Publications by authors named "Manfred Schartl"

244 Publications

Independent Origin of XY and ZW Sex Determination Mechanisms in Mosquitofish Sister Species.

Genetics 2020 Jan;214(1):193-209

Physiological Chemistry, Biocenter, University of Wuerzburg, 97074, Germany.

Fish are known for the outstanding variety of their sex determination mechanisms and sex chromosome systems. The western (Gambusia affinis) and eastern mosquitofish (G. holbrooki) are sister species for which different sex determination mechanisms have been described: ZZ/ZW for G. affinis and XX/XY for G. holbrooki. Here, we carried out restriction-site associated DNA (RAD-) and pool sequencing (Pool-seq) to characterize the sex chromosomes of both species. We found that the ZW chromosomes of G. affinis females and the XY chromosomes of G. holbrooki males correspond to different linkage groups, and thus evolved independently from separate autosomes. In interspecific hybrids, the Y chromosome is dominant over the W chromosome, and X is dominant over Z. In G. holbrooki, we identified a candidate region for the Y-linked melanic pigmentation locus, a rare male phenotype that constitutes a potentially sexually antagonistic trait and is associated with other such characteristics, e.g., large body size and aggressive behavior. We developed a SNP-based marker in the Y-linked allele of GIPC PDZ domain containing family member 1 (gipc1), which was linked to melanism in all tested G. holbrooki populations. This locus represents an example for a color locus that is located in close proximity to a putative sex determiner, and most likely substantially contributed to the evolution of the Y.
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http://dx.doi.org/10.1534/genetics.119.302698DOI Listing
January 2020

Genomic basis of striking fin shapes and colours in the fighting fish.

Mol Biol Evol 2021 Apr 19. Epub 2021 Apr 19.

Molecular Population Genetics & Breeding Group, Temasek Life Sciences Laboratory, Singapore 117604, Singapore.

Resolving the genomic basis underlying phenotypic variations is a question of great importance in evolutionary biology. However, understanding how genotypes determine the phenotypes is still challenging. Centuries of artificial selective breeding for beauty and aggression resulted in a plethora of colors, long fin varieties, and hyper-aggressive behavior in the air-breathing Siamese fighting fish (Betta splendens), supplying an excellent system for studying the genomic basis of phenotypic variations. Combining whole genome sequencing, QTL mapping, genome-wide association studies and genome editing, we investigated the genomic basis of huge morphological variation in fins and striking differences in coloration in the fighting fish. Results revealed that the double tail, elephant ear, albino and fin spot mutants each were determined by single major-effect loci. The elephant ear phenotype was likely related to differential expression of a potassium ion channel gene, kcnh8. The albinotic phenotype was likely linked to a cis-regulatory element acting on the mitfa gene and the double tail mutant was suggested to be caused by a deletion in a zic1/zic4 co-enhancer. Our data highlight that major loci and cis-regulatory elements play important roles in bringing about phenotypic innovations and establish Bettas as new powerful model to study the genomic basis of evolved changes.
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http://dx.doi.org/10.1093/molbev/msab110DOI Listing
April 2021

Neoceratodus forsteri (Australian lungfish).

Trends Genet 2021 Mar 8. Epub 2021 Mar 8.

Department of Biology, University of Konstanz, Universitätsstraße 10, 78457, Konstanz, Germany.

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http://dx.doi.org/10.1016/j.tig.2021.02.005DOI Listing
March 2021

Reconstruction of the origin of a neo-Y sex chromosome and its evolution in the spotted knifejaw, Oplegnathus punctatus.

Mol Biol Evol 2021 Mar 9. Epub 2021 Mar 9.

Yellow Sea Fisheries Research Institute, CAFS, Laboratory for Marine Fisheries Science and Food Production Processes, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, China.

Sex chromosomes are a peculiar constituent of the genome because the evolutionary forces that fix the primary sex-determining gene cause genic degeneration and accumulation of junk DNA in the heterogametic partner. One of the most spectacular phenomena in sex chromosome evolution is the occurrence of neo-Y chromosomes, which lead to X1X2Y sex-determining systems. Such neo-sex chromosomes are critical for understanding the processes of sex chromosome evolution because they rejuvenate their total gene content. We assembled the male and female genomes at the chromosome level of the spotted knifejaw (Oplegnathus punctatus), which has a cytogenetically recognized neo-Y chromosome. The full assembly and annotation of all three sex chromosomes allowed us to reconstruct their evolutionary history. Contrary to other neo-Y chromosomes, the fusion to X2 is quite ancient, estimated at 48 Mya. Despite its old age and being even older in the X1 homologous region which carries a huge inversion that occurred as early as 55-48 Mya, genetic degeneration of the neo-Y appears to be only moderate. Transcriptomic analysis showed that sex chromosomes harbor 87 genes, which may serve important functions in the testis. The accumulation of such male-beneficial genes, a large inversion on the X1 homologous region and fusion to X2 appear to be the main drivers of neo-Y evolution in the spotted knifejaw. The availability of high-quality assemblies of the neo-Y and both X chromosomes make this fish an ideal model for a better understanding of the variability of sex determination mechanisms and of sex chromosome evolution.
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http://dx.doi.org/10.1093/molbev/msab056DOI Listing
March 2021

Decontextualized learning for interpretable hierarchical representations of visual patterns.

Patterns (N Y) 2021 Feb 21;2(2):100193. Epub 2021 Jan 21.

Department of Collective Behavior, Max Planck Institute of Animal Behavior, Konstanz, Germany.

