Scandinavian Journal of Clinical & Laboratory Investigation, Jul 13, 2016
Abstract Since their discovery in 1993, microRNAs (miRNAs) have been identified as important gene... more Abstract Since their discovery in 1993, microRNAs (miRNAs) have been identified as important gene regulators in many biological processes and as key molecular players in human disease, including cancer where they show specific pathogenic deregulation. Their remarkable chemical stability, the availability of very sensitive miRNA detection methods and the fact that miRNAs can be extracted from and detected in various kinds of clinically relevant samples, such as solid tissues, body fluids and secretions make them excellent candidate biomarkers. However, no miRNA has yet entered the level of practical clinical relevance. We present a brief background and some key aspects and challenges of miRNAs as cancer biomarkers, we discuss shortfalls and identify possible routes towards the use of miRNAs as reliable biomarkers for cancer.
V Congreso de la Sociedad Española de Biología Evolutiva (2016)Micro RNAs (miRNAs) are small RNA ... more V Congreso de la Sociedad Española de Biología Evolutiva (2016)Micro RNAs (miRNAs) are small RNA molecules regulating gene expression at the post-transcriptional level. The miRNAs of several holometabolan insects ( Tribolium, Bombyx and Drosophila), have been identified but data on hemimetabolan species are scarce. We present the highly accurate miRNA complement of the hemimetabolan insect Blattella germanica. Hemimetabolan insects differ from holometabolans by showing the adult body plan already in juvenile stages. In contrast holometabolan juveniles have a morphology very different with respect to that of the adult. After filtering with stringent criteria based on miRNA biogenesis the in-silico miRNA predictions based on RNA-seq, we identified 100 miRNA genes. These were grouped in 71 miRNA families, 61 of them described in other organism and 10 new. Our findings are qualitative and quantitative concordant with the previous phylogenetic studies; however, three miRNA families (Mir-36, Mir-309 and Mir-3791) believed to be present in all hemimetabolan insects were not found in B. germanica. Moreover, 4 miRNA families that were thought to have originated on holometabolan insects (Mir-11, Mir-932, Mir- 3770 and Mir-6012) were found in B. germanica.N
The evolution of specialized cell‐types is a long‐standing interest of biologists, but given the ... more The evolution of specialized cell‐types is a long‐standing interest of biologists, but given the deep time‐scales very difficult to reconstruct or observe. microRNAs have been linked to the evolution of cellular complexity and may inform on specialization. The endothelium is a vertebrate‐specific specialization of the circulatory system that enabled a critical new level of vasoregulation. The evolutionary origin of these endothelial cells is unclear. We hypothesized that Mir‐126, an endothelial cell‐specific microRNA may be informative. We here reconstruct the evolutionary history of Mir‐126. Mir‐126 likely appeared in the last common ancestor of vertebrates and tunicates, which was a species without an endothelium, within an intron of the evolutionary much older EGF Like Domain Multiple (Egfl) locus. Mir‐126 has a complex evolutionary history due to duplications and losses of both the host gene and the microRNA. Taking advantage of the strong evolutionary conservation of the microR...
Whole genome duplications (WGDs) are major events that drastically reshape genome architecture an... more Whole genome duplications (WGDs) are major events that drastically reshape genome architecture and are causally associated with organismal innovations and radiations1. The 2R Hypothesis suggests that two WGD events (1R and 2R) occurred during early vertebrate evolution2, 3. However, the veracity and timing of the 2R event relative to the divergence of gnathostomes (jawed vertebrates) and cyclostomes (jawless hagfishes and lampreys) is unresolved4–6and whether these WGD events underlie vertebrate phenotypic diversification remains elusive7. Here we present the genome of the inshore hagfish,Eptatretus burgeri. Through comparative analysis with lamprey and gnathostome genomes, we reconstruct the early events in cyclostome genome evolution, leveraging insights into the ancestral vertebrate genome. Genome-wide synteny and phylogenetic analyses support a scenario in which 1R occurred in the vertebrate stem-lineage during the early Cambrian, and the 2R event occurred in the gnathostome ste...
