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B RIEFINGS IN FUNC TIONAL GENOMICS . VOL 13. NO 2. 79^ 81 doi:10.1093/bfgp/elt055 Editorial Fish genomics: casting the net wide Recent developments in high-throughput genomics, including the landmark ENCODE project [1], have generated an immense amount of data that motivates scholars from a wide range of fields well beyond genomics. The comprehensive attempt to annotate the human genome however raised an important problem: the need for a suitable, preferably, in vivo animal model that enables high-throughput in vivo functional testing of hypotheses generated from genome scale annotation data. Small fish models such as zebrafish (Danio rerio) and medaka (Oryzias latipes) are ideal vertebrates with sufficiently highthroughput capabilities to aspire to these large-scale experimental studies and thus may provide a suitable animal model for functional analyses of annotated genomics features. This notion is demonstrated by the ENCODE publications, one of which features medaka transgenesis experiments in validation of predicted regulatory elements [1]. However, the degree to which fish can suffice as a surrogate for mammalian functional genomics will depend on our ability to understand the extent of underlying homology and functional parallels between mammals and fish and, most importantly, will require better annotation of fish genomes throughout ontogeny. The widening application of genomics technologies to fish model systems have led to a series of important advances in this area, which look set to propel fish and particularly zebrafish, into a new era of discovery [2]. This timely special issue on fish genomics features articles, which provides an overview of several key areas where fish models have contributed substantially to the disciplines of genetics, epigenetics and (epi)genomics and demonstrates the strengthening position of these small vertebrates as a primary choice among animal models. Zebrafish has many advantages that often make it the model organism of choice in a wide variety of disciplines. It is used, for instance, in over 1200 laboratories worldwide to study organismal, cell and gene function in studies of developmental genetics, through toxicology to human disease modelling. This is because zebrafish, particularly amenable to rapid reverse genetics assays for the study of gene loss of function and forward genetics screens, have also provided the community with thousands of genetic mutants. Thus, in recent years zebrafish has gained popularity in human disease modelling due to these resources and the fact that there are common genetic foundations across vertebrates for many disorders, from congenital to multifactorial diseases such as cardiovascular, neurodegenerative, metabolic and cancer diseases (e.g. [3]). Indeed, 75–80% of human genes associated with disease—either annotated in OMIM or identified in GWAS—have at least one zebrafish orthologue, making zebrafish an attractive system in which to test the function of these disease genes [4]. With its abundantly available, transparent and externally developing embryos and larvae, zebrafish is also one of the most accessible and tractable models for the development of genomics methodologies. Indeed, the recent application of these technologies has made the process of testing gene function faster and more efficient and we can look forward to a day soon when all zebrafish genes have at least one mutation. Kettleborough and colleagues [5], for instance, performed a chemical mutagenesis screen and used exome sequencing to identify disruptive mutations [5]. Other groups have developed methods to map mutations in zebrafish using RNA-seq data from pooled embryos [6, 7]. The advent of methods that allow precise genome editing [8–10] also paves the way for specific human disease-causing mutations to be created and studied in zebrafish. The review by Varshney and Burgess in this issue gives an up-todate account of current mutagenesis technologies and phenotyping tools, evaluates their pros and cons and details their efficiency. This article will provide an excellent introduction and resource for those interested in embarking on zebrafish mutagenesis screens. In order to utilize the zebrafish genome to its full extent and to better understand the activity of the genome, annotation is critical. We have learned ß The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected] 80 Editorial much about the types of RNAs that are produced in different human tissues and cell lines through massive sequencing of the transcriptome (e.g. [11, 12]). Similar sequencing studies carried out during embryonic developmental stages and adult tissues in zebrafish complements these efforts [13–15] and reveal that, as in humans, the zebrafish genome is characterized by widespread transcription of many different types of RNAs, including microRNAs, piwiRNAs, lncRNAs and yet unexplored porst-transcripitional small RNA products [16–19].Thus, transcriptome dynamics during embryo development have been an area where zebrafish studies pushed the field of transcriptomics forward. In this issue, the review by Aanes et al. summarize the developments in this area and detail important advances in our understanding of transcriptome turnover during the transition from maternal to zygotic genome activity during early development. A timely question in the light of the ENCODE and other genome-wide annotation projects is, what portion of the genome that is not transcribed is functional and carries, for example, for cis-regulatory elements. Annotating the regulatory regions, including but not restricted to promoters and enhancers, is central to understanding such gene regulation and is a key prerequisite for zebrafish to become an useful comparative model for exploring and validating the codes of transcription regulation. Advances have been made in mapping the epigenetic features associated with transcriptional control during development [20–22]. The review by Stapel and Vastenhouw focuses on how zebrafish studies have aided in characterizing the features and role of chromatin in transmitting epigenetic information during the maternal to zygotic transition and establishing pluripotency during early development. Genomewide DNA methylation studies in zebrafish have also helped in understanding how epigenetic marks are inherited, maintained and remodelled during development [21, 23–27]. The review by Bodganovic and Gomez-Skarmeta provides an assessment of the advances made in this field. Binding of transcription factors to cis-regulatory sequences can also be mapped across the genome using ChIP-seq to better understand the transcriptional programs that regulate tissue and stage-specific gene expression during development [28–31]. While transcription factor biology is an area where zebrafish has some catching up to do due to the limited availability of antibodies, the zebrafish model has nevertheless been a great asset in exploring transcriptional regulatory networks using developmental genetic tools as demonstrated by the examples presented in the review by Ferg et al. in this issue. The utility of fish models in comparative genomics is not restricted to zebrafish and medaka. The decreasing costs of high-throughput sequencing technologies opened the way for genome-wide studies in non-model fishes including species of aquaculture importance. Together, the range of teleost genomes available expands the capabilities offered by the comparative approach. The review by Spaink et al. in this issue gives a comprehensive account of the state of the art of teleost genome projects. Besides developmental biology and disease modelling, other areas of research have benefited from fish model-based genomics. Among them, environmental toxicology is one of the most advanced areas which is boosted by the wider acceptance of fishes including zebrafish in toxicity tests [32]. The review by Williams et al. gives an overview of this area and highlights the genomics aspects of developing fish models for environmental toxicity. There are, however, areas of fish/zebrafish genetics that are unlikely to mimic mammalian mechanisms and such an example is sex determination. Yet, understanding the genetic basis of sex determination in zebrafish will be crucial for their full exploitation in epigenonimics, such as when basic questions are asked about the interaction between genetic and epigenetic mechanisms of inheritance and the influence of the environment. With this in mind, last in this issue, but not least, Liew and Orban discuss the evidence for genetic determination of sex determination in zebrafish and how genomics techniques have shed light on this complicated process. Fiona C.Wardle Randall Division of Cell and Molecular Biophysics, King’s College London, London, UK Ferenc Mu«ller School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK References 1. ENCODE Project Consortium, Bernstein BE, Birney E, et al. An integrated encyclopedia of DNA elements in the human genome. Nature 2012;489:57–74. Editorial 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 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