Apart from discriminative modeling, the application of deep convolutional neural networks to basic research utilizing natural imaging data faces unique hurdles. Here, we present decontextualized hierarchical representation learning (DHRL), designed specifically to overcome these limitations. DHRL enables the broader use of small datasets, which are typical in most studies. It also captures spatial relationships between features, provides novel tools for investigating latent variables, and achieves state-of-the-art disentanglement scores on small datasets. DHRL is enabled by a novel preprocessing technique inspired by generative model chaining and an improved ladder network architecture and regularization scheme. More than an analytical tool, DHRL enables novel capabilities for virtual experiments performed directly on a latent representation, which may transform the way we perform investigations of natural image features, directly integrating analytical, empirical, and theoretical approaches.
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http://dx.doi.org/10.1016/j.patter.2020.100193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892362PMC
February 2021

RADSex: A computational workflow to study sex determination using restriction site-associated DNA sequencing data.

Mol Ecol Resour 2021 Feb 16. Epub 2021 Feb 16.

Physiological Chemistry, Biocenter, University of Wuerzburg, Wuerzburg, Germany.

The study of sex determination and sex chromosome organization in nonmodel species has long been technically challenging, but new sequencing methodologies now enable precise and high-throughput identification of sex-specific genomic sequences. In particular, restriction site-associated DNA sequencing (RAD-Seq) is being extensively applied to explore sex determination systems in many plant and animal species. However, software specifically designed to search for and visualize sex-biased markers using RAD-Seq data is lacking. Here, we present RADSex, a computational analysis workflow designed to study the genetic basis of sex determination using RAD-Seq data. RADSex is simple to use, requires few computational resources, makes no prior assumptions about the type of sex-determination system or structure of the sex locus, and offers convenient visualization through a dedicated R package. To demonstrate the functionality of RADSex, we re-analysed a published data set of Japanese medaka, Oryzias latipes, where we uncovered a previously unknown Y chromosome polymorphism. We then used RADSex to analyse new RAD-Seq data sets from 15 fish species spanning multiple taxonomic orders. We identified the sex determination system and sex-specific markers in six of these species, five of which had no known sex-markers prior to this study. We show that RADSex greatly facilitates the study of sex determination systems in nonmodel species thanks to its speed of analyses, low resource usage, ease of application and visualization options. Furthermore, our analysis of new data sets from 15 species provides new insights on sex determination in fish.
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http://dx.doi.org/10.1111/1755-0998.13360DOI Listing
February 2021

Fixation of allelic gene expression landscapes and expression bias pattern shape the transcriptome of the clonal Amazon molly.

Genome Res 2021 Mar 5;31(3):372-379. Epub 2021 Feb 5.

Xiphophorus Genetic Stock Center, Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas 78666, USA.

The Amazon molly is a unique clonal fish species that originated from an interspecies hybrid between species and It reproduces by gynogenesis, which eliminates paternal genomic contribution to offspring. An earlier study showed that Amazon molly shows biallelic expression for a large portion of the genome, leading to two main questions: (1) Are the allelic expression patterns from the initial hybridization event stabilized or changed during establishment of the asexual species and its further evolution? (2) Is allelic expression biased toward one parental allele a stochastic or adaptive process? To answer these questions, the allelic expression of siblings was assessed to investigate intra- and inter-cohort allelic expression variability. For comparison, interspecies hybrids between and were produced in the laboratory to represent the ancestor. We have identified inter-cohort and intra-cohort variation in parental allelic expression. The existence of inter-cohort divergence suggests functional allelic expression patterns do not simply reflect the atavistic situation of the first interspecies hybrid but potentially result from long-term selection of transcriptional fitness. In addition, clonal fish show a transcriptional trend representing minimal intra-clonal variability in allelic expression patterns compared to the corresponding hybrids. The intra-clonal similarity in gene expression translates to sophisticated genetic functional regulation at the individuum level. These findings suggest the parental alleles inherited by form tightly regulated genetic networks that lead to a stable transcriptomic landscape within clonal individuals.
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http://dx.doi.org/10.1101/gr.268870.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919451PMC
March 2021

Crosstalk Between Retinoic Acid and Sex-Related Genes Controls Germ Cell Fate and Gametogenesis in Medaka.

Front Cell Dev Biol 2020 18;8:613497. Epub 2021 Jan 18.

University of Wuerzburg, Developmental Biochemistry, Biocenter, Wuerzburg, Germany.

Sex determination (SD) is a highly diverse and complex mechanism. In vertebrates, one of the first morphological differences between the sexes is the timing of initiation of the first meiosis, where its initiation occurs first in female and later in male. Thus, SD is intimately related to the responsiveness of the germ cells to undergo meiosis in a sex-specific manner. In some vertebrates, it has been reported that the timing for meiosis entry would be under control of retinoic acid (RA), through activation of . In this study, we used a fish model species for sex determination and lacking the gene, the Japanese medaka (), to investigate the connection between RA and the sex determination pathway. Exogenous RA treatments act as a stress factor inhibiting germ cell differentiation probably by activation of and . Disruption of the RA degrading enzyme gene induced precocious meiosis and oogenesis in embryos/hatchlings of female and even some males. Transcriptome analyzes of -/-adult gonads revealed upregulation of genes related to germ cell differentiation and meiosis, in both ovaries and testes. Our findings show that germ cells respond to RA in a independent model species. The responsiveness to RA is conferred by sex-related genes, restricting its action to the sex differentiation period in both sexes.
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http://dx.doi.org/10.3389/fcell.2020.613497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848095PMC
January 2021

The rise and fall of the ancient northern pike master sex-determining gene.

Elife 2021 Jan 28;10. Epub 2021 Jan 28.

INRAE, Sigenae, Genotoul Bioinfo, Toulouse, France.

The understanding of the evolution of variable sex determination mechanisms across taxa requires comparative studies among closely related species. Following the fate of a known master sex-determining gene, we traced the evolution of sex determination in an entire teleost order (Esociformes). We discovered that the northern pike () master sex-determining gene originated from a 65 to 90 million-year-old gene duplication event and that it remained sex linked on undifferentiated sex chromosomes for at least 56 million years in multiple species. We identified several independent species- or population-specific sex determination transitions, including a recent loss of a Y chromosome. These findings highlight the diversity of evolutionary fates of master sex-determining genes and the importance of population demographic history in sex determination studies. We hypothesize that occasional sex reversals and genetic bottlenecks provide a non-adaptive explanation for sex determination transitions.
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http://dx.doi.org/10.7554/eLife.62858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870143PMC
January 2021

Giant lungfish genome elucidates the conquest of land by vertebrates.

Nature 2021 02 18;590(7845):284-289. Epub 2021 Jan 18.

Developmental Biochemistry, Biocenter, University of Würzburg, Würzburg, Germany.

Lungfishes belong to lobe-fined fish (Sarcopterygii) that, in the Devonian period, 'conquered' the land and ultimately gave rise to all land vertebrates, including humans. Here we determine the chromosome-quality genome of the Australian lungfish (Neoceratodus forsteri), which is known to have the largest genome of any animal. The vast size of this genome, which is about 14× larger than that of humans, is attributable mostly to huge intergenic regions and introns with high repeat content (around 90%), the components of which resemble those of tetrapods (comprising mainly long interspersed nuclear elements) more than they do those of ray-finned fish. The lungfish genome continues to expand independently (its transposable elements are still active), through mechanisms different to those of the enormous genomes of salamanders. The 17 fully assembled lungfish macrochromosomes maintain synteny to other vertebrate chromosomes, and all microchromosomes maintain conserved ancient homology with the ancestral vertebrate karyotype. Our phylogenomic analyses confirm previous reports that lungfish occupy a key evolutionary position as the closest living relatives to tetrapods, underscoring the importance of lungfish for understanding innovations associated with terrestrialization. Lungfish preadaptations to living on land include the gain of limb-like expression in developmental genes such as hoxc13 and sall1 in their lobed fins. Increased rates of evolution and the duplication of genes associated with obligate air-breathing, such as lung surfactants and the expansion of odorant receptor gene families (which encode proteins involved in detecting airborne odours), contribute to the tetrapod-like biology of lungfishes. These findings advance our understanding of this major transition during vertebrate evolution.
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http://dx.doi.org/10.1038/s41586-021-03198-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875771PMC
February 2021

Evolution of MicroRNA Biogenesis Genes in the Sterlet () and Other Polyploid Vertebrates.

Int J Mol Sci 2020 Dec 15;21(24). Epub 2020 Dec 15.

Institute of Molecular and Cellular Biology SB RAS, Lavrentiev Ave. 8/2, 630090 Novosibirsk, Russia.

MicroRNAs play a crucial role in eukaryotic gene regulation. For a long time, only little was known about microRNA-based gene regulatory mechanisms in polyploid animal genomes due to difficulties of polyploid genome assembly. However, in recent years, several polyploid genomes of fish, amphibian, and even invertebrate species have been sequenced and assembled. Here we investigated several key microRNA-associated genes in the recently sequenced sterlet () genome, whose lineage has undergone a whole genome duplication around 180 MYA. We show that two paralogs of , , , and as well as most genes have been retained after the acipenserid-specific whole genome duplication, while and genes have lost one paralog. While most diploid vertebrates possess only a single copy of , we strikingly found four paralogs of this gene in the sterlet genome, derived from a tandem segmental duplication that occurred prior to the last whole genome duplication. and look to be prone to additional segment duplications producing up to four-five paralog copies in ray-finned fishes. We demonstrate for the first time exon microsatellite amplification in the acipenserid gene, resulting in a highly variable protein product, which may indicate sub- or neofunctionalization. Paralogous copies of most microRNA metabolism genes exhibit different expression profiles in various tissues and remain functional despite the rediploidization process. Subfunctionalization of microRNA processing gene paralogs may be beneficial for different pathways of microRNA metabolism. Genetic variability of microRNA processing genes may represent a substrate for natural selection, and, by increasing genetic plasticity, could facilitate adaptations to changing environments
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http://dx.doi.org/10.3390/ijms21249562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765534PMC
December 2020

The Developmental and Genetic Architecture of the Sexually Selected Male Ornament of Swordtails.

Curr Biol 2021 Mar 3;31(5):911-922.e4. Epub 2020 Dec 3.

Institute of Neuroscience, University of Oregon, Eugene, OR 97401, USA. Electronic address:

Sexual selection results in sex-specific characters like the conspicuously pigmented extension of the ventral tip of the caudal fin-the "sword"-in males of several species of Xiphophorus fishes. To uncover the genetic architecture underlying sword formation and to identify genes that are associated with its development, we characterized the sword transcriptional profile and combined it with genetic mapping approaches. Results showed that the male ornament of swordtails develops from a sexually non-dimorphic prepattern of transcription factors in the caudal fin. Among genes that constitute the exclusive sword transcriptome and are located in the genomic region associated with this trait we identify the potassium channel, Kcnh8, as a sword development gene. In addition to its neural function kcnh8 performs a known role in fin growth. These findings indicate that during evolution of swordtails a brain gene has been co-opted for an additional novel function in establishing a male ornament.
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http://dx.doi.org/10.1016/j.cub.2020.11.028DOI Listing
March 2021

Chromosome Distribution of Highly Conserved Tandemly Arranged Repetitive DNAs in the Siberian Sturgeon ().

Genes (Basel) 2020 Nov 20;11(11). Epub 2020 Nov 20.

Institute of Molecular and Cellular Biology SB RAS, Lavrentiev Ave., 8/2, 630090 Novosibirsk, Russia.