SummaryThe annotation of microRNAs, an important class of post-transcriptional regulators, depend... more SummaryThe annotation of microRNAs, an important class of post-transcriptional regulators, depends on the availability of transcriptomics data and expert knowledge. This led to a large gap between novel genomes made available and high-quality microRNA complements. Using >16,000 microRNAs from the manually curated microRNA gene database MirGeneDB, we generated trained covariance models for all conserved microRNA families. These models are available in MirMachine, our new tool for the annotation of conserved microRNA complements from genomes only. We successfully applied MirMachine to a wide range of animal species, including those with very large genomes, additional genome duplications and extinct species, where smallRNA sequencing will be hard to achieve. We further describe a microRNA score of expected microRNAs that can be used to assess the completeness of genome assemblies. MirMachine closes a long-persisting gap in the microRNA field facilitating automated genome annotation ...
Over the last few years, the number of microRNAs in the human genome has become a controversially... more Over the last few years, the number of microRNAs in the human genome has become a controversially debated issue. Several publications reported thousands of putative novel microRNAs not included in the curated microRNA gene database MirGeneDB and the repository miRBase. Recently, by using sequencing of ∼300 human tissues and cell lines, the human RNA atlas, an expanded inventory of human RNA annotations, was published, reporting thousands of putative microRNAs. We, the developers of established microRNA prediction tools and hosts of MirGeneDB, raise concerns about the frequently applied prediction and functional validation strategies, briefly discussing the drawbacks of false positive detections. By means of quantifying well-established biogenesis-derived features, we show that the reported novel microRNAs essentially represent false-positives and argue that the human microRNA complement, at about 550 microRNA genes, is already near complete. Output of available tools must be curated...
Soft-bodied cephalopods such as the octopus are exceptionally intelligent invertebrates with a hi... more Soft-bodied cephalopods such as the octopus are exceptionally intelligent invertebrates with a highly complex nervous system that evolved independently from vertebrates. Because of elevated RNA editing in their nervous tissues, we hypothesized that RNA regulation may play a major role in the cognitive success of this group. We thus profiled mRNAs and small RNAs in 18 tissues of the common octopus. We show that the major RNA innovation of soft-bodied cephalopods is a massive expansion of the miRNA gene repertoire. These novel miRNAs were primarily expressed in neuronal tissues, during development, and had conserved and thus likely functional target sites. The only comparable miRNA expansions happened, strikingly, in vertebrates. Thus, we propose that miRNAs are intimately linked to the evolution of complex animal brains.One-Sentence SummarymiRNAs are deeply linked to the emergence of complex brains.
Scandinavian Journal of Clinical & Laboratory Investigation, Jul 13, 2016
Abstract Since their discovery in 1993, microRNAs (miRNAs) have been identified as important gene... more Abstract Since their discovery in 1993, microRNAs (miRNAs) have been identified as important gene regulators in many biological processes and as key molecular players in human disease, including cancer where they show specific pathogenic deregulation. Their remarkable chemical stability, the availability of very sensitive miRNA detection methods and the fact that miRNAs can be extracted from and detected in various kinds of clinically relevant samples, such as solid tissues, body fluids and secretions make them excellent candidate biomarkers. However, no miRNA has yet entered the level of practical clinical relevance. We present a brief background and some key aspects and challenges of miRNAs as cancer biomarkers, we discuss shortfalls and identify possible routes towards the use of miRNAs as reliable biomarkers for cancer.
V Congreso de la Sociedad Española de Biología Evolutiva (2016)Micro RNAs (miRNAs) are small RNA ... more V Congreso de la Sociedad Española de Biología Evolutiva (2016)Micro RNAs (miRNAs) are small RNA molecules regulating gene expression at the post-transcriptional level. The miRNAs of several holometabolan insects ( Tribolium, Bombyx and Drosophila), have been identified but data on hemimetabolan species are scarce. We present the highly accurate miRNA complement of the hemimetabolan insect Blattella germanica. Hemimetabolan insects differ from holometabolans by showing the adult body plan already in juvenile stages. In contrast holometabolan juveniles have a morphology very different with respect to that of the adult. After filtering with stringent criteria based on miRNA biogenesis the in-silico miRNA predictions based on RNA-seq, we identified 100 miRNA genes. These were grouped in 71 miRNA families, 61 of them described in other organism and 10 new. Our findings are qualitative and quantitative concordant with the previous phylogenetic studies; however, three miRNA families (Mir-36, Mir-309 and Mir-3791) believed to be present in all hemimetabolan insects were not found in B. germanica. Moreover, 4 miRNA families that were thought to have originated on holometabolan insects (Mir-11, Mir-932, Mir- 3770 and Mir-6012) were found in B. germanica.N
The evolution of specialized cell‐types is a long‐standing interest of biologists, but given the ... more The evolution of specialized cell‐types is a long‐standing interest of biologists, but given the deep time‐scales very difficult to reconstruct or observe. microRNAs have been linked to the evolution of cellular complexity and may inform on specialization. The endothelium is a vertebrate‐specific specialization of the circulatory system that enabled a critical new level of vasoregulation. The evolutionary origin of these endothelial cells is unclear. We hypothesized that Mir‐126, an endothelial cell‐specific microRNA may be informative. We here reconstruct the evolutionary history of Mir‐126. Mir‐126 likely appeared in the last common ancestor of vertebrates and tunicates, which was a species without an endothelium, within an intron of the evolutionary much older EGF Like Domain Multiple (Egfl) locus. Mir‐126 has a complex evolutionary history due to duplications and losses of both the host gene and the microRNA. Taking advantage of the strong evolutionary conservation of the microR...
