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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
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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
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