Sequencing and analysis of gibbon genome sheds light on its complex evolution

09/10/14  Portland, Ore.

OHSU researcher leads team on gibbon DNA sequencing, which will provide clues for human health research

A team led by an Oregon Health & Science University researcher has sequenced and annotated the genome of the only ape whose DNA had yet to be sequenced — the gibbon, an endangered small ape that inhabits the tropical forests of Southeast Asia.

The team's work, published in the Sept. 11 edition of Nature, gives scientists new insight into the evolution of the gibbon genome and its extraordinary number of chromosomal rearrangements. Chromosomal rearrangements are structural changes in the DNA that are often problematic in other species — including causing cancer in humans — but seem to have happened in gibbons at a very high frequency. The genome sequencing work also provides new details on the family tree and evolutionary history of the gibbon lineage that has been a longstanding source of debate. Additionally, the team uncovered some genetic clues on how gibbon species over millions of years developed longer arms and powerful shoulder and arm tendons — important for these tree-dwelling primates whose main mode of locomotion is swinging from tree to tree in the dense tropical forest.

Finally, like the DNA sequencing of other apes and non-human primates, the team's work gives science new insight into the human genome — since apes are so genetically similar to humans. Unraveling primate genomes is vitally important as researchers try to understand the genetic factors in human health and disease.

“We do this work to learn as much as we can about gibbons, which are some of the rarest species on the planet,” said Lucia Carbone, Ph.D., assistant professor of behavioral neuroscience in the OHSU School of Medicine and an assistant scientist in the Division of Neuroscience at OHSU's Oregon National Primate Research Center. “But we also do this work to better understand our own evolution and get some clues on the origin of human diseases.”

Carbone worked on the project for more than two years, in collaboration with scientists at the Human Genome Sequencing Center at Baylor College of Medicine in Houston, Texas, and The Genome Institute at Washington University in St. Louis, Missouri. Other collaborators on the project included scientists from the University of Arizona, the University of Washington and international labs from Spain, Italy and Germany.

Gibbons, together with the other apes — orangutans, gorillas, chimpanzees and bonobos — are the closest relatives to humans. Humans and these apes all belong to the "superfamily" called Hominoidea.

But unlike other apes and humans, gibbons have undergone a high number of chromosomal rearrangements as they have evolved.

"You might think about chromosomes as constructions made of different plastic toy bricks. In the rearrangement, one or more toy pieces separate from the others and reattach in a different orientation or location. Or, they might get lost or duplicated,” said Carbone. “We know that these types of events have been occurring in the other apes, including humans, but gibbons show a much higher frequency. One of our goals while analyzing the genome was to try to identify the cause of this instability.”

Such chromosomal rearrangements can cause major problems in cells, and can contribute to birth defects and cancer in humans. But they seem to have been well tolerated by gibbons. The gibbon genome will now be a tool to better understand the mechanisms behind these “errors.”

In particular, the analysis of the gibbon genome exposed an intriguing role for a new repetitive DNA sequence that emerged exclusively in the gibbon genome. It’s called the “LAVA” element and more than one thousand copies have been found in the gibbon genome. Several LAVA elements have been inserted in a group of genes that are important for guaranteeing the correct separation of chromosomes when cells divide.

“The LAVA element is an evolutionary novelty that is only present in the DNA of gibbon species,” Carbone said. “We think that it played a major role by increasing the ‘errors’ during cell division and chance for chromosomal rearrangements.”

Interestingly, many of the genes impacted by the LAVA element in gibbons are mutated in some types of tumors in humans. The gibbon genome project shows that by understanding how evolution experiments with genomic rearrangement, we might then be able to apply that knowledge to human health.

“This is the last ape to be sequenced and the end of an era in human comparative genomics,” said Tomas Marques-Bonet, evolutionary geneticist at Institut de Biologia Evolutiva (CSIC/UPF) and the National Center of Genomic Analysis (CNAG) in Barcelona, Catalonia, Spain, and co-author on the paper. “Now we have tools — the genomes — for all the closest species to humans.”

As part of the project, the team sequenced the whole genome of eight different gibbon species using next-generation sequencing and revealed more about the order in which the four different gibbon genera — or a group of species — diverged from each other. While in most cases it is possible to determine the order in which different species diverged from each other, this is not the case for gibbons. Evolutionary biologists within the team found that the four gibbon genera diverged almost instantaneously about four million years ago. That prevents scientists from determining the order in which they separated from each other.

Around that time, there were major changes in the tropical and subtropical forests and significant shifts in sea levels in the territory occupied by the gibbons. Those geographical changes likely contributed to the rapid divergence of the gibbon genera by generating isolation between groups. Isolation is one of the major forces to drive the rise of new species.

“We hope that by learning more about the genome of these species we will also be able to implement better strategies for their conservation — as some of these species are critically endangered and about to disappear,” Carbone said.

The gibbon genome project was funded by the National Human Genome Research Institute, including grants U54HG003273 andU54 HG003079, with further support from National Institutes of Health (grants NIH/NIAAA P30 AA019355 and NIH/NCRR P51 RR000163). Other funding agencies included the National Science Foundation, the Howard Hughes Medical Institute and the European Research Council. The work was possible thanks to contributions from the Gibbon Conservation Center in Santa Clarita, California.

About OHSU

Oregon Health & Science University is a nationally prominent research university and Oregon’s only public academic health center. It serves patients throughout the region with a Level 1 trauma center and nationally recognized Doernbecher Children’s Hospital. OHSU operates dental, medical, nursing and pharmacy schools that rank high both in research funding and in meeting the university’s social mission. OHSU’s Knight Cancer Institute helped pioneer personalized medicine through a discovery that identified how to shut down cells that enable cancer to grow without harming healthy ones. OHSU Brain Institute scientists are nationally recognized for discoveries that have led to a better understanding of Alzheimer’s disease and new treatments for Parkinson’s disease, multiple sclerosis and stroke. OHSU’s Casey Eye Institute is a global leader in ophthalmic imaging, and in clinical trials related to eye disease.

About ONPRC

The Oregon National Primate Research Center is one of the eight National Primate Research Centers supported by the NIH. ONPRC is a registered research institution, inspected regularly by the United States Department of Agriculture. It operates in compliance with the Animal Welfare Act and has an assurance of regulatory compliance on file with the National Institutes of Health. The ONPRC also participates in the voluntary accreditation program overseen by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC).