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Elephant shark genome provides new insights into bone formation and adaptive immunity in humans
Scientists at A*STAR's Institute of Molecular and Cell Biology (IMCB) led an international team of researchers that sequenced and analyzed the genome of the elephant shark. A comparison of the elephant shark genome with human and other vertebrate genomes revealed why the skeleton of sharks consists entirely of cartilage instead of bones. The findings carry potential implications for human bone disease treatment. The analysis also sheds new light on the origin of the adaptive immune system.

The collaboration with 12 international institutions was headed by IMCB's Prof Byrappa Venkatesh, who is also a chairperson of the "Genome10K" Project. The project was largely funded by the National Institutes of Health (NIH), USA, the world's foremost center for the support of biomedical research.

Analysis of the elephant shark genome

Elephant shark is a member of cartilaginous fishes, which are the oldest living group of jawed vertebrates that diverged from bony vertebrates about 450 million years ago. Cartilaginous fishes include sharks, rays, skates and chimaeras. Unlike humans and other bony vertebrates, cartilaginous fishes are unable to replace cartilage with bone. Among over 1,200 species of cartilaginous fishes, the elephant shark was sequenced due to its compact genome size. Analysis of the elephant shark genome identified a family of genes absent in elephant shark but present in all bony vertebrates. A significant reduction in bone formation was observed when a member of this gene family was knocked out in zebrafish, thereby indicating the importance of this gene family in bone formation. The finding has important implications towards our understanding of bone-related diseases such as osteoporosis and hence the development of effective therapeutic strategies for them.

An unexpected finding was that elephant shark appears to lack special types of immune cells previously considered essential for defense against viral/bacterial infections and preventing autoimmune reactions such as diabetes and rheumatoid arthritis. Despite this seemingly primitive organization of the immune system, sharks exhibit robust immune defenses and are long-lived. By challenging long-held notions, this discovery has opened up a new avenue towards the development of non-intuitive strategies to shape the immune functions of humans.

The study also found that the elephant shark genome is the slowest evolving among all vertebrates, including the coelacanth, popularly known as a "living fossil", whose genes were recently shown to be evolving slower than those of other bony vertebrates. Furthermore, large blocks of elephant shark and human chromosomes were found to be highly similar. The markedly slow evolution of the elephant shark genome and its similarity to the human genome, further underscores its importance as a reference genome for comparative genomic studies aimed at better understanding of the human genome.

Professor Byrappa Venkatesh, Research Director at IMCB added, "The slow evolving genome of the elephant shark is probably the best proxy for the ancestor of all jawed-vertebrates that became extinct a long time ago. It is a cornerstone for improving our understanding of the development and physiology of human and other vertebrates as illustrated by our analysis of the skeletal system and immune system genes."

Dr. Wes Warren, senior author of the study's paper commented, "Although cartilaginous vertebrates and bony vertebrates diverged about 450 million years ago, with the elephant shark genome in hand, we can now begin to identify key genetic adaptations in the evolutionary tree."

Professor Hong Wanjin, Executive Director of IMCB, said, "Over the years, IMCB has carried out several remarkable genomic projects and we are excited to showcase yet another milestone. Not only has our research team sequenced the first shark-family member genome, they have also uncovered many insights significant to the field of genomic and medical research through the genome analysis."

Professor Sir David Lane, Chief Scientist at A*STAR, said, "We are delighted that a Singapore laboratory conceived and led a major international genome project. The international research grant from NIH, USA is a testimony of Singapore's world-class standard in genomics research."

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