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Genome Study Offers Insights into Gibbon Biology, Chromosomal Rearrangements

NEW YORK (GenomeWeb) – In a study appearing online today in Nature, an international team outlined findings from an effort to genomically characterize gibbons, a group of small apes that diverged between the Old World monkeys and the great apes.

"They're basically the link between the Old World monkeys and the great apes," the study's corresponding author Lucia Carbone, a behavioral neuroscience researcher affiliated with Oregon Health & Science University and the Oregon National Primate Research Center, told GenomeWeb Daily News, explaining that the animals "can teach us a lot about what happened during this transition."

Carbone and her colleagues started by establishing a 3 billion base reference genome assembly for the northern white-cheeked gibbon, Nomascus leucogenys. From there, they used high-throughput sequencing approaches to re-sequence the genomes of two individuals apiece from each of the four gibbon genera.

Among the most notable features in the gibbon genome were a group of retrotransposons called "LAVA" elements, which appear to explain the rampant chromosomal rearrangements present in gibbon genomes. The team believes these
LAVA elements cause early transcription termination in genes contributing to chromosomal segregation — a notion supported by the group's subsequent assays and analyses.

Nevertheless, Carbone noted that this abbreviated transcription seems to occur in just a subset of transcripts from affected gibbon genes.

"This is not occurring 100 percent of the time … because these genes are essential for life," she said. "But we think this is increasing the mutation rate in genes, so that the errors in segregation that occur at very low frequency in other species are at higher frequency in the gibbon, causing chromosomal rearrangements."

Gibbon species fall into four genera, each found in tropical forests from distinct parts of Southeast Asia. The animals are considered critically endangered, despite their diverse chromosomal contents.

Hoolock gibbons from places such as China, Myanmar, India, and Bangladesh have 38 diploid chromosomes, for example, while the N.leucogenys gibbons from Vietnam and Laos carry 52 chromosomes pairs, with the Symphalangus and Hylobates species falling in between.

To delve into the basis of the gibbons' chromosomal variability, propensity for chromosomal rearrangement, and more, collaborators at Baylor College of Medicine's Human Genome Sequencing Center and the Genome Institute at Washington University did Sanger sequencing on genomic DNA from a female northern white-cheeked gibbon named Asia from Norfolk's Virginia Zoo.

When the project began, a genome assembly had already been established from the Sanger sequences, Carbone explained. With the help of cytogenetic data, the team put together a second assembly in which scaffolds were re-organized into chromosomes.

With that 2.9 million base reference assembly in hand, researchers at other participating centers went on to re-sequence the genomes of two individuals apiece from each of the gibbon genera, including members of two Hylobates species, using Illumina's HiSeq 2000.

Using polymorphism patterns identified in these genomes and in exome sequences for two of the gibbons, the researchers attempted to produce a phylogenetic tree for the gibbon genera — a task that proved difficult due to the rapid species radiation in the group.

Their results suggest the gibbon lineage expanded rapidly around 5 million years ago, at roughly the same time that the animals' habitats in southeastern Asia began to swell and shrink, though the details of the gibbon phylogeny remain murky.

"They diverged from each other so quickly — we're talking about almost instantaneous radiation — that they didn't have time to accumulate the kind of variation that allows us to understand the order in which they diverged," Carbone said.

When they compared the N. leucogenys genome reference to the human genome and sequences from other primates, meanwhile, the researchers saw signs of positive selection in and around genes such as TBX5 and COL1A1 that are believed to contribute to forelimb development and connective tissue function, respectively — biological features that may have contributed to the creatures' ability to move between trees with their arms.

A comparison between the human and gibbon reference genomes also highlighted chromosomal sequence swaps at numerous sites in the gibbon genome.

Those rearrangements do not seem to be the result of excessive segmental duplication in the gibbon code. Instead, the team's subsequent analyses suggest that the chromosomal alterations are related to a set of gibbon-specific LAVA elements that Carbone and her colleagues got wind of a few years ago from cytogenetic data.

A closer look at these retrotransposons revealed that they tend to land in genes involved in chromosome segregation, cell division, and related cell cycle checkpoints, prompting speculation that they might interfere with transcription of genes tasked with ensuring chromosomal fidelity.

The team's results so far support that hypothesis, though more research is needed to understand why certain chromosomal rearrangements have become fixed in each of the gibbon species.

Carbone and collaborators at the University of California, San Francisco and the University of Arizona have already sequenced at least 10 more N. leucogenys individuals and representatives from other gibbon species. Carbone is also interested in shoring up funding to sequence a sarcoma tumor obtained from a gibbon in captivity.

"We're curious to see what's conserved between a sarcoma developing in a gibbon and what we see in humans, with the idea that pathways that are conserved are likely to be important for the development of the tumor," Carbone said.

"Because this tumor emerged in a genetic background that's already kind of unstable," she added, "I'm curious to see if the genome of the gibbon got even more shuffled … or if, on the contrary, there's some kind of protection."

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