April 18, 2013
Zebrafish Genome Could Have Significant Implications For Human Health
April Flowers for redOrbit.com - Your Universe Online
Two new studies from the Wellcome Trust Sanger Institute involving the genome of zebrafish have been published in the journal Nature this week, giving insight into the relationship between humans, zebrafish and genetic mutations.
According to the first study, 70 percent of protein-coding human genes are related to zebrafish genes, and 84 percent of the genes known to be associated with human disease have a counterpart in the zebrafish genome. These findings highlight the importance of the zebrafish model in human disease research.
To make this comparison, the team developed a high-quality annotated zebrafish genome sequence. To date, only two other large genomes have been sequenced to this level: the human genome, and the mouse genome. This new sequence will be an essential resource to drive the study of genetic function and disease in humans.
Fish seem to be very different from humans, with different body structures and living environments. This makes them a seemingly strange choice as a comparator for humans. Like us, though, they are vertebrates and as such share a common ancestor and a remarkable biological similarity. Sharing the majority of genes with humans makes them an important model for understanding how genes work in health and disease.
"Our aim with this project, like with all biomedical research, is to improve human health," says Dr. Derek Stemple, from Sanger. "This genome will allow researchers to understand how our genes work and how genetic variants can cause disease in ways that cannot be easily studied in humans or other organisms."
Research into the zebrafish genome has already led to biological advances in cancer and heart disease research. It has advanced our understanding of muscle and organ development, and been used to verify the causal gene in muscular dystrophy (MD) disorders and the formation of skin cancers.
"The vast majority of human genes have counterparts in the zebrafish, especially genes related to human disease," says Professor Jane Rogers, formerly of The Genome Analysis Centre (TGAC). "This high quality genome is testament to the many scientists who worked on this project and will spur biological research for years to come."
"By modeling these human disease genes in zebrafish, we hope that resources worldwide will produce important biological information regarding the function of these genes and possibly find new targets for drug development," she added.
Some unique features, not found in other vertebrates, can be seen in the zebrafish genome, such as having the highest repeat content in their genome sequences reported in any vertebrate species. This repeat content is almost twice as high as in their nearest relative, the common carp. The team has identified chromosomal regions unique to zebrafish that influence sex determination.
Compared to the human genome, the zebrafish genome contains few pseudogenes, or genes thought to have lost their function through evolution. There are approximately 13,000 pseudogenes in the human genome, compared to the 154 found in the zebrafish sequence.
"To realize the benefits the zebrafish can make to human health, we need to understand the genome in its entirety — both the similarities to the human genome and the differences," says Professor Christiane NÃ¼sslein-Volhard, Nobel laureate from the Max Planck Institute (MPG) for Developmental Biology. "Armed with the zebrafish genome, we can now better understand how changes to our genomes result in disease."
In the second study, researchers armed with the zebrafish genome designed a method to assay the function of each and every gene. The assay also allows them to explore the effect of genetic variation on zebrafish. To date, the team has generated one or more mutations in almost 40 percent of all zebrafish genes.
The goal is to create a comprehensive catalog of how changes to genes can have physical and biochemical consequences, and to give other researchers the tools to understand human diseases.
There are many similar genes between the human genome and those of less complex animals. The zebrafish (Danio rerio), as a vertebrate, has the same major organs and tissues as humans. For instance, they share many features with the human systems of muscle, kidney and optical structures.
Zebrafish embryos are transparent, making it easy to study their development as genetic mutations are introduced.
"There are several advantages of the zebrafish model," says Dr. Leonard Zon, MD, Children's Hospital of Boston MA. "We can readily create variations in their genome that are relevant to human health and disease. This has allowed a greater understanding of gene function and the finding of new targets for drug treatments."
"Several small molecules discovered using the zebrafish system have recently entered into clinical trials. The availability of the genome sequence, coupled with the rapid expansion of disease models and chemical screening ability, ensures that the zebrafish system has a major place in biomedicine," Zon continued.
The team has been able to create different mutations in more than 10,000 genes using the high-quality zebrafish reference genome sequence. 5,494 genes are known to be involved in human disease and the team has identified mutations in 3,188 zebrafish gene counterparts to those associated with human disease.
The team developed a new approach based on traditional methods to more efficiently find the consequences of genetic variation in the zebrafish. The new approach creates random mutations throughout the genome, and then links the mutations to physical or biochemical changes.
"Our aim is to reveal the function of each gene in the zebrafish to shed light on the role of their human counterpart," says Dr. Elisabeth Busch-Nentwich from Sanger. "We make these zebrafish models freely available to the wider scientific and medical communities to support their effort to understand human disease and increase the pace at which medical advancements can be made."
Previous Institute research found that specific mutations in the gene Titin are the potential driving force for the growth of some forms of cancer. The current research team found that the main function of Titin in zebrafish may be associated with the division of cells in the body, explaining why changes to this gene can affect the way cells divide. This provides insight into why this gene would be a driving force in the growth of cancer.
"Our zebrafish models have already been used to confirm the identity of a gene responsible for a rare disease affecting the development of bones," says Dr. Ross Kettleborough of Sanger. "This is just one of many examples where this project has and will advance our understanding of human disease."
Zebrafish are an important model for unlocking the mechanisms of cancer and other disease, and have already played a central role in helping to unravel the biological processes behind muscular dystrophies. The new study will aid in uncovering the processes that underlie both common and rare diseases, reveal the gene or genes that cause the diseases, and may lead to eventual new treatments.
"Our challenge is to develop a comprehensive, functional understanding of all human genes as quickly as possible," adds Dr. Stemple. "Our systematic analysis of zebrafish gene function will advance understanding of human disease."
"This is a resource that will help researchers and clinicians find the gene variations responsible for our inheritance of, and susceptibility to, diseases."