Polyploid genomes present a challenge for cytogenetic and genomic studies, due to the high number of similar size chromosomes and the simultaneous presence of hardly distinguishable paralogous elements. The karyotype of the Siberian sturgeon () contains around 250 chromosomes and is remarkable for the presence of paralogs from two rounds of whole-genome duplications (WGD). In this study, we applied the sterlet-derived acipenserid satDNA-based whole chromosome-specific probes to analyze the Siberian sturgeon karyotype. We demonstrate that the last genome duplication event in the Siberian sturgeon was accompanied by the simultaneous expansion of several repetitive DNA families. Some of the repetitive probes serve as good cytogenetic markers distinguishing paralogous chromosomes and detecting ancestral syntenic regions, which underwent fusions and fissions. The tendency of minisatellite specificity for chromosome size groups previously observed in the sterlet genome is also visible in the Siberian sturgeon. We provide an initial physical chromosome map of the Siberian sturgeon genome supported by molecular markers. The application of these data will facilitate genomic studies in other recent polyploid sturgeon species.
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http://dx.doi.org/10.3390/genes11111375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699875PMC
November 2020

Macrophages Switch to an Osteo-Modulatory Profile Upon RANKL Induction in a Medaka () Osteoporosis Model.

JBMR Plus 2020 Nov 1;4(11):e10409. Epub 2020 Oct 1.

Department of Biological Sciences and Centre for Bioimaging Sciences National University of Singapore Singapore Singapore.

In mammals, osteoclasts differentiate from macrophages in the monocyte lineage. Although many factors driving osteoclast formation are known, the detailed processes underlying precursor recruitment, differentiation, and interaction of macrophages with other cell types involved in bone remodeling are poorly understood. Using live imaging in a transgenic medaka osteoporosis model, where ectopic osteoclasts are induced by RANKL expression, we show that a subset of macrophages is recruited to bone matrix to physically interact with bone-forming osteoblast progenitors. These macrophages subsequently differentiate into () positive osteoclasts. One day later, other macrophages are recruited to clear dying osteoclasts from resorbed bone by phagocytosis. To better understand the molecular changes underlying these dynamic processes, we performed transcriptome profiling of activated macrophages upon RANKL induction. This revealed an upregulation of several bone-related transcripts. Besides osteoclast markers, we unexpectedly also found expression of osteoblast-promoting signals in activated macrophages, suggesting a possible non-cell autonomous role in osteogenesis. Finally, we show that macrophage differentiation into osteoclasts is dependent on inflammatory signals. Medaka deficient for TNFα or treated with the TNFα-inhibitor pentoxifylline exhibited impaired macrophage recruitment and osteoclast differentiation. These results show the involvement of inflammatory signals and the dynamics of a distinct subset of macrophages during osteoclast formation. © 2020 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657398PMC
November 2020

Global assessment of organ specific basal gene expression over a diurnal cycle with analyses of gene copies exhibiting cyclic expression patterns.

BMC Genomics 2020 Nov 11;21(1):787. Epub 2020 Nov 11.

The Xiphophorus Genetic Stock Center, Department of Chemistry and Biochemistry, Texas State University, 419 Centennial Hall, 601 University Drive, San Marcos, TX, 78666, USA.

Background: Studying functional divergences between paralogs that originated from genome duplication is a significant topic in investigating molecular evolution. Genes that exhibit basal level cyclic expression patterns including circadian and light responsive genes are important physiological regulators. Temporal shifts in basal gene expression patterns are important factors to be considered when studying genetic functions. However, adequate efforts have not been applied to studying basal gene expression variation on a global scale to establish transcriptional activity baselines for each organ. Furthermore, the investigation of cyclic expression pattern comparisons between genome duplication created paralogs, and potential functional divergence between them has been neglected. To address these questions, we utilized a teleost fish species, Xiphophorus maculatus, and profiled gene expression within 9 organs at 3-h intervals throughout a 24-h diurnal period.

Results: Our results showed 1.3-21.9% of genes in different organs exhibited cyclic expression patterns, with eye showing the highest fraction of cycling genes while gonads yielded the lowest. A majority of the duplicated gene pairs exhibited divergences in their basal level expression patterns wherein only one paralog exhibited an oscillating expression pattern, or both paralogs exhibit oscillating expression patterns, but each gene duplicate showed a different peak expression time, and/or in different organs.

Conclusions: These observations suggest cyclic genes experienced significant sub-, neo-, or non-functionalization following the teleost genome duplication event. In addition, we developed a customized, web-accessible, gene expression browser to facilitate data mining and data visualization for the scientific community.
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http://dx.doi.org/10.1186/s12864-020-07202-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659085PMC
November 2020

Skipping sex: A nonrecombinant genomic assemblage of complementary reproductive modules.

Bioessays 2021 Jan 9;43(1):e2000111. Epub 2020 Nov 9.

Department of Developmental Biochemistry, Biocenter, University of Wuerzburg, Wuerzburg, Germany.

The unusual occurrence and developmental diversity of asexual eukaryotes remain a puzzle. De novo formation of a functioning asexual genome requires a unique assembly of sets of genes or gene states to disrupt cellular mechanisms of meiosis and gametogenesis, and to affect discrete components of sexuality and produce clonal or hemiclonal offspring. We highlight two usually overlooked but essential conditions to understand the molecular nature of clonal organisms, that is, a nonrecombinant genomic assemblage retaining modifiers of the sexual program, and a complementation between altered reproductive components. These subtle conditions are the basis for physiologically viable and genetically balanced transitions between generations. Genomic and developmental evidence from asexual animals and plants indicates the lack of complementation of molecular changes in the sexual reproductive program is likely the main cause of asexuals' rarity, and can provide an explanatory frame for the developmental diversity and lability of developmental patterns in some asexuals as well as for the discordant time to extinction estimations.
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http://dx.doi.org/10.1002/bies.202000111DOI Listing
January 2021

Oncogenic allelic interaction in highlights hybrid incompatibility.

