Gene annotation

If we could switch the right genes on in humans then we could live longer and survive better after a heart attack.


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These projects explain why the zebrafish has become such a pin-up animal for scientists. But exactly how do researchers turn information from a creature that last shared a common ancestor with humanity about m years ago? The answer is provided by Stemple. The researcher is sitting in an office filled with bicycles, crash helmets and various items of discarded clothing. His room overlooks a vast construction site at the edge of Cambridgeshire's Genome Campus where a new centre for the European Bioinformatics Institute, which shares the site with the Sanger Institute, is being built.

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First developed in the last century, the Genome Campus has been the focus of intense expansion ever since, driven by the remarkable boom in gene technology. Scientists took years, and spent billions of pounds, to sequence the very first human genome. Today, that task can be done for a few thousand pounds and takes only a few hours. Trillions of bits of data now pour daily from the automated gene sequencers at the Sanger Institute as its researchers probe the genetic structures of patients, animals — including zebrafish — and tumour cells, an avalanche of data that is controlled from a set of powerful computers that have their own, impressively large building.

Being able to analyse vast chunks of data is important in using zebrafish to tease out the secrets of human genes. The underlying procedures employed to generate this information are based on more traditional approaches to genetic research, however.

Genes are responsible for directing the manufacture of proteins in the bodies of all animals.

Tiny fish, big splash: the story of the zebrafish | Stories | theranchhands.com

So a mutation in a gene will disrupt the protein that it makes. For example, it might manufacture a protein that is cut in half. The trick for researchers is to link a specific mutation in a gene with a change in the appearance or behaviour of the zebrafish, a connection that will lead them to uncover the protein that is usually made by that gene.

To do this, researchers — once they have created their mutated zebrafish males — breed them with untreated, normal female zebrafish. The males' mutations are then passed on to a new generation of zebrafish. This first generation of fish is then crossbred to create a second generation in which some fish possess two copies of the same mutated gene — one from their mothers, one from their fathers — and which will clearly manifest itself in the physiology of the young fish.

For example, we recently found one family of zebrafish, created through our mutation research, that completely lacked pigmentation. There was a clear link indicating this gene is involved in pigmentation. More to the point, there is a human equivalent to that gene which we now believe is responsible for coding for genes that are involved in pigmentation in humans. Another example of the value of the zebrafish to medicine is provided by research carried out by Carss at the Sanger. She works on a form of muscular dystrophy known as dystroglycanopathy, which is generally found in babies and young children and causes weakness and loss of movement.

Using zebrafish, Carss has discovered that mutations in the genes B3galnt2 and GmppB produced embryos that were small and bent compared to healthy embryos. Knowing these genes are involved gives us clues as to what treatments we might be able to give these children. For good measure, zebrafish embryos could be used to test these treatments. Enthusiasm for zebrafish research is also shared by Leonard Zon, professor of paediatric medicine, at Boston Children's Hospital, part of the Harvard Medical School.

So it is easy to induce mutations in their genes. In one set of experiments carried out by his team, Zon added various drugs to zebrafish embryos and discovered one, called prostaglandin E2, that increased their levels of blood stem cells — and by inference blood stem cell levels in humans. These cells, which are made in our bone marrow, are the precursors of all the types of cells that make up our blood including white cells that form our immune systems.

The discovery could be significant, says Zon, because it could be used to enhance stem cell transplants for patients, in particular those suffering from cancers. If a patient doesn't have a relative whose bone marrow matches theirs, a doctor will use blood stem cells taken from umbilical cords.

Tiny fish, big splash: the story of the zebrafish

These are routinely stored in cord banks today. Transfusions of cord blood can restore patients' immune systems. However, these cords hold only a few cells and we need to find ways to boost blood stem cell numbers quickly while patients are immune compromised. Prostaglandin E2 — which we pinpointed from our work on zebrafish — suggests a way for us to do that. This idea has already been backed by early experiments on zebrafish and mice. Zon and his team took bone marrow out of mice and treated some with prostaglandin. Some was left untreated. Then the scientists returned the bone marrow to the mice.

The marrow treated with prostaglandin restored the mouse's blood and immune systems much more quickly than the untreated version. This animal work has now been repeated in a phase one clinical trial in humans, added Zon.

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In leukaemia patients who had undergone chemotherapy, it was found that cord blood transfusions that were treated with prostaglandin restored white blood cells and platelets several days earlier compared with patients who had no prostaglandin added to their cord blood transfusions. Males are slender and torpedo-shaped usually with a pink or yellow tinge. Females tend to be less pink than the males and are fatter due to the eggs they carry. Zebrafish have already been used to help unlock a number of the biological processes behind muscular dystrophy , and are an important model for understanding the mechanisms of development and diseases such as cancer.

The complete genome sequence of the zebrafish was published in Tiny fish, big splash: What are model organisms?


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