miRTissue: a web application for the analysis of miRNA-target interactions in human tissues

Background

microRNAs act as regulators of gene expression interacting with their gene targets. Current bioinformatics services, such as databases of validated miRNA-target interactions and prediction tools, usually provide interactions without any information about what tissue that interaction is more likely to appear nor information about the type of interactions, causing mRNA degradation or translation inhibition respectively.

Results

In this work, we introduce miRTissue, a web application that combines validated miRNA-target interactions with statistical correlation among expression profiles of miRNAs, genes and proteins in 15 different human tissues. Validated interactions are taken from the miRTarBase database, while expression profiles are downloaded from The Cancer Genome Atlas repository. As a result, the service provides a tissue-specific characterisation of each couple of miRNA and gene together with its statistical significance (p-value). The inclusion of protein data also allows providing the type of interaction. Moreover, miRTissue offers several views for analysing interactions, focusing for example on the comparison between different cancer types or different tissue conditions. All the results are freely downloadable in the most common formats.

Conclusions

miRTissue fills a gap concerning current bioinformatics services related to miRNA-target interactions because it provides a tissue-specific context to each validated interaction and the type of interaction itself. miRTissue is easily browsable allowing the user to select miRNAs, genes, cancer types and tissue conditions. The results can be sorted according to p-values to immediately identify those interactions that are more likely to occur in a given tissue. miRTissue is available at http://tblab.pa.icar.cnr.it/mirtissue.html.

     

Perfect seed pairing is not a generally reliable predictor for miRNA-target interactions

We use Caenorhabditis elegans to test proposed general rules for microRNA (miRNA)-target interactions. We show that G.U base pairing is tolerated in the 'seed' region of the lsy-6 miRNA interaction with its in vivo target cog-1, and that 6- to 8-base-pair perfect seed pairing is not a generally reliable predictor for an interaction of lsy-6 with a 3' untranslated region (UTR). Rather, lsy-6 can functionally interact with its target site only in specific 3' UTR contexts. Our findings illustrate the difficulty of establishing generalizable rules of miRNA-target interactions.     

Local and global effects of Mg2+ on Ago and miRNA-target interactions

Three magnesium ions (Mg(2+)), named Mg1 (in Mid domain), Mg2 and Mg3 (both in PIWI domain), located at the small RNA binding domain of Argonaute (Ago) protein, are important for sequence-specific miRNA-target interactions. Such conjunction between the Ago protein and miRNA raises the question: How do Mg(2+) ions participate in the recognition process of miRNA by Ago or its target. Furthermore, it is still unclear whether the Mg(2+) ions contribute to the local or global stability of the miRNA complex. In this work, we have performed a series of 16 independent molecular dynamic simulations (MD) to characterize the functions of Mg(2+), hydration patterns and the conformational events involved in the miRNA-target interactions. The cross correlation analysis shows that Mg1 and Mg2 significantly enhance a locally cooperated movement of the PAZ, PIWI and Mid domains with the average correlation coefficient of ～0.65, producing an "open-closed" motion (rotation Angle, 46.5°) between the PAZ and PIWI domains. Binding of Mg3 can globally stabilize the whole Ago protein with the average RMSD of ～0.34 ?, compared with the systems in absence of Mg3 (average RMSD?=?～0.43 ?). Three structural water molecules surrounding the Mg(2+)-binding regions also stabilize these ions, thus facilitating the recognition of miRNA to its target. In addition, the thermodynamic analysis also verifies the positive contribution of all three Mg(2+) to the binding of miRNA to Ago, as well as the importance Mg2 plays in the cleavage of the miRNA targets.     

Evolution of sex determination in mammals

This review summarizes current concepts concerning the evolution of sex chromosomes and the cascade of sex-determining genes in mammals. Untypical sex-determination systems in rodents lacking the Y chromosome and Sry gene are considered using Ellobius as an example.     

Borrelia burgdorferi protein interactions critical for microbial persistence in mammals

Borrelia burgdorferi is the causative agent of Lyme disease that persists in a complex enzootic life cycle, involving Ixodes ticks and vertebrate hosts. The microbe invades ticks and vertebrate hosts in spite of active immune surveillance and potent microbicidal responses, and establishes long‐term infection utilising mechanisms that are yet to be unravelled. The pathogen can cause multi‐system disorders when transmitted to susceptible mammalian hosts, including in humans. In the past decades, several studies identified a limited number of B. burgdorferi gene‐products critical for pathogen persistence, transmission between the vectors and the host, and host–pathogen interactions. This review will focus on the interactions between B. burgdorferi proteins, as well as between microbial proteins and host components, protein and non‐protein components, highlighting their roles in pathogen persistence in the mammalian host. A better understanding of the contributions of protein interactions in the microbial virulence and persistence of B. burgdorferi would support development of novel therapeutics against the infection.     

