Vamsi Kundeti

PMS5: an efficient exact algorithm for the (ℓ, d )-motif finding problem

BackgroundMotifs are patterns found in biological sequences that are vital for understanding gene function, human disease, drug design, etc. They are helpful in finding transcriptional regulatory elements, transcription factor binding sites, and so on. As a result, the problem of identifying motifs is very crucial in biology.ResultsMany facets of the motif search problem have been identified in the literature. One of them is (ℓ, d)-motif search (or Planted Motif Search (PMS)). The PMS problem has been well investigated and shown to be NP-hard. Any algorithm for PMS that always finds all the (ℓ, d)-motifs on a given input set is called an exact algorithm. In this paper we focus on exact algorithms only. All the known exact algorithms for PMS take exponential time in some of the underlying parameters in the worst case scenario. But it does not mean that we cannot design exact algorithms for solving practical instances within a reasonable amount of time. In this paper, we propose a fast algorithm that can solve the well-known challenging instances of PMS: (21, 8) and (23, 9). No prior exact algorithm could solve these instances. In particular, our proposed algorithm takes about 10 hours on the challenging instance (21, 8) and about 54 hours on the challenging instance (23, 9). The algorithm has been run on a single 2.4GHz PC with 3GB RAM. The implementation of PMS5 is freely available on the web at http://www.pms.engr.uconn.edu/downloads/PMS5.zip.ConclusionsWe present an efficient algorithm PMS5 that uses some novel ideas and combines them with well-known algorithm PMS1 and PMSPrune. PMS5 can tackle the large challenging instances (21, 8) and (23, 9). Therefore, we hope that PMS5 will help biologists discover longer motifs in the futures.

A computational tool for identifying minimotifs in protein-protein interactions and improving the accuracy of minimotif predictions

Protein–protein interactions are important to understanding cell functions; however, our theoretical understanding is limited. There is a general discontinuity between the well‐accepted physical and chemical forces that drive protein–protein interactions and the large collections of identified protein–protein interactions in various databases. Minimotifs are short functional peptide sequences that provide a basis to bridge this gap in knowledge. However, there is no systematic way to study minimotifs in the context of protein–protein interactions or vice versa. Here we have engineered a set of algorithms that can be used to identify minimotifs in known protein–protein interactions and implemented this for use by scientists in Minimotif Miner. By globally testing these algorithms on verified data and on 100 individual proteins as test cases, we demonstrate the utility of these new computation tools. This tool also can be used to reduce false‐positive predictions in the discovery of novel minimotifs. The statistical significance of these algorithms is demonstrated by an ROC analysis (P = 0.001). Proteins 2010.

Secondary Structure, a Missing Component of Sequence-Based Minimotif Definitions

Minimotifs are short contiguous segments of proteins that have a known biological function. The hundreds of thousands of minimotifs discovered thus far are an important part of the theoretical understanding of the specificity of protein-protein interactions, posttranslational modifications, and signal transduction that occur in cells. However, a longstanding problem is that the different abstractions of the sequence definitions do not accurately capture the specificity, despite decades of effort by many labs. We present evidence that structure is an essential component of minimotif specificity, yet is not used in minimotif definitions. Our analysis of several known minimotifs as case studies, analysis of occurrences of minimotifs in structured and disordered regions of proteins, and review of the literature support a new model for minimotif definitions that includes sequence, structure, and function.

MimoSA: a system for minimotif annotation

BackgroundMinimotifs are short peptide sequences within one protein, which are recognized by other proteins or molecules. While there are now several minimotif databases, they are incomplete. There are reports of many minimotifs in the primary literature, which have yet to be annotated, while entirely novel minimotifs continue to be published on a weekly basis. Our recently proposed function and sequence syntax for minimotifs enables us to build a general tool that will facilitate structured annotation and management of minimotif data from the biomedical literature.ResultsWe have built the MimoSA application for minimotif annotation. The application supports management of the Minimotif Miner database, literature tracking, and annotation of new minimotifs. MimoSA enables the visualization, organization, selection and editing functions of minimotifs and their attributes in the MnM database. For the literature components, Mimosa provides paper status tracking and scoring of papers for annotation through a freely available machine learning approach, which is based on word correlation. The paper scoring algorithm is also available as a separate program, TextMine. Form-driven annotation of minimotif attributes enables entry of new minimotifs into the MnM database. Several supporting features increase the efficiency of annotation. The layered architecture of MimoSA allows for extensibility by separating the functions of paper scoring, minimotif visualization, and database management. MimoSA is readily adaptable to other annotation efforts that manually curate literature into a MySQL database.ConclusionsMimoSA is an extensible application that facilitates minimotif annotation and integrates with the Minimotif Miner database. We have built MimoSA as an application that integrates dynamic abstract scoring with a high performance relational model of minimotif syntax. MimoSAs TextMine, an efficient paper-scoring algorithm, can be used to dynamically rank papers with respect to context.

