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Transposable elements (TEs) are characterized by their ability to change their genomic position. Through insertion or recombination leading to deletions and other chromosomal aberrations, they can cause genetic instability. The extent to which they thereby exert regulatory influence on cellular functions is unclear. To better characterize TEs in processes such as carcinogenesis, we used the well-established Xiphophorus melanoma model. By transcriptome sequencing, we show that an increasing total number in transposons correlates with progression of malignancy in melanoma samples from Xiphophorus interspecific hybrids. Further, by comparing the presence of TEs in the parental genomes of Xiphophorus maculatus and Xiphophorus hellerii, we could show that even in closely related species, genomic location and spectrum of TEs are considerably different. [ABSTRACT FROM AUTHOR]

The bamboos (Bambusoideae, Poaceae) comprise a major grass lineage with a complex evolutionary history involving ancient hybridization and allopolyploidy. About 1700 described species are classified into three tribes, Olyreae (herbaceous bamboos), Bambuseae (tropical woody bamboos), and Arundinarieae (temperate woody bamboos). Nuclear analyses strongly support monophyly of the woody tribes, whereas plastome analyses strongly support paraphyly, with Bambuseae sister to Olyreae. Our objectives were to clarify the origin(s) of the woody bamboo tribes and resolve the nuclear vs. plastid conflict using genomic tools. For the first time, plastid and nuclear genomic information from the same bamboo species were combined in a single study. We sampled 51 species of bamboos representing the three tribes, estimated their genome sizes and generated low-depth sample sequence data, from which plastomes were assembled and nuclear repeats were analyzed. The distribution of repeat families was found to agree with nuclear gene phylogenies, but also provides novel insights into nuclear evolutionary history. We infer two early, independent hybridization events, one between an Olyreae ancestor and a woody ancestor giving rise to the two Bambuseae lineages, and another between two woody ancestors giving rise to the Arundinarieae. Retention of the Olyreae plastome associated with differential dominance of nuclear genomes and subsequent diploidization in some lineages explains the paraphyly observed in plastome phylogenetic estimations. We confirm ancient hybridization and allopolyploidy in the origins of the extant woody bamboo lineages and propose biased fractionation and diploidization as important factors in their evolution. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is an inflammation-associated cancer arising from viral or non-viral etiologies including steatotic liver diseases (SLDs). Expansion of immunosuppressive myeloid cells is a hallmark of inflammation and cancer, but their heterogeneity in HCC is not fully resolved and might underlie immunotherapy resistance. Here, we present a high-resolution atlas of innate immune cells from patients with HCC that unravels an SLD-associated contexture characterized by influx of inflammatory and immunosuppressive myeloid cells, including a discrete population of THBS1+ regulatory myeloid (M reg) cells expressing monocyte- and neutrophil-affiliated genes. THBS1+ M reg cells expand in SLD-associated HCC, populate fibrotic lesions, and are associated with poor prognosis. THBS1+ M reg cells are CD163+ but distinguished from macrophages by high expression of triggering receptor expressed on myeloid cells 1 (TREM1), which contributes to their immunosuppressive activity and promotes HCC tumor growth in vivo. Our data support myeloid subset-targeted immunotherapies to treat HCC. [Display omitted] • Atlas of hepatic innate immune cells from patients with HCC • THBS1+ M reg cells expand in SLD-associated HCC and populate fibrotic lesions • TREM1 engagement potentiates immunosuppression and HCC growth in vivo • THBS1+ M reg density and TREM1 expression associate with HCC poor prognosis Giraud et al. characterize the innate immune landscape of HCC. They identify an immunosuppressive THBS1+ myeloid population co-expressing TREM1 and CD163 that expands in the steatotic liver disease etiology of HCC and contributes to unfavorable prognosis through TREM1. TREM1 blockade elicits an immunogenic TME and rapid tumor eradication. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most common liver tumor and among the deadliest cancers worldwide. Advanced HCC overall survival is meager and has not improved over the last decade despite approval of several tyrosine kinase inhibitors (TKi) for first and second-line treatments. The recent approval of immune checkpoint inhibitors (ICI) has revolutionized HCC palliative care. Unfortunately, the majority of HCC patients fail to respond to these therapies. Here, we elaborate on the immune landscapes of the normal and cirrhotic livers and of the unique HCC tumor microenvironment. We describe the molecular and immunological classifications of HCC, discuss the role of specific immune cell subsets in this cancer, with a focus on myeloid cells and pathways in anti-tumor immunity, tumor promotion and immune evasion. We also describe the challenges and opportunities of immunotherapies in HCC and discuss new avenues based on harnessing the anti-tumor activity of myeloid, NK and γδ T cells, vaccines, chimeric antigen receptors (CAR)-T or -NK cells, oncolytic viruses, and combination therapies. [ABSTRACT FROM AUTHOR]