The many facets of facial interactions in mammals

Facial interactions are prominent behaviors in primates. Primate facial signaling, which includes the expression of emotions, mimicking of facial movements, and gaze interactions, is visually dominated. Correspondingly, in primate brains an elaborate network of face processing areas exists within visual cortex. But other mammals also communicate through facial interactions using additional sensory modalities. In rodents, multisensory facial interactions are involved in aggressive behaviors and social transmission of food preferences. The eusocial naked mole-rat, whose face is dominated by prominent incisors, uses facial aggression to enforce reproductive suppression. In burrow-living mammals like the naked mole-rat in particular, and in rodents in general, somatosensory face representations in cortex are enlarged. Diversity of sensory domains mediating facial communication might belie underlying common mechanisms. As a case in point, neurogenetics has revealed strongly heritable traits in face processing and identified gene defects that disrupt facial interactions both in humans and rodents.     

Mechanical model for theoretical determination of maximum running speed in mammals

A mechanical model for the determination of maximum speed in terrestrial tetrapods, designed for application to extinct species, is proposed. Only external bone measures and average body mass estimations are used as input data, and the hypothesis is made that leg bones are strong enough to endure the stress of running at maximum speed at a certain universal safety factor. The model is applied to a broad sample of living mammalian species to test its predictive power, and it is found to provide very good estimates of maximum running speed.     

The end of gonad-centric sex determination in mammals

The 20th-century theory of mammalian sex determination states that the embryo is sexually indifferent until the differentiation of gonads, after which sex differences in phenotype are caused by the differential effects of gonadal hormones. However, this theory is inadequate because some sex differences precede differentiation of the gonads and/or are determined by non-gonadal effects of the sexual inequality in the number and type of sex chromosomes. In this article, I propose a general theory of sex determination, which recognizes multiple parallel primary sex-determining pathways initiated by genes or factors encoded by the sex chromosomes. The separate sex-specific pathways interact to synergize with or antagonize each other, enhancing or reducing sex differences in phenotype.     

The influence of body-size and diet on road-kill trends in mammals

Roads negatively impact animals in a variety of ways. One of the most obvious impacts is vehicle-induced mortality. We have little understanding of the patterns and rates of road mortality for mammals. The aims of this study were to determine representative road-kill rates for local mammal species, compare road-kill rates between mammals of different sizes and diets, and compare patterns of road mortality between seasons. We hypothesized that carnivores would be killed less often than herbivores or omnivores and that medium sized mammals (1.0–10.0 kg) would be killed more often than expected based on their frequency in the area. At least 50% of the mammal species in the study area were impacted by road mortality, representing 21 species from 5 mammalian orders. Carnivores were found less often and medium-sized mammals more often than predicted. Porcupines (Erithizon dorsatum), raccoons (Procyon lotor), cottontails (Sylvilagus floridanus) and striped skunks (Mephitis mephitis) were the most frequent species to be killed. On average, 3.8 mammals were killed per 100 km of road. The road-kill rate varied between seasons and species and peaked in mid June. We also looked across studies to determine general rates of vehicle-induced mortality for mammals and found that an average of 8.8 mammals are killed per 100 km. Given the rapid decline of many mammal species and the consistent increase in vehicle miles traveled, efforts to preserve roadless areas and develop strategies to mitigate the effects of roads on mammals are warranted.     

Quantitative determination of methanogenic bacteria in the feces of different mammals

In this research on fresh human, cattle, swine, and rabbit feces, methanogenic bacteria were found in all samples examined, at the following concentrations per gram dry weight: swine, 10⁸; human, 10⁷; cattle, 10⁶; and rabbit, 10⁴. Anaerobic heterotrophic bacteria were found in the following concentrations per gram dry weight: human, 10¹¹; swine, 10¹¹; cattle, 10¹¹; and rabbit, 10¹⁰. The total number of O₂-intolerant was higher than that of O₂-tolerant bacteria: about 10–100 times for methanogenic and 100–1000 times for anaerobic heterotrophic bacteria.     

