Finding composite regulatory patterns in DNA sequences

Pattern discovery in unaligned DNA sequences is a fundamental problem in computational biology with important applications in finding regulatory signals. Current approaches to pattern discovery focus on monad patterns that correspond to relatively short contiguous strings. However, many of the actual regulatory signals are composite patterns that are groups of monad patterns that occur near each other. A difficulty in discovering composite patterns is that one or both of the component monad patterns in the group may be 'too weak'. Since the traditional monad-based motif finding algorithms usually output one (or a few) high scoring patterns, they often fail to find composite regulatory signals consisting of weak monad parts. In this paper, we present a MITRA (MIsmatch TRee Algorithm) approach for discovering composite signals. We demonstrate that MITRA performs well for both monad and composite patterns by presenting experiments over biological and synthetic data.     

Subtle motifs: defining the limits of motif finding algorithms

MOTIVATION: What constitutes a subtle motif? Intuitively, it is a motif that is almost indistinguishable, in the statistical sense, from random motifs. This question has important practical consequences: consider, for example, a biologist that is generating a sample of upstream regulatory sequences with the goal of finding a regulatory pattern that is shared by these sequences. If the sequences are too short then one risks losing some of the regulatory patterns that are located further upstream. Conversely, if the sequences are too long, the motif becomes too subtle and one is then likely to encounter random motifs which are at least as significant statistically as the regulatory pattern itself. In practical terms one would like to recognize the sequence length threshold, or the twilight zone, beyond which the motifs are in some sense too subtle. RESULTS: The paper defines the motif twilight zone where every motif finding algorithm would be exposed to random motifs which are as significant as the one which is sought. We also propose an objective tool for evaluating the performance of subtle motif finding algorithms. Finally we apply these tools to evaluate the success of our MULTIPROFILER algorithm to detect subtle motifs.     

Colored de Bruijn graphs and the genome halving problem

Breakpoint graph analysis is a key algorithmic technique in studies of genome rearrangements. However, breakpoint graphs are defined only for genomes without duplicated genes, thus limiting their applications in rearrangement analysis. We discuss a connection between the breakpoint graphs and de Bruijn graphs that leads to a generalization of the notion of breakpoint graph for genomes with duplicated genes. We further use the generalized breakpoint graphs to study the genome halving problem (first introduced and solved by Nadia El-Mabrouk and David Sankoff). The El-Mabrouk-Sankoff algorithm is rather complex, and, in this paper, we present an alternative approach that is based on generalized breakpoint graphs. The generalized breakpoint graphs make the El-Mabrouk-Sankoff result more transparent and promise to be useful in future studies of genome rearrangements     

Microbiota and mitobiota. Putting an equal sign between mitochondria and bacteria

The recent revival of old theories and setting them on modern scientific rails to a large extent are also relevant to mitochondrial science. Given the widespread belief that mitochondria are symbionts of ancient bacterial origin, the processes inherent to mitochondrial physiology can be revised based on their comparative analysis with possible involvement of bacteria. Such comparison combined with discussion of the role of microbiota in pathogenesis allows discussion of the role of “mitobiota” (we introduce this term) as the combination of different phenotypic manifestations of mitochondria in the organism reflecting pathological changes in the mitochondrial genome. When putting an equal sign between mitochondria and bacteria, we find similarity between the mitochondrial and bacterial theories of cancer. The presence of the term “bacterial infection” suggests “mitochondrial infection”, and mitochondrial (oxidative) theory of aging can in some way be transformed into a “bacterial theory of aging”. The possible existence of such processes and the data confirming their presence are discussed in this review. If such a comparison has the right to exist, the homeostasis of “mitobiota” is of not lesser physiological importance than homeostasis of microbiota, which has been so intensively discussed recently.     

Comparative genomics reveals birth and death of fragile regions in mammalian evolution

Background  

An important question in genome evolution is whether there exist fragile regions (rearrangement hotspots) where chromosomal rearrangements are happening over and over again. Although nearly all recent studies supported the existence of fragile regions in mammalian genomes, the most comprehensive phylogenomic study of mammals raised some doubts about their existence.     

Understanding the basic biology underlying the flavor world of children

Health organizations worldwide recommend that adults and children minimize intakes of excess energy and salty, sweet, and fatty foods (all of which are highly preferred tastes) and eat diets richer in whole grains, low- and non- fat dairy products, legumes, fish, lean meat, fruits, and vegetables (many of which taste bitter). Despite such recommendations and the well-established benefits of these foods to human health, adults are not complying, nor are their children. A primary reason for this difficulty is...     

Comparative genomics reveals unusually long motifs in mammalian genomes

MOTIVATION: The recent discovery of the first small modulatory RNA (smRNA) presents the challenge of finding other molecules of similar length and conservation level. Unlike short interfering RNA (siRNA) and micro-RNA (miRNA), effective computational and experimental screening methods are not currently known for this species of RNA molecule, and the discovery of the one known example was partly fortuitous because it happened to be complementary to a well-studied DNA binding motif (the Neuron Restrictive Silencer Element). RESULTS: The existing comparative genomics approaches (e.g., phylogenetic footprinting) rely on alignments of orthologous regions across multiple genomes. This approach, while extremely valuable, is not suitable for finding motifs with highly diverged "non-alignable" flanking regions. Here we show that several unusually long and well conserved motifs can be discovered de novo through a comparative genomics approach that does not require an alignment of orthologous upstream regions. These motifs, including Neuron Restrictive Silencer Element, were missed in recent comparative genomics studies that rely on phylogenetic footprinting. While the functions of these motifs remain unknown, we argue that some may represent biologically important sites. AVAILABILITY: Our comparative genomics software, a web-accessible database of our results and a compilation of experimentally validated binding sites for NRSE can be found at http://www.cse.ucsd.edu/groups/bioinformatics.