Glycine receptors (GlyRs) are ligand-gated chloride channels mediating inhibitory neurotransmission in the brain stem and spinal cord. They function as pentamers composed of alpha and beta subunits for which 5 genes have been identified in human (GLRA1, GLRA2, GLRA3, GLRA4, GLRB). Several in vitro studies showed that the pentameric subtype composition as well as its stoichiometry influence the distribution and the molecular function of the receptor. Moreover, mutations in some of these genes are involved in different human conditions ranging from tinnitus to epilepsy and hyperekplexia, suggesting distinct functions of the different subunits. Although the beta subunit is essential for synaptic clustering of the receptor, the specific role of each alpha subtype is still puzzling in vivo. The zebrafish genome encodes for five glycine receptor alpha subunits (glra1, glra2, glra3, glra4a, glra4b) thus offering a model of choice to investigate the respective role of each subtype on general motor behaviour. After establishing a phylogeny of GlyR subunit evolution between human and zebrafish, we checked the temporal expression pattern of these transcripts during embryo development. Interestingly, we found that glra1 is the only maternally transmitted alpha subunit. We also showed that the expression of the different GlyR subunits starts at different time points during development. Lastly, in order to decipher the role of each alpha subunit on the general motor behaviour of the fish, we knocked out individually each alpha subunit by CRISPR/Cas9-targeted mutagenesis. Surprisingly, we found that knocking out any of the alpha2, 3, a4a or a4b subunit did not lead to any obvious developmental or motor phenotype. However, glra1-/- (hitch) embryos depicted a strong motor dysfunction from 3 days, making them incapable to swim and thus leading to their premature death. Our results infer a strong functional redundancy between alpha subunits and confirm the central role played by glra1 for proper inhibitory neurotransmission controlling locomotion. The genetic tools we developed here will be of general interest for further studies aiming at dissecting the role of GlyRs in glycinergic transmission in vivo and the hitch mutant (hic) is of specific relevance as a new model of hyperekplexia. [ABSTRACT FROM AUTHOR]

Teleost fish have been shown to contain many superfamilies of transposable elements (TEs) that are absent from most tetrapod genomes. Since theories predict an increase in TE activity following polyploidization, such diversity might be linked to the 3R whole-genome duplication that occurred approximately 300 million years ago before the teleost radiation. To test this hypothesis, we have analyzed the genome of the spotted gar Lepisosteus oculatus, which diverged from the teleost lineage before the 3R duplication. Our results indicate that TE diversity and copy numbers are similar in gar and teleost genomes, suggesting that TE diversity was ancestral and not linked to the 3R whole-genome duplication. We propose that about 25 distinct superfamilies of TEs were present in the last ancestor of gars and teleost fish about 300 million years ago in the ray-finned fish lineage. [ABSTRACT FROM AUTHOR]