On the Hardness of the Border Length Minimization Problem

DNA microarray technology has proven to be an invaluable tool for molecular biologists. Microarrays are used extensively in SNP detection, genomic hybridization, alternative splicing and gene expression profiling. However the manufacturers of the microarrays are often stuck with the problem of minimizing the effects of unwanted illumination (border length minimization (BLM)) which is a hard combinatorial problem. In this paper we prove that the BLM problem on a rectangular grid is NP-hard. We also give the first integer linear programming (ILP) formulation to solve BLM problem optimally. Experimental results indicate that our ILP method produces superior results (both in runtime and cost) compared to the current state of the art algorithms to solve the BLM problem optimally.

Extending the Four Russian Algorithm to Compute the Edit Script in Linear Space

Computing the edit distancebetween two strings is one of the most fundamental problems in computer science. The standard dynamic programming based algorithm computes the edit distanceand edit scriptin O(n2) time and space. Often the edit scriptis of more importance than the value of the edit distance. The Four Russian Algorithm [1] computes the edit distancein O(n2/logn) time but does not address how to compute edit scriptwithin that runtime. Hirschberg [2] gave an algorithm to compute edit scriptin linear space but the runtime remained O(n2). In this paper we present algorithms that compute both the edit scriptand edit distancein

Border Length Minimization Problem on a Square Array

O(\frac{n^2}{\log n})

AN EFFICIENT ALGORITHM FOR CHINESE POSTMAN WALK ON BI-DIRECTED DE BRUIJN GRAPHS

time using O(n) space.

Efficient out-of-core sorting algorithms for the Parallel Disks Model

Protein/peptide microarrays are rapidly gaining momentum in the diagnosis of cancer. High-density and high-throughput peptide arrays are being extensively used to detect tumor biomarkers, examine kinase activity, identify antibodies having low serum titers, and locate antibody signatures. Improving the yield of microarray fabrication involves solving a hard combinatorial optimization problem called the border length minimization problem (BLMP). An important question that remained open for the past 7 years is if the BLMP is tractable or not. We settle this open problem by proving that the BLMP is [Formula: see text]-hard. We also present a hierarchical refinement algorithm that can refine any heuristic solution for the BLMP and prove that the TSP+1-threading heuristic is an O(N)-approximation.

Efficient Algorithms for Computing With Protein-Based Volumetric Memory Processors

Sequence assembly from short reads is an important problem in biology. It is known that solving the sequence assembly problem exactly on a bi-directed de Bruijn graph or a string graph is intractable. However, finding a shortest double stranded DNA string (SDDNA) containing all the k-long words in the reads seems to be a good heuristic to get close to the original genome. This problem is equivalent to finding a cyclic Chinese Postman (CP) walk on the underlying unweighted bi-directed de Bruijn graph built from the reads. The Chinese Postman walk Problem (CPP) is solved by reducing it to a general bi-directed flow on this graph which runs in O(|E|2log2(|V|)) time. In this paper we show that the cyclic CPP on bi-directed graphs can be solved without reducing it to bi-directed flow. We present a Θ(p(|V| + |E|)log(|V|) + (dmaxp)3) time algorithm to solve the cyclic CPP on a weighted bi-directed de Bruijn graph, where p = max{|{v|din(v) - dout(v) > 0}|, |{v|din(v) - dout(v) < 0}|} and dmax = max{|din(v) - dout(v)}. Our algorithm performs asymptotically better than the bi-directed flow algorithm when the number of imbalanced nodes p is much less than the nodes in the bi-directed graph. From our experimental results on various datasets, we have noticed that the value of p/|V| lies between 0.08% and 0.13% with 95% probability. Many practical bi-directed de Bruijn graphs do not have cyclic CP walks. In such cases it is not clear how the bi-directed flow can be useful in identifying contigs. Our algorithm can handle such situations and identify maximal bi-directed sub-graphs that have CP walks. A Θ(p(|V| + |E|)) time heuristic algorithm based on these ideas has been implemented for the SDDNA problem. This algorithm was tested on short reads from a plant genome and achieves an approximation ratio of at most 1.0134. We also present a Θ((|V| + |E|)log(V)) time algorithm for the single source shortest path problem on bi-directed de Bruijn graphs, which may be of independent interest.