-1 to IGF-1R leads to the transphosphorylation of tyrosine residues in the β subunits of the receptor and the activation of its tyrosine kinase activity. Activated IGF-1R stimulates the phosphatidylinositol 3-kinase (PI3K)–Akt and mitogen-activated protein kinase (MAPK) signaling pathways, which promote cell growth and proliferation. Noting that the activities of IGF-1R and other RTKs are modulated by posttranslational modifications, such as ubiquitination, Sehat et al. investigated a role for small ubiquitin-like modifier (SUMO) protein in the regulation of IGF-1R signaling. IGF-1 stimulated the SUMOylation of IGF-1R at three lysine residues in the β subunit of the receptor, which led to its nuclear translocation. Mutation of these residues blocked SUMOylation of the receptor and prevented its accumulation in the nucleus but did not interfere with endocytosis of the receptor or its activation of the PI3K or MAPK pathways. Nuclear IGF-1R bound to putative enhancer sites in genomic DNA and drove transcription of target genes in reporter assays. Together, these findings present an alternative mechanism of signaling by the IGF-1R that may have implications for gene expression. The insulin-like growth factor 1 receptor (IGF-1R) plays crucial roles in developmental and cancer biology. Most of its biological effects have been ascribed to its tyrosine kinase activity, which propagates signaling through the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. Here, we report that IGF-1 promotes the modification of IGF-1R by small ubiquitin-like modifier protein–1 (SUMO-1) and its translocation to the nucleus. Nuclear IGF-1R associated with enhancer-like elements and increased transcription in reporter assays. The SUMOylation sites of IGF-1R were identified as three evolutionarily conserved lysine residues—Lys1025, Lys1100, and Lys1120—in the β subunit of the receptor. Mutation of these SUMO-1 sites abolished the ability of IGF-1R to translocate to the nucleus and activate transcription but did not alter its kinase-dependent signaling. Thus, we demonstrate a SUMOylation-mediated mechanism of IGF-1R signaling that has potential implications for gene regulation.

Simultaneous Bayesian gene tree reconstruction and reconciliation analysis

We present GSR, a probabilistic model integrating gene duplication, sequence evolution, and a relaxed molecular clock for substitution rates, that enables genomewide analysis of gene families. The gene duplication and loss process is a major cause for incongruence between gene and species tree, and deterministic methods have been developed to explain such differences through tree reconciliations. Although probabilistic methods for phylogenetic inference have been around for decades, probabilistic reconciliation methods are far less established. Based on our model, we have implemented a Bayesian analysis tool, PrIME-GSR, for gene tree inference that takes a known species tree into account. Our implementation is sound and we demonstrate its utility for genomewide gene-family analysis by applying it to recently presented yeast data. We validate PrIME-GSR by comparing with previous analyses of these data that take advantage of gene order information. In a case study we apply our method to the ADH gene family and are able to draw biologically relevant conclusions concerning gene duplications creating key yeast phenotypes. On a higher level this shows the biological relevance of our method. The obtained results demonstrate the value of a relaxed molecular clock. Our good performance will extend to species where gene order conservation is insufficient.

Gene tree reconstruction and orthology analysis based on an integrated model for duplications and sequence evolution

Gene tree and species tree reconstruction, orthology analysis and reconciliation, are problems important in multigenome-based comparative genomics and biology in general. In the present paper, we advance the frontier of these areas in several respects and provide important computational tools. First, exact algorithms are given for several probabilistic reconciliation problems with respect to the probabilistic gene evolution model, previously developed by the authors. Until now, those problems were solved by MCMC estimation algorithms. Second, we extend the gene evolution model to the gene sequence evolution model, by including sequence evolution. Third, we develop MCMC algorithms for the gene sequence evolution model that, given gene sequence data allows: (1) orthology analysis, reconciliation analysis, and gene tree reconstruction, w.r.t. a species tree, that balances a likely/unlikely reconciliation and a likely/unlikely gene tree and (2) species tree reconstruction that balance a likely/unlikely reconciliation and a likely/unlikely gene trees. These MCMC algorithms take advantage of the exact algorithms for the gene evolution model. We have successfully tested our dynamical programming algorithms on real data for a biogeography problem. The MCMC algorithms perform very well both on synthetic and biological data.

Efficient algorithms for lateral gene transfer problems

This paper develops a model for lateral gene transfer events (a.k.a. horizontal gene transfer events) between a set of gene trees T1, T2, …, Tk and a species tree S. To the best of our knowledge, this model possesses a higher degree of biological and mathematical soundness than any other model proposed in the literature. Among other biological considerations, the model respects the partial order of evolution implied by S. Within our model, we identify an activity parameter that measures the number of genes that are allowed to be simultaneously active in the genome of a taxa and show that finding the most parsimonious scenario that reconciles the disagreeing gene trees with the species tree is doable in polynomial time when the activity level and number of transfers are small, but intractable in general. To the best of our knowledge, all other models proposed in the literature assume implicitly that the activity is one. Finally, using a dataset of bacterial gene sequences from [4], our implementations found 5 optimal scenarios; one of which is the scenario proposed by the authors in [4].