Background: A growing number of studies report an abnormal expression of Piwi-interacting RNAs (piRNAs) and the piRNA processing enzyme Piwi in many cancers. Whether this finding is an epiphenomenon of the chaotic molecular biology of the fast dividing, neoplastically transformed cells or is functionally relevant to tumorigenesisis is difficult to discern at present. To better understand the role of piRNAs in cancer development small laboratory fish models can make a valuable contribution. However, little is known about piRNAs in somatic and neoplastic tissues of fish. Results: To identify piRNA clusters that might be involved in melanoma pathogenesis, we use several transgenic lines of medaka, and platyfish/swordtail hybrids, which develop various types of melanoma. In these tumors Piwi, is expressed at different levels, depending on tumor type. To quantify piRNA levels, whole piRNA populations of testes and melanomas of different histotypes were sequenced. Because no reference piRNA cluster set for medaka or Xiphophorus was yet available we developed a software pipeline to detect piRNA clusters in our samples and clusters were selected that were enriched in one or more samples. We found several loci to be overexpressed or down-regulated in different melanoma subtypes as compared to hyperpigmented skin. Furthermore, cluster analysis revealed a clear distinction between testes, low-grade and high-grade malignant melanoma in medaka. Conclusions: Our data imply that dysregulation of piRNA expression may be associated with development of melanoma. Our results also reinforce the importance of fish as a suitable model system to study the role of piRNAs in tumorigenesis. [ABSTRACT FROM AUTHOR]

Background: Xiphophorus fishes are represented by 26 live-bearing species of tropical fish that express many attributes (e.g., viviparity, genetic and phenotypic variation, ecological adaptation, varied sexual developmental mechanisms, ability to produce fertile interspecies hybrids) that have made attractive research models for over 85 years. Use of various interspecies hybrids to investigate the genetics underlying spontaneous and induced tumorigenesis has resulted in the development and maintenance of pedigreed Xiphophorus lines specifically bred for research. The recent availability of the X. maculatus reference genome assembly now provides unprecedented opportunities for novel and exciting comparative research studies among Xiphophorus species. Results: We present sequencing, assembly and annotation of two new genomes representing Xiphophorus couchianus and Xiphophorus hellerii. The final X. couchianus and X. hellerii assemblies have total sizes of 708 Mb and 734 Mb and correspond to 98 % and 102 % of the X. maculatus Jp 163 A genome size, respectively. The rates of single nucleotide change range from 1 per 52 bp to 1 per 69 bp among the three genomes and the impact of putatively damaging variants are presented. In addition, a survey of transposable elements allowed us to deduce an ancestral TE landscape, uncovered potential active TEs and document a recent burst of TEs during evolution of this genus. Conclusions: Two new Xiphophorus genomes and their corresponding transcriptomes were efficiently assembled, the former using a novel guided assembly approach. Three assembled genome sequences within this single vertebrate order of new world live-bearing fishes will accelerate our understanding of relationship between environmental adaptation and genome evolution. In addition, these genome resources provide capability to determine allele specific gene regulation among interspecies hybrids produced by crossing any of the three species that are known to produce progeny predisposed to tumor development. [ABSTRACT FROM AUTHOR]

In many organisms, the sex chromosome pair can be recognized due to heteromorphy; the Y and W chromosomes have often lost many genes due to the absence of recombination during meiosis and are frequently heterochromatic. Repetitive sequences are found at a high proportion on such heterochromatic sex chromosomes and the evolution and emergence of sex chromosomes has been connected to the dynamics of repeats and transposable elements. With an amazing plasticity of sex determination mechanisms and numerous instances of independent emergence of novel sex chromosomes, fish represent an excellent lineage to investigate the early stages of sex chromosome differentiation, where sex chromosomes often are homomorphic and not heterochromatic. We have analyzed the composition, distribution, and relative age of TEs from available sex chromosome sequences of seven teleost fish. We observed recent bursts of TEs and simple repeat accumulations around young sex determination loci. More strikingly, we detected transposable element (TE) amplifications not only on the sex determination regions of the Y and W sex chromosomes, but also on the corresponding regions of the X and Z chromosomes. In one species, we also clearly demonstrated that the observed TE-rich sex determination locus originated from a TE-poor genomic region, strengthening the link between TE accumulation and emergence of the sex determination locus. Altogether, our results highlight the role of TEs in the initial steps of differentiation and evolution of sex chromosomes. [ABSTRACT FROM AUTHOR]