Sex chromosomes and sex determination in weird mammals

Weird mammals are of two types. Highly divergent mammals, such as the marsupials and monotremes, have informed us of the evolutionary history of the Y chromosome and sex-determining gene, and the recently specialized rodents can help us predict its future. The Y chromosome has had a short but eventful history, and is already heading briskly for oblivion. It originated as a homologous partner of the X when it acquired a sex-determining gene (not necessarily SRY). Most of the genes on the Y, even those with a male-specific function, evolved from genes now on the X. At the mercy of a high rate of variability and the forces of drift and selection, the Y has lost genes at a rate of 3-6 genes/million years, sparing those that acquired critical male-specific functions. Even these genes have disappeared from one mammalian lineage or another as their functions were usurped by genes elsewhere in the genome. The mammalian testis-determining gene, SRY, is a typical Y-borne gene. It arose by truncation of a gene (SOX3) on the X that is expressed in brain development, and it may work by interacting with (inhibiting?) related genes, including SOX9. Variant sex-determining systems in rodents show that the action of SRY can change, as it evidently has in the mouse, and SRY can be inactivated, as in akodont rodents, or even completely superseded, as in mole voles.     

Genetic mechanisms underlying male sex determination in mammals

Genetic control of gonadal development proceeds through either the male or female molecular pathways, driving bipotential gonadal anlage differentiation into a testis or ovary. Antagonistic interactions between the 2 pathways determine the gonadal sex. Essentially sex determination is the enhancement of one of the 2 pathways according to genetic sex. Initially, Sry with other factors upregulatesSox9 expression in XY individuals. Afterwards the expression ofSox9 is maintained by a positive feedback loop withFgf9 and prostaglandin D₂ as well as by autoregulative ability of Sox9. If these factors reach high concentrations, then Sox9 and/or Fgf9 may inhibit the female pathway. Surprisingly, splicing, nuclear transport, and extramatrix proteins may be involved in sex determination. The male sex determination pathway switches on the expression of genes driving Sertoli cell differentiation. Sertoli cells orchestrate testicular differentiation. In the absence of Sry, the predomination of the female pathway results in the realization of a robust genetic program that drives ovarian differentiation.     

Genetic control of spermatogenesis and sex determination in mammals

The material was analyzed on the main problems of genetics of mammalian spermatogenesis, sex determination, its reversion and other defects from the standpoint of current cytological and molecular-genetic concepts of functional activity of the parental genomes after fertilization and behavior of their chromosomes at the early embroyonic stages. On the basis of this analysis, a hypothesis has been proposed, which explains a high percentage (50% or more) of early embryonic mortality in placental mammals under the conditions of natural and extracorporeal fertilization, as well as regular appearance of defects in the course of natural sex determination, including the appearance of representatives of both sex minorities. We do not make pretense to comprehensive and deep analysis of male gametogenesis and sex determination in mammals.     

Genetic tools in the management of invasive mammals: recent trends and future perspectives

1. Invasive non-native species are now considered to be one of the greatest threats to biodiversity worldwide. Therefore, efficient and cost-effective management of species invasions requires robust knowledge of their demography, ecology and impacts, and genetic-based techniques are becoming more widely adopted in acquiring such knowledge.
2. We focus on the use of genetic tools in the applied management of mammalian invasions globally, as well as on their inherent advantages and disadvantages. We cover tools that are used in: 1) detecting and monitoring mammalian invaders; 2) identifying origins and invasive pathways; 3) assessing and quantifying the negative impacts of invaders; and 4) population management and potential eradication of invasive mammals.
3. We highlight changes in sequencing technologies, including how the use of techniques such as Sanger sequencing and microsatellite genotyping, for monitoring and tracing invasive pathways respectively, are now giving way to the use of high-throughput sequencing methods. These include the emergence of environmental DNA (eDNA) metabarcoding for the early detection of invasive mammals, and single nucleotide polymorphisms or whole genomes to trace the sources of invasive populations. We are now moving towards trials of genome-editing techniques and gene drives to control or eradicate invasive rodents.
4. Genetic tools can provide vital information that may not be accessible with non-genetic methods, for the implementation of conservation policies (e.g. early detection using systematic eDNA surveillance, the identification of novel pathogens). However, the lack of clear communication of novel genetic methods and results (including transparency and reproducibility) to relevant stakeholders can be prohibitive in translating these findings to appropriate management actions. Geneticists should engage early with stakeholders to co-design experiments in relation to management goals for invasive mammals.