The impact of age, biogenesis, and genomic clustering on Drosophila microRNA evolution

The molecular evolutionary signatures of miRNAs inform our understanding of their emergence, biogenesis, and function. The known signatures of miRNA evolution have derived mostly from the analysis of deeply conserved, canonical loci. In this study, we examine the impact of age, biogenesis pathway, and genomic arrangement on the evolutionary properties of Drosophila miRNAs. Crucial to the accuracy of our results was our curation of high-quality miRNA alignments, which included nearly 150 corrections to ortholog calls and nucleotide sequences of the global 12-way Drosophilid alignments currently available. Using these data, we studied primary sequence conservation, normalized free-energy values, and types of structure-preserving substitutions. We expand upon common miRNA evolutionary patterns that reflect fundamental features of miRNAs that are under functional selection. We observe that melanogaster-subgroup-specific miRNAs, although recently emerged and rapidly evolving, nonetheless exhibit evolutionary signatures that are similar to well-conserved miRNAs and distinct from other structured noncoding RNAs and bulk conserved non-miRNA hairpins. This provides evidence that even young miRNAs may be selected for regulatory activities. More strikingly, we observe that mirtrons and clustered miRNAs both exhibit distinct evolutionary properties relative to solo, well-conserved miRNAs, even after controlling for sequence depth. These studies highlight the previously unappreciated impact of biogenesis strategy and genomic location on the evolutionary dynamics of miRNAs, and affirm that miRNAs do not evolve as a unitary class

Analytical derivation of elasticity in breast phantoms for deformation tracking

Patient-specific biomedical modeling of the breast is of interest for medical applications such as image registration, image guided procedures and the alignment for biopsy or surgery purposes. The computation of elastic properties is essential to simulate deformations in a realistic way. This study presents an innovative analytical method to compute the elastic modulus and evaluate the elasticity of a breast using magnetic resonance (MRI) images of breast phantoms.An analytical method for elasticity computation was developed and subsequently validated on a series of geometric shapes, and on four physical breast phantoms that are supported by a planar frame. This method can compute the elasticity of a shape directly from a set of MRI scans. For comparison, elasticity values were also computed numerically using two different simulation software packages.Application of the different methods on the geometric shapes shows that the analytically derived elongation differs from simulated elongation by less than 9% for cylindrical shapes, and up to 18% for other shapes that are also substantially vertically supported by a planar base. For the four physical breast phantoms, the analytically derived elasticity differs from numeric elasticity by 18% on average, which is in accordance with the difference in elongation estimation for the geometric shapes. The analytic method has shown to be multiple orders of magnitude faster than the numerical methods.It can be concluded that the analytical elasticity computation method has good potential to supplement or replace numerical elasticity simulations in gravity-induced deformations, for shapes that are substantially supported by a planar base perpendicular to the gravitational field. The error is manageable, while the calculation procedure takes less than one second as opposed to multiple minutes with numerical methods. The results will be used in the MRI and Ultrasound Robotic Assisted Biopsy (MURAB) project

Iterative simulations to estimate the elastic properties from a series of MRI images followed by MRI-US validation

The modeling of breast deformations is of interest in medical applications such as image-guided biopsy, or image registration for diagnostic purposes. In order to have such information, it is needed to extract the mechanical properties of the tissues. In this work, we propose an iterative technique based on finite element analysis that estimates the elastic modulus of realistic breast phantoms, starting from MRI images acquired in different positions (prone and supine), when deformed only by the gravity force. We validated the method using both a single-modality evaluation in which we simulated the effect of the gravity force to generate four different configurations (prone, supine, lateral, and vertical) and a multi-modality evaluation in which we simulated a series of changes in orientation (prone to supine). Validation is performed, respectively, on surface points and lesions using as ground-truth data from MRI images, and on target lesions inside the breast phantom compared with the actual target segmented from the US image. The use of pre-operative images is limited at the moment to diagnostic purposes. By using our method we can compute patient-specific mechanical properties that allow compensating deformations

Adaptive evolution of testis-specific, recently evolved, clustered miRNAs in Drosophila