Since their discovery, a growing body of evidence has emerged demonstrating that transposable elements are important drivers of species diversity. These mobile elements exhibit a great variety in structure, size and mechanisms of transposition, making them important putative actors in organism evolution. The vertebrates represent a highly diverse and successful lineage that has adapted to a wide range of different environments. These animals also possess a rich repertoire of transposable elements, with highly diverse content between lineages and even between species. Here, we review how transposable elements are driving genomic diversity and lineage-specific innovation within vertebrates. We discuss the large differences in TE content between different vertebrate groups and then go on to look at how they affect organisms at a variety of levels: from the structure of chromosomes to their involvement in the regulation of gene expression, as well as in the formation and evolution of non-coding RNAs and protein-coding genes. In the process of doing this, we highlight how transposable elements have been involved in the evolution of some of the key innovations observed within the vertebrate lineage, driving the group's diversity and success. [ABSTRACT FROM AUTHOR]

The coelacanth has long been regarded as a “living fossil,” with extant specimens looking very similar to fossils dating back to the Cretaceous period. The hypothesis of a slowly or even not evolving genome has been proposed to account for this apparent morphological stasis. While this assumption seems to be sustained by different evolutionary analyses on protein-coding genes, recent studies on transposable elements have provided more conflicting results. Indeed, the coelacanth genome contains many transposable elements and has been shaped by several major bursts of transposition during evolution. In addition, comparison of orthologous genomic regions from the genomes of the 2 extant coelacanth speciesL. chalumnaeandL. menadoensisrevealed multiple species-specific insertions, indicating transposable element recent activity and contribution to post-speciation genome divergence. These observations, which do not support the genome stasis hypothesis, challenge either the impact of transposable elements on organismal evolution or the status of the coelacanth as a “living fossil.” Closer inspection of fossil and molecular data indicate that, even if coelacanths might evolve more slowly than some other lineages due to demographic and/or ecological factors, this variation is still in the range of a “non-fossil” vertebrate species. [ABSTRACT FROM PUBLISHER]

Transposable elements (TEs) are major components of vertebrate genomes, with major roles in genome architecture and evolution. In order to characterize both common patterns and lineage-specific differences in TE content and TE evolution, we have compared the mobilomes of 23 vertebrate genomes, including 10 actinopterygian fish, 11 sarcopterygians, and 2 nonbony vertebrates. We found important variations in TE content (from 6% in the pufferfish tetraodon to 55% in zebrafish), with a more important relative contribution of TEs to genome size in fish than in mammals. Some TE superfamilies were found to be widespread in vertebrates, but most elements showed a more patchy distribution, indicative of multiple events of loss or gain. Interestingly, loss of major TE families was observed during the evolution of the sarcopterygian lineage, with a particularly strong reduction in TE diversity in birds and mammals. Phylogenetic trends in TE composition and activity were detected: Teleost fish genomes are dominated by DNA transposons and contain few ancient TE copies, while mammalian genomes have been predominantly shaped by nonlong terminal repeat retrotransposons, along with the persistence of older sequences. Differences were also found within lineages: The medaka fish genome underwent more recent TE amplification than the related platyfish, as observed for LINE retrotransposons in the mouse compared with the human genome. This study allows the identification of putative cases of horizontal transfer of TEs, and to tentatively infer the composition of the ancestral vertebrate mobilome. Taken together, the results obtained highlight the importance of TEs in the structure and evolution of vertebrate genomes, and demonstrate their major impact on genome diversity both between and within lineages. [ABSTRACT FROM PUBLISHER]