Proc Natl Acad Sci U S A 2020 11 9;117(47):29786-29794. Epub 2020 Nov 9.

The Xiphophorus Genetic Stock Center, Texas State University, San Marcos, TX 78666;

Mixing genomes of different species by hybridization can disrupt species-specific genetic interactions that were adapted and fixed within each species population. Such disruption can predispose the hybrids to abnormalities and disease that decrease the overall fitness of the hybrids and is therefore named as hybrid incompatibility. Interspecies hybridization between southern platyfish and green swordtails leads to lethal melanocyte tumorigenesis. This occurs in hybrids with tumor incidence following progeny ratio that is consistent with two-locus interaction, suggesting melanoma development is a result of negative epistasis. Such observations make one of the only two vertebrate hybrid incompatibility examples in which interacting genes have been identified. One of the two interacting loci has been characterized as a mutant epidermal growth factor receptor. However, the other locus has not been identified despite over five decades of active research. Here we report the localization of the melanoma regulatory locus to a single gene, , which shows all expected features of the long-sought oncogene interacting locus. Our findings provide insights into the role of regulation in regard to cancer etiology. Finally, they provide a molecular explainable example of hybrid incompatibility.
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http://dx.doi.org/10.1073/pnas.2010133117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703647PMC
November 2020

Intra-Strain Genetic Variation of Platyfish () Strains Determines Tumorigenic Trajectory.

Front Genet 2020 6;11:562594. Epub 2020 Oct 6.

Xiphophorus Genetic Stock Center, Texas State University, San Marcos, TX, United States.

interspecies hybrids represent a valuable model system to study heritable tumorigenesis, and the only model system that exhibits both spontaneous and inducible tumors. Types of tumorigenesis depend on the specific pedigree of the parental species, , utilized to produce interspecies hybrids. Although the ancestors of the two currently used parental lines, Jp163 A and Jp163 B, were originally siblings produced by the same mother, backcross interspecies hybrid progeny between and Jp163 A develop spontaneous melanoma initiating at the dorsal fin due to segregation of an oncogene and a regulator encoded by the genome, while the backcross hybrid progeny with or and Jp163 B exhibit melanoma on the flanks of their bodies, especially after treatment with ultraviolet light. Therefore, dissecting the genetic differences between these two closely related lines may lead to better understanding of functional molecular differences associated with tumorigenic mechanisms. For this purpose, comparative genomic analyses were undertaken to establish genetic variants between these two lines. Surprisingly, given the heritage of these two fish lines, we found genetic variants are clustered together in select chromosomal regions. Among these variants are non-synonymous mutations located in 381 genes. The non-random distribution of genetic variants between these two may highlight ancestral chromosomal recombination patterns that became fixed during subsequent inbreeding. Employing comparative transcriptomics, we also determined differences in the skin transcriptional landscape between the two lines. The genetic differences observed are associated with pathways highlighting fundamental cellular functions including inter-cellular and microenvironment-cellular interactions, and DNA repair. These results collectively lead to the conclusion that diverged functional genetic baselines are present between Jp163 A and B strains. Further, disruption of these fixed genetic baselines in the hybrids may give rise to spontaneous or inducible mechanisms of tumorigenesis.
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http://dx.doi.org/10.3389/fgene.2020.562594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573281PMC
October 2020

Reconstruction of the birth of a male sex chromosome present in Atlantic herring.

Proc Natl Acad Sci U S A 2020 09 16;117(39):24359-24368. Epub 2020 Sep 16.

Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, 75123 Uppsala, Sweden;

The mechanisms underlying sex determination are astonishingly plastic. Particularly the triggers for the molecular machinery, which recalls either the male or female developmental program, are highly variable and have evolved independently and repeatedly. Fish show a huge variety of sex determination systems, including both genetic and environmental triggers. The advent of sex chromosomes is assumed to stabilize genetic sex determination. However, because sex chromosomes are notoriously cluttered with repetitive DNA and pseudogenes, the study of their evolution is hampered. Here we reconstruct the birth of a Y chromosome present in the Atlantic herring. The region is tiny (230 kb) and contains only three intact genes. The candidate male-determining gene encodes a truncated form of a BMP1B receptor, which originated by gene duplication and translocation and underwent rapid protein evolution. BMPR1BBY phosphorylates SMADs in the absence of ligand and thus has the potential to induce testis formation. The Y region also contains two genes encoding subunits of the sperm-specific Ca channel CatSper required for male fertility. The herring Y chromosome conforms with a characteristic feature of many sex chromosomes, namely, suppressed recombination between a sex-determining factor and genes that are beneficial for the given sex. However, the herring Y differs from other sex chromosomes in that suppression of recombination is restricted to an ∼500-kb region harboring the male-specific and sex-associated regions. As a consequence, any degeneration on the herring Y chromosome is restricted to those genes located in the small region affected by suppressed recombination.
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http://dx.doi.org/10.1073/pnas.2009925117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533707PMC
September 2020

Sex chromosome and sex locus characterization in goldfish, Carassius auratus (Linnaeus, 1758).

BMC Genomics 2020 Aug 11;21(1):552. Epub 2020 Aug 11.

INRAE, LPGP, 35000, Rennes, France.

Background: Goldfish is an important model for various areas of research, including neural development and behavior and a species of significant importance in aquaculture, especially as an ornamental species. It has a male heterogametic (XX/XY) sex determination system that relies on both genetic and environmental factors, with high temperatures being able to produce female-to-male sex reversal. Little, however, is currently known on the molecular basis of genetic sex determination in this important cyprinid model. Here we used sequencing approaches to better characterize sex determination and sex-chromosomes in an experimental strain of goldfish.

