Norwich, UK (Scicasts) — Professor Federica Di Palma shares her research questions and insights beyond the recent Nature paper, explaining what spotted gar and other bizarre fish can teach us about health and disease.

Prof. Di Palma is a former Director of The Vertebrate Genome Biology Program at the Broad Institute at Harvard and MIT. Two years ago, she moved her scientific work to Norwich where she became Director of Science at The Genome Analysis Centre, although she still remains affiliated with the Broad Institute and her former research group.

At the beginning of our interview, my mind is racing. I am frantically searching for that single question which will allow the Director of Science at The Genome Analysis Centre explain me all about the genome of the spotted gar.

Soon enough I give up and realize that, in truth, I want to hear about everything – not just about the study thoroughly described last week in Nature Genetics or about spotted gar, but more – what questions drive researchers studying rare genomes, what has already been discovered and what else they are hoping to find.

So I simply ask Prof. Di Palma:

What would she like to share about her research?

She is interested in genome evolution, she explains, as well as understanding genome diversity and its effects on regulation of phenotypical traits in different organisms.

“Once I have [sequenced] the genome, I am also interested in comparing it to genomes of other species,” adds Prof. Di Palma, “in order to understand more about evolution and ultimately, about us as human beings. Finally, I want to understand the implications of my research on human health.”

“The states of health or disease are the expressions of the success or failure experienced by the organism in its efforts to respond adaptively to environmental challenges,” goes the quote from an American microbiologist and science philosopher of the 20th century, Rene Dubos.

Prof. Di Palma: “For me, this quote justifies how important it is to look at the variety of species, even the non-conventional model organisms, like the spotted gar, a rabbit, a dog, or a fish of the East-African lake. It is important to try and understand: how did these organisms adapt to survive? What is it in their genome that makes them so special?”

What is special about the spotted gar?

Understanding the mechanisms which allow the other organisms to survive, will help the humans understand more about ourselves and the mechanisms working within us.

Prof. Federica Di Palma

The spotted gar is an ancient fish that belongs to a group of organisms which Charles Darwin in his “Origin of Species” referred to as ‘living fossils’. The protein coding sequences of all ‘living fossils’ seem to evolve rather slowly but in the genome of the gar even the evolution of transposable (non-coding) elements occurs at a slower rate.

Comparison of the genome of spotted gar to the genome of humans or mammals shows that many important genes, which contribute to the regulation of physiological mechanisms, e.g. circadian rhythms, are conserved among all vertebrates.

The research on the gar genome also clarifies the evolution of mechanisms of bone mineralization in vertebrates. The teeth and protective scales of the gar contain enamel, a kind of mineralized bone tissue similar to the substance that encapsulates and protects human teeth.

Earlier, when the researchers studied another fish, the marine stickleback, they found that the same gene which allows the fish to develop their armour, is also present in humans. In fact, this gene seems to be undergoing a positive selection in the human Asian population as this particular pathway contributes to the distinctive hair morphology of the Asian people.

“The genetic pathways encoding the production of enamel and other protective substances turn out to be conserved among vertebrates, all the way to humans,” explains Prof. Di Palma.

Another unique feature of the gar is that it represents a ‘bridge’ between tetrapods and the fish. Most of our familiar fish species fall into the category of teleosts, who in the process of evolution have undergone the whole genome duplication. Hence their genomes are quite complex to study.

“When you compare the genome of zebrafish to the human genome, you will find that for each human gene there is at least one or even more copies of that gene in zebrafish,” says Prof. Di Palma.

"The spotted gar, on the other hand, predates the whole genome duplication. It occupies the place in the evolutionary tree before the teleosts split from the tetrapods (somewhat 450 million years ago).

"One can now compare the human genome to the genome of the gar and then to the zebrafish genome. This way, gar becomes an important biomedical model, which can be used to identify genetic features that one might not even see when comparing the human and zebrafish genomes.”

Do they study other living fossils?

“I previously worked on a genome of the fish called the coelacanth,” says Prof. Di Palma.

The article featuring that research came out in Nature and made the cover of the journal in April 2013.

"The coelacanth genome," says Prof. Di Palma, "presents an essential repertoire of our ancestors’ genetic material."

In the above mentioned publication, the team also makes reference to another ‘living fossil’ – the lungfish. After conducting the phylogenomic analysis, the researchers concluded that the lungfish is, in fact, the closest living relative of tetrapods.

“However, genome of the lungfish is very large and is virtually impossible to sequence,” says Prof. Di Palma. “We can only use some of its RNA to make comparisons with other organisms at the level of gene expression.”

Why do ‘living fossils’ evolve slower than the other species?

“It is not entirely clear,” responds Prof. Di Palma. “If we speak of coelacanths, I think the reason is that they live at such depths that their environment remains largely undisturbed.

“Coelacanths were thought to be extinct and it wasn’t until 1918 that the first specimen was found near the coast of South Africa. These fish live in such deep environment that it’s almost impossible to ever see them.”

Where did this research begin?

Large-scale research into the genomes of ‘living fossils’ dates back over a decade, when the National Human Genome Research Institute in the US commissioned a program to sequence a number of new genomes.

The members of the scientific community then pitched several white papers to the NIH, suggesting which genomes should be studied and why.

Following the reviewing process, twelve genomes were approved by the NHGRI who assigned the work to one of the five sequencing centres - Agencourt Bioscience Corp. in Beverly, Baylor College of Medicine in Houston, the Broad Institute of MIT and Harvard in Cambridge, The J. Craig Venter Science Institute in Rockville, and Washington University School of Medicine in St. Louis.

Prof. Di Palma: “The Broad Institute, where I was working at the time, was given the coelacanth genome, several mammalian genomes, as well as the genome of the spotted gar. Our recent work on the subject was therefore funded by the NIH through The NHGRI Genome Sequencing Program (GSP).“

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We will soon be posting more about the research from TGAC Vertebrates and the University of Oregon genomics groups.