Coelacanths are lobe-finned fish represented by two extant species, Latimeria chalumnae in South Africa and Comoros and L. menadoensis in Indonesia. Due to their intermediate phylogenetic position between ray-finned fish and tetrapods in the vertebrate lineage, they are of great interest from an evolutionary point of view. In addition, extant specimens look similar to 300 million-year-old fossils; because of their apparent slowly evolving morphology, coelacanths have been often described as « living fossils ». As an underlying cause of such a morphological stasis, several authors have proposed a slow evolution of the coelacanth genome. Accordingly, sequencing of the L. chalumnae genome has revealed a globally low substitution rate for protein-coding regions compared to other vertebrates. However, genome and gene evolution can also be influenced by transposable elements, which form a major and dynamic part of vertebrate genomes through their ability to move, duplicate and recombine. In this work, we have searched for evidence of transposition activity in coelacanth genomes through the comparative analysis of orthologous genomic regions from both Latimeria species. Comparison of 5.7 Mb (0.2%) of the L. chalumnae genome with orthologous Bacterial Artificial Chromosome clones from L. menadoensis allowed the identification of 27 species-specific transposable element insertions, with a strong relative contribution of CR1 non-LTR retrotransposons. Species-specific homologous recombination between the long terminal repeats of a new coelacanth endogenous retrovirus was also detected. Our analysis suggests that transposon activity is responsible for at least 0.6% of genome divergence between both Latimeria species. Taken together, this study demonstrates that coelacanth genomes are not evolutionary inert: they contain recently active transposable elements, which have significantly contributed to post-speciation genome divergence in Latimeria. [ABSTRACT FROM AUTHOR]

ABSTRACT The morphological stasis of coelacanths has long suggested a slow evolutionary rate. General genomic stasis might also imply a decrease of transposable elements activity. To evaluate the potential activity of transposable elements (TEs) in 'living fossil' species, transcriptomic data of Latimeria chalumnae and its Indonesian congener Latimeria menadoensis were compared through the RNA-sequencing mapping procedures in three different organs (liver, testis, and muscle). The analysis of coelacanth transcriptomes highlights a significant percentage of transcribed TEs in both species. Major contributors are LINE retrotransposons, especially from the CR1 family. Furthermore, some particular elements such as a LF-SINE and a LINE2 sequences seem to be more expressed than other elements. The amount of TEs expressed in testis suggests possible transposition burst in incoming generations. Moreover, significant amount of TEs in liver and muscle transcriptomes were also observed. Analyses of elements displaying marked organ-specific expression gave us the opportunity to highlight exaptation cases, that is, the recruitment of TEs as new cellular genes, but also to identify a new Latimeria-specific family of Short Interspersed Nuclear Elements called CoeG-SINEs. Overall, transcriptome results do not seem to be in line with a slow-evolving genome with poor TE activity. J. Exp. Zool. (Mol. Dev. Evol.) 322B: 379-389, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT The apparent morphological stasis in the lineage of the coelacanth, which has been called a 'living fossil' by many, has been suggested to be causally related to a slow evolution of its genome, with strongly reduced activity of transposable elements (TEs). Analysis of the African coelacanth showed that at least 25% of its genome is constituted of transposable elements including retrotransposons, endogenous retroviruses and DNA transposons, with a strong predominance of non-Long Terminal Repeat (non-LTR) retrotransposons. The coelacanth genome has been shaped by four major general bursts of transposition during evolution, with major contributions of LINE1, LINE2, CR1, and Deu non-LTR retrotransposons. Many transposable elements are expressed in different tissues and might be active. The number of TE families in coelacanth, but also in lungfish, is lower than in teleost fish, but is higher than in chicken and human. This observation is in agreement with the hypothesis of a sequential elimination of many TE families in the sarcopterygian lineage during evolution. Taken together, our analysis indicates that the coelacanth contains more TE families than birds and mammals, and that these elements have been active during the evolution of the coelacanth lineage. Hence, at the level of transposable element activity, the coelacanth genome does not appear to evolve particularly slowly. J. Exp. Zool. (Mol. Dev. Evol.) 322B: 322-333, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background Teleost fish present a high diversity of sex determination systems, with possible frequent evolutionary turnover of sex chromosomes and sex-determining genes. In order to identify genes involved in male sex determination and differentiation in the platyfish Xiphophorus maculatus, bacterial artificial chromosome contigs from the sex-determining region differentiating the Y from the X chromosome have been assembled and analyzed. Results A novel three-copy gene called teximY (for testis-expressed in Xiphophorus maculatus on the Y) was identified on the Y but not on the X chromosome. A highly related sequence called texim1, probably at the origin of the Y-linked genes, as well as three more divergent texim genes were detected in (pseudo)autosomal regions of the platyfish genome. Texim genes, for which no functional data are available so far in any organism, encode predicted esterases/lipases with a SGNH hydrolase domain. Texim proteins are related to proteins from very different origins, including proteins encoded by animal CR1 retrotransposons, animal platelet-activating factor acetylhydrolases (PAFah) and bacterial hydrolases. Texim gene distribution is patchy in animals. Texim sequences were detected in several fish species including killifish, medaka, pufferfish, sea bass, cod and gar, but not in zebrafish. Texim-like genes are also present in Oikopleura (urochordate), Amphioxus (cephalochordate) and sea urchin (echinoderm) but absent from mammals and other tetrapods. Interestingly, texim genes are associated with a Helitron transposon in different fish species but not in urochordates, cephalochordates and echinoderms, suggesting capture and mobilization of an ancestral texim gene in the bony fish lineage. RT-qPCR analyses showed that Y-linked teximY genes are preferentially expressed in testis, with expression at late stages of spermatogenesis (late spermatids and spermatozeugmata). Conclusions These observations suggest either that TeximY proteins play a role in Helitron transposition in the male germ line in fish, or that texim genes are spermatogenesis genes mobilized and spread by transposable elements in fish genomes. [ABSTRACT FROM AUTHOR]