Results: Our results confirmed that sex determination in goldfish is a mix of environmental and genetic factors and that its sex determination system is male heterogametic (XX/XY). Using reduced representation (RAD-seq) and whole genome (pool-seq) approaches, we characterized sex-linked polymorphisms and developed male specific genetic markers. These male specific markers were used to distinguish sex-reversed XX neomales from XY males and to demonstrate that XX female-to-male sex reversal could even occur at a relatively low rearing temperature (18 °C), for which sex reversal has been previously shown to be close to zero. We also characterized a relatively large non-recombining region (~ 11.7 Mb) on goldfish linkage group 22 (LG22) that contained a high-density of male-biased genetic polymorphisms. This large LG22 region harbors 373 genes, including a single candidate as a potential master sex gene, i.e., the anti-Mullerian hormone gene (amh). However, no sex-linked polymorphisms were detected in the coding DNA sequence of the goldfish amh gene.

Conclusions: These results show that our goldfish strain has a relatively large sex locus on LG22, which is likely the Y chromosome of this experimental population. The presence of a few XX males even at low temperature also suggests that other environmental factors in addition to temperature could trigger female-to-male sex reversal. Finally, we also developed sex-linked genetic markers, which will be important tools for future research on sex determination in our experimental goldfish population. However, additional work would be needed to explore whether this sex locus is conserved in other populations of goldfish.
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http://dx.doi.org/10.1186/s12864-020-06959-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430817PMC
August 2020

Cxcl9l and Cxcr3.2 regulate recruitment of osteoclast progenitors to bone matrix in a medaka osteoporosis model.

Proc Natl Acad Sci U S A 2020 08 27;117(32):19276-19286. Epub 2020 Jul 27.

Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore;

Bone homeostasis requires continuous remodeling of bone matrix to maintain structural integrity. This involves extensive communication between bone-forming osteoblasts and bone-resorbing osteoclasts to orchestrate balanced progenitor cell recruitment and activation. Only a few mediators controlling progenitor activation are known to date and have been targeted for intervention of bone disorders such as osteoporosis. To identify druggable pathways, we generated a medaka () osteoporosis model, where inducible expression of receptor-activator of nuclear factor kappa-Β ligand (Rankl) leads to ectopic formation of osteoclasts and excessive bone resorption, which can be assessed by live imaging. Here we show that upon Rankl induction, osteoblast progenitors up-regulate expression of the chemokine ligand Cxcl9l. Ectopic expression of Cxcl9l recruits -positive macrophages to bone matrix and triggers their differentiation into osteoclasts. We also demonstrate that the chemokine receptor Cxcr3.2 is expressed in a distinct subset of macrophages in the aorta-gonad-mesonephros (AGM). Live imaging revealed that upon Rankl induction, Cxcr3.2-positive macrophages get activated, migrate to bone matrix, and differentiate into osteoclasts. Importantly, mutations in prevent macrophage recruitment and osteoclast differentiation. Furthermore, Cxcr3.2 inhibition by the chemical antagonists AMG487 and NBI-74330 also reduced osteoclast recruitment and protected bone integrity against osteoporotic insult. Our data identify a mechanism for progenitor recruitment to bone resorption sites and Cxcl9l and Cxcr3.2 as potential druggable regulators of bone homeostasis and osteoporosis.
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http://dx.doi.org/10.1073/pnas.2006093117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431079PMC
August 2020

Melanocortin 4 receptor signaling and puberty onset regulation in Xiphophorus swordtails.

Gen Comp Endocrinol 2020 09 26;295:113521. Epub 2020 May 26.

Physiological Chemistry, Biocenter, University of Wuerzburg, Wuerzburg, Germany; Developmental Biochemistry, Biocenter, University of Wuerzburg, Wuerzburg, Germany; The Xiphophorus Genetic Stock Center, Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, USA. Electronic address:

Fish of the genus Xiphophorus provide a prominent example of genetic control of male body size and reproductive tactics. In X.nigrensis and X.multilineatus, puberty onset and body length are determined by melanocortin 4 receptor (Mc4r) allelic and copy number variations which were proposed to fine-tune the signaling output of the system. Accessory protein Mrap2 is required for growth across species by affecting Mc4r signaling. The molecular mechanism how Mc4r signaling controls puberty regulation in Xiphophorus and whether the interaction with Mrap2 is also involved was so far unclear. Hence, we examined Mc4r and Mrap2 in X.nigrensis and X.multilineatus, in comparison to a more distantly related species, X.hellerii. mc4r and mrap2 transcripts co-localized in the hypothalamus and preoptic regions in large males, small males and females of X.nigrensis, with similar signal strength for mrap2 but higher expression of mc4r in large males. This overexpression is constituted by wild-type and one subtype of mutant alleles. In vitro studies revealed that Mrap2 co-expressed with Mc4r increased cAMP production but did not change EC50. Cells co-expressing the wild-type and one mutant allele showed lower cAMP signaling than Mc4r wild-type cells. This indicates a role of Mc4r alleles, but not Mrap2, in puberty signaling. Different from X.nigrensis and X.multilineatus, X.hellerii has only wild-type alleles, but also shows a puberty onset and body length polymorphism, despite the absence of mutant alleles. Like in the two other species, mc4r and mrap2 transcripts colocalized and mc4r is expressed at substantially higher levels in large males. This demonstrates that puberty and growth regulation mechanism may not be identical even within same genus.
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http://dx.doi.org/10.1016/j.ygcen.2020.113521DOI Listing
September 2020

Natural hybridization reveals incompatible alleles that cause melanoma in swordtail fish.