The propensity of animal miRNAs to regulate targets bearing modest complementarity, most notably via pairing with miRNA positions approximately 2-8 (the "seed"), is believed to drive major aspects of miRNA evolution. First, minimal targeting requirements have allowed most conserved miRNAs to acquire large target cohorts, thus imposing strong selection on miRNAs to maintain their seed sequences. Second, the modest pairing needed for repression suggests that evolutionarily nascent miRNAs may generally induce net detrimental, rather than beneficial, regulatory effects. Hence, levels and activities of newly emerged miRNAs are expected to be limited to preserve the status quo of gene expression. In this study, we unexpectedly show that Drosophila testes specifically express a substantial miRNA population that contravenes these tenets. We find that multiple genomic clusters of testis-restricted miRNAs harbor recently evolved miRNAs, whose experimentally verified orthologs exhibit divergent sequences, even within seed regions. Moreover, this class of miRNAs exhibits higher expression and greater phenotypic capacities in transgenic misexpression assays than do non-testis-restricted miRNAs of similar evolutionary age. These observations suggest that these testis-restricted miRNAs may be evolving adaptively, and several methods of evolutionary analysis provide strong support for this notion. Consistent with this, proof-of-principle tests show that orthologous miRNAs with divergent seeds can distinguish target sensors in a species-cognate manner. Finally, we observe that testis-restricted miRNA clusters exhibit extraordinary dynamics of miRNA gene flux in other Drosophila species. Altogether, our findings reveal a surprising tissue-directed influence of miRNA evolution, involving a distinct mode of miRNA function connected to adaptive gene regulation in the testis

Parking functions, labeled trees and DCJ sorting scenarios

In genome rearrangement theory, one of the elusive questions raised in recent years is the enumeration of rearrangement scenarios between two genomes. This problem is related to the uniform generation of rearrangement scenarios, and the derivation of tests of statistical significance of the properties of these scenarios. Here we give an exact formula for the number of double-cut-and-join (DCJ) rearrangement scenarios of co-tailed genomes. We also construct effective bijections between the set of scenarios that sort a cycle and well studied combinatorial objects such as parking functions and labeled trees.Comment: 12 pages, 3 figure

Gene regulation by CcpA and catabolite repression explored by RNA-Seq in Streptococcus mutans

A bacterial transcriptome of the primary etiological agent of human dental caries, Streptococcus mutans, is described here using deep RNA sequencing. Differential expression profiles of the transcriptome in the context of carbohydrate source, and of the presence or absence of the catabolite control protein CcpA, revealed good agreement with previously-published DNA microarrays. In addition, RNA-seq considerably expanded the repertoire of DNA sequences that showed statistically-significant changes in expression as a function of the presence of CcpA and growth carbohydrate. Novel mRNAs and small RNAs were identified, some of which were differentially expressed in conditions tested in this study, suggesting that the function of the S. mutans CcpA protein and the influence of carbohydrate sources has a more substantial impact on gene regulation than previously appreciated. Likewise, the data reveal that the mechanisms underlying prioritization of carbohydrate utilization are more diverse than what is currently understood. Collectively, this study demonstrates the validity of RNA-seq as a potentially more-powerful alternative to DNA microarrays in studying gene regulation in S. mutans because of the capacity of this approach to yield a more precise landscape of transcriptomic changes in response to specific mutations and growth conditions

Accurate reconstruction of insertion-deletion histories by statistical phylogenetics

The Multiple Sequence Alignment (MSA) is a computational abstraction that represents a partial summary either of indel history, or of structural similarity. Taking the former view (indel history), it is possible to use formal automata theory to generalize the phylogenetic likelihood framework for finite substitution models (Dayhoff's probability matrices and Felsenstein's pruning algorithm) to arbitrary-length sequences. In this paper, we report results of a simulation-based benchmark of several methods for reconstruction of indel history. The methods tested include a relatively new algorithm for statistical marginalization of MSAs that sums over a stochastically-sampled ensemble of the most probable evolutionary histories. For mammalian evolutionary parameters on several different trees, the single most likely history sampled by our algorithm appears less biased than histories reconstructed by other MSA methods. The algorithm can also be used for alignment-free inference, where the MSA is explicitly summed out of the analysis. As an illustration of our method, we discuss reconstruction of the evolutionary histories of human protein-coding genes.Comment: 28 pages, 15 figures. arXiv admin note: text overlap with arXiv:1103.434