Sanger Centre to sequence zebrafish genome in new Wellcome Trust Initiative
In a major new initiative, the Wellcome Trust announced that the next target for genome sequencing would be a small fish called the zebrafish. With a genome only half the size of that of mouse or human, the zebrafish will play a key role in finding genes in the other genomes. The new project is predicted to take three years.
The announcement closely follows a Workshop held at the Wellcome Trust Genome Campus – home of the Sanger Centre – attended by international scientists in the zebrafish research community.
The small zebrafish is a powerful force in biology. Adults are about 4 cm long, the female can lay 200 eggs per week, and the embryos are transparent and reach maturity in 2-3 months. Exquisitely precise tools have been developed to generate and analyse alterations in the zebrafish genome. In combination, these features mean that exchange of sequence information between human and zebrafish projects will accelerate progress in each. The humble zebrafish will be used to find meaning for the code in the human genome.
“One of the great advantages of zebrafish is the ability to produce, very readily, mutations that are relevant to human health and disease. This genomics initiative will superimpose those mutations on disease loci identified through the work of the Human Genome Project.”
Leonard I Zon MD, Children’s Hospital of Boston MA
Development of blood cells is one example where mutations in the zebrafish genome closely resemble human disease such as anaemia or thalassaemia.
“Zebrafish is the ideal organism to study the function of human genes.”
Professor Christiane Nüsslein-Volhard From the Max-Planck Institute in Tübingen, Germany
Professor Nüsslein-Volhard, Nobel Prize Winner in 1995, is studying the way the body plan is laid down during development. The Tübingen group has identified more than 1000 mutations in the zebrafish, many of which affect processes with great relevance to human physiology and disease, such as heart function, hearing, blood formation, vision, cartilage and bone formation, nervous system development. These are now studied in many laboratories worldwide.
“Sequencing the zebrafish genome will provide a rapid route to discovering the molecular basis of these mutations and hence to an understanding of the biochemical function of the genes which they identify.”
Professor Philip Ingham University of Sheffield, UK
One area of Professor Ingham’s research is an important gene in development called sonic hedgehog: mutations in this gene cause one of the most common forms of human birth defect, holoprosencephaly.
“This builds on the seminal work, supported by the Wellcome Trust, on the human genome sequencing project and will help all our future studies on gene function, leading to health care benefits.”
Dr Michael Dexter Director of the Wellcome Trust
Many genes are similar between genomes of human and those of less complex animals. The genomic information from the worm C. elegans, the first animal to be sequenced, has been used to find Alzheimer’s genes. However, the worm and the fly Drosophila do not possess many of the complex organ systems found in higher organisms. Being a vertebrate, the zebrafish (Danio rerio) has blood, kidney and optical systems that share many features of the human systems. Work on this organism will complement that on the mouse, which is the most widely used mammalian genetic model organism. The Sanger Centre and the Wellcome Trust are also participating in an international consortium to sequence the mouse (press release 6 October).
Layering of genomic information of different species – comparative genomics – is an especially useful method for identifying genes and gene control regions because similarities are revealed. If the organism provides unique methods for biological study – as do both the zebrafish and the mouse – then the combination of biological and sequence information can advance research more rapidly.
As with all projects undertaken by the Sanger Centre and the Wellcome Trust, the sequence information will be released rapidly, and made available to researchers without cost or restriction.
More information
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The Wellcome Trust is the world’s largest medical research charity with an annual spend of some £600 million in financial year 1999/2000. The Wellcome Trust supports more than 5000 researchers at 300 locations in 42 different countries, laying the foundations for the healthcare advances of the 21st century and helping to maintain the UK’s reputation as one of the worlds leading scientific nations. As well as funding major initiatives in the public understanding of science, the Wellcome Trust is the country’s leading supporter of research into the history of medicine.
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The Sanger Centre, which receives the majority of its funding from the Wellcome Trust, is one of the world’s leading genome sequencing centres. Both the Sanger Centre and the Wellcome Trust have been at the forefront of efforts to keep sequence data in the public domain. The Sanger Centre employs about 570 people in the purpose-built campus at Hinxton. The Centre is a leading partner in the Human Genome Project, and is responsible for sequencing one-third of the human genome sequence and also contributes to international projects to sequence the genomes of disease-causing organisms.
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The zebrafish: Many aspects of the development of fish embryo mirror the processes that shape the form of higher vertebrate organisms, including humans. Because of their small size and ease of culture, the tropical fish Danio rerio – better known as the zebrafish – has become a favourite model system for biologists studying embryonic development. Large numbers of mutations that disrupt embryonic development have now been isolated in the zebrafish, many of which may serve as models for human disease syndromes. For example, screening zebrafish populations has identified mutations in a number of genes – including sonic hedgehog – that result in a phenotype reminiscent of the holoprosencephaly syndrome. These mutants allow the entire genetic network responsible for this condition to be examined in a developing system that closely resembles mammalian development. The zebrafish genome is about 1.7 x 109 base-pairs, compared with mammalian genome sizes of about 3.2 x 109 base-pairs.
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DNA of every living organism is made up of four chemical ‘bases’ represented by the letters A, C, G and T. The bases are paired together, A with T and C with G to produce double-stranded DNA in the familiar helix. DNA is a digital code and it is the order of base-pairs that contains the information. Thus, the sequence of DNA bases contains all the instructions to make an organism: decoding that set of instructions is the heart of a sequencing project. The number of base-pairs varies from a few thousand for the smallest viruses to several billions for complex organisms. Comparing sequences from different organisms is a valuable method to identify genes and the genetic switches that control them. Regions that are important for gene function are often similar (conserved) between dissimilar species: regions that are not important tend to differ (diverge).
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Other resources
The zebrafish research community provides a valuable resource at:
http://www.zfin.orgMassachusetts General Hospital:
http://cvrc.massgeneral.org/programs/development-and-regeneration/Stanford zebrafish:
http://zebrafish.stanford.edu/