Science 2020 05;368(6492):731-736

Department of Biology, Stanford University and Howard Hughes Medical Institute, Stanford, CA, USA.

The establishment of reproductive barriers between populations can fuel the evolution of new species. A genetic framework for this process posits that "incompatible" interactions between genes can evolve that result in reduced survival or reproduction in hybrids. However, progress has been slow in identifying individual genes that underlie hybrid incompatibilities. We used a combination of approaches to map the genes that drive the development of an incompatibility that causes melanoma in swordtail fish hybrids. One of the genes involved in this incompatibility also causes melanoma in hybrids between distantly related species. Moreover, this melanoma reduces survival in the wild, likely because of progressive degradation of the fin. This work identifies genes underlying a vertebrate hybrid incompatibility and provides a glimpse into the action of these genes in natural hybrid populations.
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http://dx.doi.org/10.1126/science.aba5216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074799PMC
May 2020

The sterlet sturgeon genome sequence and the mechanisms of segmental rediploidization.

Nat Ecol Evol 2020 06 30;4(6):841-852. Epub 2020 Mar 30.

Developmental Biochemistry, Biocenter, University of Wuerzburg, Wuerzburg, Germany.

Sturgeons seem to be frozen in time. The archaic characteristics of this ancient fish lineage place it in a key phylogenetic position at the base of the ~30,000 modern teleost fish species. Moreover, sturgeons are notoriously polyploid, providing unique opportunities to investigate the evolution of polyploid genomes. We assembled a high-quality chromosome-level reference genome for the sterlet, Acipenser ruthenus. Our analysis revealed a very low protein evolution rate that is at least as slow as in other deep branches of the vertebrate tree, such as that of the coelacanth. We uncovered a whole-genome duplication that occurred in the Jurassic, early in the evolution of the entire sturgeon lineage. Following this polyploidization, the rediploidization of the genome included the loss of whole chromosomes in a segmental deduplication process. While known adaptive processes helped conserve a high degree of structural and functional tetraploidy over more than 180 million years, the reduction of redundancy of the polyploid genome seems to have been remarkably random.
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http://dx.doi.org/10.1038/s41559-020-1166-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269910PMC
June 2020

The transcriptome of the newt Cynops orientalis provides new insights into evolution and function of sexual gene networks in sarcopterygians.

Sci Rep 2020 03 25;10(1):5445. Epub 2020 Mar 25.

Developmental Biochemistry, Biocenter, University of Wuerzburg, Wuerzburg, Germany.

Amphibians evolved in the Devonian period about 400 Mya and represent a transition step in tetrapod evolution. Among amphibians, high-throughput sequencing data are very limited for Caudata, due to their largest genome sizes among terrestrial vertebrates. In this paper we present the transcriptome from the fire bellied newt Cynops orientalis. Data here presented display a high level of completeness, comparable to the fully sequenced genomes available from other amphibians. Moreover, this work focused on genes involved in gametogenesis and sexual development. Surprisingly, the gsdf gene was identified for the first time in a tetrapod species, so far known only from bony fish and basal sarcopterygians. Our analysis failed to isolate fgf24 and foxl3, supporting the possible loss of both genes in the common ancestor of Rhipidistians. In Cynops, the expression analysis of genes described to be sex-related in vertebrates singled out an expected functional role for some genes, while others displayed an unforeseen behavior, confirming the high variability of the sex-related pathway in vertebrates.
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http://dx.doi.org/10.1038/s41598-020-62408-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096497PMC
March 2020

Spatial and temporal expression pattern of sex-related genes in ovo-testis of the self-fertilizing mangrove killifish (Kryptolebias marmoratus).

Gene 2020 Jun 12;742:144581. Epub 2020 Mar 12.

University of Wuerzburg, Physiological Chemistry, Biocenter, Am Hubland, D-97074 Wuerzburg, Germany; University of Wuerzburg, Developmental Biochemistry, Biocenter, Am Hubland, D-97074 Wuerzburg, Germany. Electronic address:

In vertebrates, sex determination and differentiation comprehend a fine balance between female and male factors, leading the bipotential anlage to develop towards ovary or testis, respectively. Nevertheless, the mangrove killifish, (Kryptolebias marmoratus) a simultaneous hermaphroditic species, could overcome those antagonistic pathways and evolved to develop and maintain reproductively active ovarian and testicular tissues in the same organ. Morphological and mRNA localization analyzes of developing and adult gonads demonstrate that genes related to testis (dmrt1 and amh) and ovary differentiation (foxl2 and sox9a) follow the same expression pattern observed in gonochoristic species, thus functioning as two independent organs. In addition, Amh expression patterns make it a strong candidate for initiation of the formation and maintenance of the testicular tissue in the hermaphroditic gonad. Differently from described so far, foxl3 seems to have an important role in oogenesis as well as spermatogenesis and gonadal structure.
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http://dx.doi.org/10.1016/j.gene.2020.144581DOI Listing
June 2020

Genome Sequence of the Euryhaline Javafish Medaka, : A Small Aquarium Fish Model for Studies on Adaptation to Salinity.

G3 (Bethesda) 2020 03 5;10(3):907-915. Epub 2020 Mar 5.