Genetic sex determination by W and Z chromosomes has developed independently in different groups of organisms. To better understand the evolution of sex chromosomes and the plasticity of sex-determination mechanisms, we sequenced the whole genomes of a male (ZZ) and a female (ZW) half-smooth tongue sole (Cynoglossus semilaevis). In addition to insights into adaptation to a benthic lifestyle, we find that the sex chromosomes of these fish are derived from the same ancestral vertebrate protochromosome as the avian W and Z chromosomes. Notably, the same gene on the Z chromosome, dmrt1, which is the male-determining gene in birds, showed convergent evolution of features that are compatible with a similar function in tongue sole. Comparison of the relatively young tongue sole sex chromosomes with those of mammals and birds identified events that occurred during the early phase of sex-chromosome evolution. Pertinent to the current debate about heterogametic sex-chromosome decay, we find that massive gene loss occurred in the wake of sex-chromosome 'birth'. [ABSTRACT FROM AUTHOR]

Several attributes intuitively considered to be typical mammalian features, such as complex behavior, live birth and malignant disease such as cancer, also appeared several times independently in lower vertebrates. The genetic mechanisms underlying the evolution of these elaborate traits are poorly understood. The platyfish, X. maculatus, offers a unique model to better understand the molecular biology of such traits. We report here the sequencing of the platyfish genome. Integrating genome assembly with extensive genetic maps identified an unexpected evolutionary stability of chromosomes in fish, in contrast to in mammals. Genes associated with viviparity show signatures of positive selection, identifying new putative functional domains and rare cases of parallel evolution. We also find that genes implicated in cognition show an unexpectedly high rate of duplicate gene retention after the teleost genome duplication event, suggesting a hypothesis for the evolution of the behavioral complexity in fish, which exceeds that found in amphibians and reptiles. [ABSTRACT FROM AUTHOR]

The discovery of a living coelacanth specimen in 1938 was remarkable, as this lineage of lobe-finned fish was thought to have become extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features. Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues show the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution. [ABSTRACT FROM AUTHOR]

Due to their ability to drive DNA rearrangements and to serve as a source of new coding and regulatory sequences, transposable elements (TEs) are considered as powerful evolutionary agents within genomes. In this paper, we review the mechanism of molecular domestication, which corresponds to the formation of new genes derived from TE sequences. Many genes derived from retroelements and DNA transposons have been identified in mammals and other vertebrates, some of them fulfilling essential functions for the development and survival of their host organisms. We will particularly focus on the evolution and expression of Gypsy integrase (GIN) genes, which have been formed from ancient event(s) of molecular domestication and have evolved differentially in some vertebrate sublineages. What we describe here is probably only the tip of the evolutionary iceberg, and future genome analyses will certainly uncover new TE-derived genes and biological functions driving genetic innovation in vertebrates and other organisms [ABSTRACT FROM AUTHOR]