Whole genome duplications (WGDs) are major events that drastically reshape genome architecture an... more Whole genome duplications (WGDs) are major events that drastically reshape genome architecture and are causally associated with organismal innovations and radiations1. The 2R Hypothesis suggests that two WGD events (1R and 2R) occurred during early vertebrate evolution2, 3. However, the veracity and timing of the 2R event relative to the divergence of gnathostomes (jawed vertebrates) and cyclostomes (jawless hagfishes and lampreys) is unresolved4–6and whether these WGD events underlie vertebrate phenotypic diversification remains elusive7. Here we present the genome of the inshore hagfish,Eptatretus burgeri. Through comparative analysis with lamprey and gnathostome genomes, we reconstruct the early events in cyclostome genome evolution, leveraging insights into the ancestral vertebrate genome. Genome-wide synteny and phylogenetic analyses support a scenario in which 1R occurred in the vertebrate stem-lineage during the early Cambrian, and the 2R event occurred in the gnathostome ste...
SummaryThe annotation of microRNAs, an important class of post-transcriptional regulators, depend... more SummaryThe annotation of microRNAs, an important class of post-transcriptional regulators, depends on the availability of transcriptomics data and expert knowledge. This led to a large gap between novel genomes made available and high-quality microRNA complements. Using >16,000 microRNAs from the manually curated microRNA gene database MirGeneDB, we generated trained covariance models for all conserved microRNA families. These models are available in MirMachine, our new tool for the annotation of conserved microRNA complements from genomes only. We successfully applied MirMachine to a wide range of animal species, including those with very large genomes, additional genome duplications and extinct species, where smallRNA sequencing will be hard to achieve. We further describe a microRNA score of expected microRNAs that can be used to assess the completeness of genome assemblies. MirMachine closes a long-persisting gap in the microRNA field facilitating automated genome annotation ...
Over the last few years, the number of microRNAs in the human genome has become a controversially... more Over the last few years, the number of microRNAs in the human genome has become a controversially debated issue. Several publications reported thousands of putative novel microRNAs not included in the curated microRNA gene database MirGeneDB and the repository miRBase. Recently, by using sequencing of ∼300 human tissues and cell lines, the human RNA atlas, an expanded inventory of human RNA annotations, was published, reporting thousands of putative microRNAs. We, the developers of established microRNA prediction tools and hosts of MirGeneDB, raise concerns about the frequently applied prediction and functional validation strategies, briefly discussing the drawbacks of false positive detections. By means of quantifying well-established biogenesis-derived features, we show that the reported novel microRNAs essentially represent false-positives and argue that the human microRNA complement, at about 550 microRNA genes, is already near complete. Output of available tools must be curated...
Soft-bodied cephalopods such as the octopus are exceptionally intelligent invertebrates with a hi... more Soft-bodied cephalopods such as the octopus are exceptionally intelligent invertebrates with a highly complex nervous system that evolved independently from vertebrates. Because of elevated RNA editing in their nervous tissues, we hypothesized that RNA regulation may play a major role in the cognitive success of this group. We thus profiled mRNAs and small RNAs in 18 tissues of the common octopus. We show that the major RNA innovation of soft-bodied cephalopods is a massive expansion of the miRNA gene repertoire. These novel miRNAs were primarily expressed in neuronal tissues, during development, and had conserved and thus likely functional target sites. The only comparable miRNA expansions happened, strikingly, in vertebrates. Thus, we propose that miRNAs are intimately linked to the evolution of complex animal brains.One-Sentence SummarymiRNAs are deeply linked to the emergence of complex brains.
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Papers by Bastian Fromm