INRAE, UR 1037 Fish Physiology and Genomics, F-35000 Rennes, France, and

The genus consists of 35 medaka-fish species each exhibiting various ecological, morphological and physiological peculiarities and adaptations. Beyond of being a comprehensive phylogenetic group for studying intra-genus evolution of several traits like sex determination, behavior, morphology or adaptation through comparative genomic approaches, all medaka species share many advantages of experimental model organisms including small size and short generation time, transparent embryos and genome editing tools for reverse and forward genetic studies. The Java medaka, , is one of the two species of medaka perfectly adapted for living in brackish/sea-waters. Being an important component of the mangrove ecosystem, is also used as a valuable marine test-fish for ecotoxicology studies. Here, we sequenced and assembled the whole genome of , and anticipate this resource will be catalytic for a wide range of comparative genomic, phylogenetic and functional studies. Complementary sequencing approaches including long-read technology and data integration with a genetic map allowed the final assembly of 908 Mbp of the genome. Further analyses estimate that the genome contains 33% of repeat sequences and has a heterozygosity of 0.96%. The achieved draft assembly contains 525 scaffolds with a total length of 809.7 Mbp, a N50 of 6,3 Mbp and a L50 of 37 scaffolds. We identified 21454 predicted transcripts for a total transcriptome size of 57, 146, 583 bps. We provide here a high-quality chromosome scale draft genome assembly of the euryhaline Javafish medaka (321 scaffolds anchored on 24 chromosomes (representing 97.7% of the total bases)), and give emphasis on the evolutionary adaptation to salinity.
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http://dx.doi.org/10.1534/g3.119.400725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056978PMC
March 2020

Characterization of a Y-specific duplication/insertion of the anti-Mullerian hormone type II receptor gene based on a chromosome-scale genome assembly of yellow perch, Perca flavescens.

Mol Ecol Resour 2020 Mar 27;20(2):531-543. Epub 2020 Jan 27.

INRAE, UR 1037 Fish Physiology and Genomics, Rennes, France.

Yellow perch, Perca flavescens, is an ecologically and economically important species native to a large portion of the northern United States and southern Canada and is also a promising candidate species for aquaculture. However, no yellow perch reference genome has been available to facilitate improvements in both fisheries and aquaculture management practices. By combining Oxford Nanopore Technologies long-reads, 10X Genomics Illumina short linked reads and a chromosome contact map produced with Hi-C, we generated a high-continuity chromosome-scale yellow perch genome assembly of 877.4 Mb. It contains, in agreement with the known diploid chromosome yellow perch count, 24 chromosome-size scaffolds covering 98.8% of the complete assembly (N50 = 37.4 Mb, L50 = 11). We also provide a first characterization of the yellow perch sex determination locus that contains a male-specific duplicate of the anti-Mullerian hormone type II receptor gene (amhr2by) inserted at the proximal end of the Y chromosome (chromosome 9). Using this sex-specific information, we developed a simple PCR genotyping assay which accurately differentiates XY genetic males (amhr2by ) from XX genetic females (amhr2by ). Our high-quality genome assembly is an important genomic resource for future studies on yellow perch ecology, toxicology, fisheries and aquaculture research. In addition, characterization of the amhr2by gene as a candidate sex-determining gene in yellow perch provides a new example of the recurrent implication of the transforming growth factor beta pathway in fish sex determination, and highlights gene duplication as an important genomic mechanism for the emergence of new master sex determination genes.
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http://dx.doi.org/10.1111/1755-0998.13133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050324PMC
March 2020

Independent Origin of XY and ZW Sex Determination Mechanisms in Mosquitofish Sister Species.

Genetics 2020 01 8;214(1):193-209. Epub 2019 Nov 8.

Physiological Chemistry, Biocenter, University of Wuerzburg, 97074, Germany

Fish are known for the outstanding variety of their sex determination mechanisms and sex chromosome systems. The western () and eastern mosquitofish () are sister species for which different sex determination mechanisms have been described: ZZ/ZW for and XX/XY for Here, we carried out restriction-site associated DNA (RAD-) and pool sequencing (Pool-seq) to characterize the sex chromosomes of both species. We found that the ZW chromosomes of females and the XY chromosomes of males correspond to different linkage groups, and thus evolved independently from separate autosomes. In interspecific hybrids, the Y chromosome is dominant over the W chromosome, and X is dominant over Z. In , we identified a candidate region for the Y-linked melanic pigmentation locus, a rare male phenotype that constitutes a potentially sexually antagonistic trait and is associated with other such characteristics, , large body size and aggressive behavior. We developed a SNP-based marker in the Y-linked allele of (), which was linked to melanism in all tested populations. This locus represents an example for a color locus that is located in close proximity to a putative sex determiner, and most likely substantially contributed to the evolution of the Y.
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http://dx.doi.org/10.1534/genetics.119.302698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944411PMC
January 2020

Sex and the TEs: transposable elements in sexual development and function in animals.

Mob DNA 2019 3;10:42. Epub 2019 Nov 3.

1Institut de Genomique Fonctionnelle de Lyon, Univ Lyon, CNRS UMR 5242, Ecole Normale Superieure de Lyon, Universite Claude Bernard Lyon 1, 46 allee d'Italie, F-69364 Lyon, France.

Transposable elements are endogenous DNA sequences able to integrate into and multiply within genomes. They constitute a major source of genetic innovations, as they can not only rearrange genomes but also spread ready-to-use regulatory sequences able to modify host gene expression, and even can give birth to new host genes. As their evolutionary success depends on their vertical transmission, transposable elements are intrinsically linked to reproduction. In organisms with sexual reproduction, this implies that transposable elements have to manifest their transpositional activity in germ cells or their progenitors. The control of sexual development and function can be very versatile, and several studies have demonstrated the implication of transposable elements in the evolution of sex. In this review, we report the functional and evolutionary relationships between transposable elements and sexual reproduction in animals. In particular, we highlight how transposable elements can influence expression of sexual development genes, and how, reciprocally, they are tightly controlled in gonads. We also review how transposable elements contribute to the organization, expression and evolution of sexual development genes and sex chromosomes. This underscores the intricate co-evolution between host functions and transposable elements, which regularly shift from a parasitic to a domesticated status useful to the host.
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http://dx.doi.org/10.1186/s13100-019-0185-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825717PMC
November 2019