New algorithms for the duplication-loss model

We consider the problem of constructing a species tree given a number of gene trees. In the frameworks introduced by Goodman et al. [3], Page [10], and Guigó, Muchnik, and Smith [5] this is formulated as an optimization problem; namely, that of finding the species tree requiring the minimum number of duplications and/ or losses in order to explain the gene trees. In this paper, we introduce the WIDTH k DUPLICATION-LOSS and WIDTH k DUPLICATION problems. A gene tree has width k w.r.t. a species tree, if the species tree can be reconciled with the gene tree using at most k simultaneously active copies of the gene along its branches. We explain w.r.t. to the underlying biological model, why this width is typically very small in comparison to the total number of duplications and losses. We show polynomial time algorithms for finding optimal species trees having bounded width w.r.t. at least one of the input gene trees. Furthermore, we present the first algorithm for input gene trees that are unrooted. Lastly, we apply our algorithms to a dataset from [5] and show a species tree requiring significantly fewer duplications and fewer duplications/losses than the trees given in the original paper.

Simultaneous Identification of Duplications and Lateral Gene Transfers

The incongruency between a gene tree and a corresponding species tree can be attributed to evolutionary events such as gene duplication and gene loss. This paper describes a combinatorial model where so-called DTL-scenarios are used to explain the differences between a gene tree and a corresponding species tree taking into account gene duplications, gene losses, and lateral gene transfers (also known as horizontal gene transfers). The reasonable biological constraint that a lateral gene transfer may only occur between contemporary species leads to the notion of acyclic DTL-scenarios. Parsimony methods are introduced by defining appropriate optimization problems. We show that finding most parsimonious acyclic DTL-scenarios is NP-hard. However, by dropping the condition of acyclicity, the problem becomes tractable, and we provide a dynamic programming algorithm as well as a fixed-parameter tractable algorithm for finding most parsimonious DTL-scenarios.

Genome-wide survey for biologically functional pseudogenes

According to current estimates there exist about 20,000 pseudogenes in a mammalian genome. The vast majority of these are disabled and nonfunctional copies of protein-coding genes which, therefore, evolve neutrally. Recent findings that a Makorin1 pseudogene, residing on mouse Chromosome 5, is, indeed, in vivo vital and also evolutionarily preserved, encouraged us to conduct a genome-wide survey for other functional pseudogenes in human, mouse, and chimpanzee. We identify to our knowledge the first examples of conserved pseudogenes common to human and mouse, originating from one duplication predating the human–mouse species split and having evolved as pseudogenes since the species split. Functionality is one possible way to explain the apparently contradictory properties of such pseudogene pairs, i.e., high conservation and ancient origin. The hypothesis of functionality is tested by comparing expression evidence and synteny of the candidates with proper test sets. The tests suggest potential biological function. Our candidate set includes a small set of long-lived pseudogenes whose unknown potential function is retained since before the human–mouse species split, and also a larger group of primate-specific ones found from human–chimpanzee searches. Two processed sequences are notable, their conservation since the human–mouse split being as high as most protein-coding genes; one is derived from the protein Ataxin 7-like 3 (ATX7NL3), and one from the Spinocerebellar ataxia type 1 protein (ATX1). Our approach is comparative and can be applied to any pair of species. It is implemented by a semi-automated pipeline based on cross-species BLAST comparisons and maximum-likelihood phylogeny estimations. To separate pseudogenes from protein-coding genes, we use standard methods, utilizing in-frame disablements, as well as a probabilistic filter based on Ka/Ks ratios.

The gene evolution model and computing its associated probabilities

Phylogeny is both a fundamental tool in biology and a rich source of fascinating modeling and algorithmic problems. Todays wealth of sequenced genomes makes it increasingly important to understand evolutionary events such as duplications, losses, transpositions, inversions, lateral transfers, and domain shuffling. We focus on the gene duplication event, that constitutes a major force in the creation of genes with new function [Ohno 1970; Lynch and Force 2000] and, thereby also, of biodiversity. We introduce the probabilistic gene evolution model, which describes how a gene tree evolves within a given species tree with respect to speciation, gene duplication, and gene loss. The actual relation between gene tree and species tree is captured by a reconciliation, a concept which we generalize for more expressiveness. The model is a canonical generalization of the classical linear birth-death process, obtained by replacing the interval where the process takes place by a tree. For the gene evolution model, we derive efficient algorithms for some associated probability distributions: the probability of a reconciled tree, the probability of a gene tree, the maximum probability reconciliation, the posterior probability of a reconciliation, and sampling reconciliations with respect to the posterior probability. These algorithms provides the basis for several applications, including species tree construction, reconciliation analysis, orthology analysis, biogeography, and host-parasite co-evolution.

A-to-I editing of microRNAs in the mammalian brain increases during development

Adenosine-to-inosine (A-to-I) RNA editing targets double-stranded RNA stem-loop structures in the mammalian brain. It has previously been shown that miRNAs are substrates for A-to-I editing. For the first time, we show that for several definitions of edited miRNA, the level of editing increases with development, thereby indicating a regulatory role for editing during brain maturation. We use high-throughput RNA sequencing to determine editing levels in mature miRNA, from the mouse transcriptome, and compare these with the levels of editing in pri-miRNA. We show that increased editing during development gradually changes the proportions of the two miR-376a isoforms, which previously have been shown to have different targets. Several other miRNAs that also are edited in the seed sequence show an increased level of editing through development. By comparing editing of pri-miRNA with editing and expression of the corresponding mature miRNA, we also show an editing-induced developmental regulation of miRNA expression. Taken together, our results imply that RNA editing influences the miRNA repertoire during brain maturation.